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Central, peripheral, and generalized adaptations in cardiac rehabilitation 1988

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CENTRAL, PERIPHERAL, AND GENERALIZED ADAPTATIONS IN CARDIAC REHABILITATION By LEONARD STEPHEN GOODMAN B.P.H.E. The U n i v e r s i t y of Toronto, 1979 M.P.E. The U n i v e r s i t y of B r i t i s h Columbia, 1982 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES ( I n t e r d i s c i p l i n a r y S t u d i e s , Medicine, P h y s i c a l E d u c a t i o n , Sports Medicine) We accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA June 1988 © Leonard Stephen Goodman, 1988 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of ^'Interdisciplinary Studies, Graduate Studies The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date August 3. 1988 DE-6(3/81) Abstract The purpose of t h i s study was to i n v e s t i g a t e whether c e n t r a l adaptations are r e s p o n s i b l e for. a t r a n s f e r of f i t n e s s t o u n t r a i n e d limbs i n 13, 9 and 7 CAD/post-MI p a t i e n t s e x e r c i s i n g i n a walk/jog (WJ) (Legs only) , an aerobic c i r c u i t (CT) (arm+legs) program, and a low e x e r c i s e i n t e n s i t y c o n t r o l group (LC) r e s p e c t i v e l y , f o r 6 months. Graded e x e r c i s e t e s t s t o determine maximum arm and c y c l e (leg) aerobic c a p a c i t y (VC>2peak) and v e n t i l a t o r y t h r e s h o l d (VT) was measured using a SensorMedics Met a b o l i c Measurement Cart, and an arm ergometer and e l e c t r o n i c a l l y braked c y c l e ergometer, r e s p e c t i v e l y . L e f t v e n t r i c u l a r (LV) f u n c t i o n and absolute volumes ( c a l c u l a t e d by non-geometric methods) duri n g c y c l e ergometry were measured by gated bloodpool r a d i o n u c l i d e angiograms (RNA). Cycle maximal aerobic c a p a c i t y (VC^peak) increased i n CT and' WJ:. 1.96. ± 0.58 t o 2.17 ± 0.70 (P<.01) vs. 1.93 ± 0.51 t o 2.22 ± 0.54 (P<.004) l - m i n - 1 , r e s p e c t i v e l y . Arm VC^peak incre a s e d from 1.32 ± 0.42 t o 1.52 ± 0.47 (P<.001) vs. 1.35 ± 0.32 t o 1.45 ± 0.34 1-min- 1 (P<.01)for the CT and WJ groups, r e s p e c t i v e l y . In both e x e r c i s e w i t h arm and l e g s , VT was i n c r e a s e d i n the WJ and CT groups, but the g r e a t e s t changes were f o r VT as expressed as absolute VO2. Both arm and l e g VC^peak data were c o r r e l a t e d w i t h arm and l e g VT. The LC group demonstrated no changes i n VC^peak or VT f o r arms or l e g s . Peak LV E j e c t i o n F r a c t i o n (LVEFpeak) incre a s e d more i n the WJ group than the CT group: 53.3 ± 0.11 to 64.8 ± 0.10 vs. 50.7 ± 0.12 to 55.3 ± 0.11% (P<.02), as did E j e c t i o n Rate, and LVESV (changes pre vs." post ; 0.52 vs. -0.13 EDV/sec, and -21.59 vs. 6.89 ml, respectively (P<.05). Cardiac output and stroke volume (SV) increased s i g n i f i c a n t l y at rest and exercise i n the WJ and CT groups, but Peak t o t a l peripheral resistance (TPR) however was r e l a t e d to SV and LVESV (r=-.69 P< .003, r=-.42, P<.05), obscuring . apparent i n t r i n s i c cardiac adaptations. In addition, neither group demonstrated a l t e r a t i o n s i n body composition and blood l i p i d s as a r e s u l t of t r a i n i n g , despite s i g n i f i c a n t increases i n functional capacity. Results suggest that transfer of f i t n e s s to untrained limbs i n these patients i s due i n part, but not s o l e l y to increased LV function. TPR or other u n i d e n t i f i e d contributing factors could s t i l l account for these e f f e c t s . i v Table of Contents Abstract i i Table of Contents i v L i s t of Tables v i L i s t of Figures v i i Acknowledgment ix 1. 0 Introduction 1 2.0 Methodology 2.1 Subject Recruitment 7 2.2 Exercise Training 8 2.3 Exercise Testing: 2.3.1 Maximum Oxygen Uptake 13 2.3.2 Body Composition 16 2.3.3 Blood L i p i d Analysis 16 2.4 Nuclear Imaging: 2.4.1 Supine Left Ventricular Radionuclide Angiogram (RNA) 17 2.4.2 Exercise Gated Bloodpool RNA 18 2.5 S t a t i s t i c a l Analysis 23 3.0 Results 3.1 Physical Charac t e r i s t i c s 26 3.1.2 Exercise Training 26 3.2 Body Composition and Blood Lipids 27 3.3 Aerobic Capacity: 3.3.1 Lower Extremity Aerobic Capacity 30 3.3.2 Lower Extremity Ventilatory Threshold 35 3.3.3 Upper Extremity Aerobic Capacity 38 3.3.4 Upper Extremity Ventilatory Threshold 40 3.3.5 ST-Segment Alterations After Training 46 3.3.6 Submaximal Heart Rate Responses 47 3.4 Cardiac Function and Exercise Training: 3.4.1 F i r s t Pass RNA 50 3.4.2 Exercise Gated Bloodpool RNA Submaximal Heart Rate Responses 51 3.4.3 Ejection Fraction and Absolute Cardiac Chamber Volumes After Exercise Training..55 3.4.4 Derived Measures of Left V entricular Function; E f f e c t s of Exercise Training..69 V 4.0 Discussion 4.1 Body Composition 7 6 4.2 Blood Li p i d s 77 4.3 Lower and Upper Extremity Aerobic Capacity: 4.3.1 Lower Extremity Changes i n Aerobic Capacity 82 4.3.2 Upper Extremity Changes in Aerobic Capacity 88 4.4 Cardiac Function: 4.4.1 F i r s t Pass Radionuclide Angiography: ...93 4.4.2 Gated Bloodpool RNA Exercise Testing; Submaximal Hemodynamic and HR Responses... 93 4.4.3 R e l i a b i l i t y and V a l i d i t y 95 4.4.4 Left Ventricular Ejection Fraction 96 4.4.5 Cardiac Output and Absolute Left Ventricular Volumes 100 5.0 Conclusions 112 6.0 Bibliography 117 7.0 Appendix I Review of Literature 136 Appendix II Nuclear Medicine Calculations and Raw Data Processing 223 Appendix III Sample Ventilatory Threshold Plots....225 Appendix IV Sample Consent Form 22 6 Appendix V Raw Data: Group Mean Data 227 v i L i s t of Tables Table 3.1 Physical Charac t e r i s t i c s of Subjects. 29 Table 3.2 Body Composition and Lipids A f t e r Exercise Training 30 Table 3.3 Lower Extremity Aerobic Capacity 33 Table 3.4 Lower Extremity Ventilatory Threshold 36 Table 3.5 Arm Ergometry Aerobic Capacity 39 Table 3.6 Arm Ergometry Ventilatory Threshold 41 Table 3.7 Changes i n Submaximal Heart Rate: Arm, Leg....48 Table 3.8 Heart Rate and Blood Pressure Responses During Gated Bloodpool RNA Exercise Testing...53 Table 3.9 Changes i n Ejection Fraction After Exercise Training 56 Table 3.10 Changes i n Left Ventricular Volumes After Exercise Training 58 Table 3.11 Alter a t i o n s i n Peripheral Resistance: E f f e c t of Exercise Training 71 Table 3.12 Derived Left Ventricular Function Variables: E f f e c t of Exercise Training 72 Table 7.1 Cardiovascular Adaptations After Exercise Training 147 Table 7.2 Change i n V02max After Training i n CAD 173 Table 7.3 Indirect Indicies of Myocardial Oxygen Consumption and Training i n CAD 180 Table 7.4 Factors A f f e c t i n g Cardiac Morbidity and Mortality; Postulated Cardiac Mechanisms 194 Table 7.5 Reasons for F a i l u r e to Identify I n t r i n s i c Cardiac Adaptations After Exercise Training...204 v i i L i s t of Figures F i g u r e 3.1a Arm Peak O2 Uptake Before and A f t e r T r a i n i n g 34 F i g u r e 3.1b Leg Peak O2 Uptake Before and A f t e r T r a i n i n g 34 F i g u r e 3.2 V e n t i l a t o r y T h r e s h o l d f o r Leg and Arm Ergometry A f t e r T r a i n i n g 37 F i g u r e 3.3 Arm VC^peak v s . Absolute Arm V e n t i l a t o r y T h r e s h o l d 43 F i g u r e 3.4 C y c l e (Leg) VC^peak v s . Leg V e n t i l a t o r y T h r e s h o l d 44 F i g u r e 3.5 P l o t o f C y c l e VC^peak v s . T o t a l P e r i p h e r a l R e s i s t a n c e 45 F i g u r e 3.6a Arm Crank HR Response at 25W 4 9 F i g u r e 3.6b C y c l e Heart Rate Response at 65W 4 8 F i g u r e 3.7 A l t e r a t i o n s i n Submaximal Heart Rate A f t e r T r a i n i n g 54 F i g u r e 3.8 E j e c t i o n F r a c t i o n Before A f t e r E x e r c i s e T r a i n i n g 61 F i g u r e 3.9 Peak E j e c t i o n F r a c t i o n v s . Peak S y s t o l i c BP A f t e r E x e r c i s e T r a i n i n g 62 F i g u r e 3.10 C a r d i a c Output Before and A f t e r E x e r c i s e T r a i n i n g 63 F i g u r e 3.11 Change i n Submaximal Stroke Volume v s . S y s t o l i c Blood Pressure 64 F i g u r e 3.12 Changes i n Stroke Volume v s . S y s t o l i c Blood Volume Before, A f t e r T r a i n i n g 65 F i g u r e 3.13 P l o t o f Stroke Volume (WL-90) v s . T o t a l P e r i p h e r a l R e s i s t a n c e at WL-90 66 F i g u r e 3.14 Changes i n Stroke Volume vs. T o t a l P e r i p h e r a l R e s i s t a n c e A f t e r E x e r c i s e T r a i n i n g 67 F i g u r e 3.15 Changes i n End S y s t o l i c Volume v s . S y s t o l i c Blood P r e s s u r e at Peak E x e r c i s e 68 F i g u r e 3.16 Changes i n Stroke Work and LVEDV A f t e r E x e r c i s e T r a i n i n g 73 v i i i Figure 3.17 S y s t o l i c Blood Pressure/LVESV Ratio After Exercise Training 74 Figure 3.18 Plot of Total Peripheral Resistance vs. Left Ventricular Stroke Work ...75 Figure 7.1 Normal Cardiorespiratory Response to Acute Dynamic Exercise ..143 Figure 7.2 The Frank-Starling Law of the Heart 152 Figure 7.3 I n t r i n s i c Cardiac C o n t r a c t i l i t y 155 Figure 7.4 Summary of Acute Exercise Responses i n The Cardiac Patient 165 Figure 7.5 Exercise Training and Increased Capacity i n Cardiac Patients 177 Figure 7.6 Exercise S p e c i f i c i t y and Transfer E f f e c t of Training 218 i x Acknowledgments I t would have been considerably beyond the l i m i t s of my personal s k i l l s and resources to have s u c c e s s f u l l y attempted a Ph.D. t h e s i s of t h i s type without the help and encouragement I have r e c e i v e d from many i n d i v i d u a l s both on and o f f the UBC campus. I e s p e c i a l l y would l i k e t o thank my academic a d v i s o r / r e s e a r c h supervisor Dr. Don McKenzie f o r i n i t i a l l y agreeing to be my advisor at short n o t i c e at a p a r t i c u l a r l y dark time f o r me back i n 1984; he has come through w i t h the u l t i m a t e l y important f a c t o r s which make a Ph.D. p o s s i b l e : f i n a n c i a l , academic and personal support. His s u p e r v i s i o n and d i r e c t i o n during both my Masters and now Ph.D t r a i n i n g have been I f e e l , d i r e c t l y r e s p o n s i b l e f o r my maturation from an inexperienced graduate student t o a beginning s c i e n t i s t . I would l i k e to acknowledge the B.C. Heart Foundation and Health and Welfare Canada f o r the personal f i n a n c i a l support during my tenure at UBC through graduate awards. Dr. Mike P l y l e y at the U n i v e r s i t y of Toronto was my s u p e r v i s o r f o r my f i r s t year, completed at t h a t i n s t i t u t i o n . Many thanks go to him f o r support through t h a t year and encouragement a l l the way through. This study would not have been p o s s i b l e without the help of a great many s t a f f at the UBC-HSCH. I would l i k e to e s p e c i a l l y thank Dr. Walter Ammann and h i s t e c h n o l o g i s t s t a f f ( C h r i s t a McRae, S h e l i a Woloshyn, and Tony McLintock) who always made me f e e l part of t h e i r Nuclear Medicine department, and who t i r e l e s s l y but gave t h e i r e x p e r t i s e and s k i l l s t o the study. Many thanks go t o Dr. Max Walters, who w h i l e r e t i r e d from Medicine and my committee, was i n i t i a l l y a strong support i n the beginnings of the study. More r e c e n t l y , the e x c e p t i o n a l support of Dr. C o l i n Nath and the D i v i s i o n of Cardiology during a l l the (volunteer) s u p e r v i s i o n of a l l the upper and lower extremity s t r e s s t e s t s must be acknowledged and thanked. I would a l s o l i k e t o thank the s t a f f i n R e s p i r a t o r y Medicine (Mary-Ann, Carmen and Louise) f o r the p r i v i l e g e of using the e x e r c i s e l a b o r a t o r y and Beckman MMC f o r the t e s t i n g , and the support during t r o u b l e - s h o o t i n g . Thanks i s due M a r y l i n Harkley and Anna Bozak who helped w i t h the data c o l l e c t i o n i n the l a b . This help c o n s i d e r a b l y reduced the s t r a i n during these days, and c e r t a i n l y made t h i s process much more enjoyable f o r me, as w e l l as the p a t i e n t s due t o t h e i r wonderful nature and energy. I would l i k e to thank Peter Schumacker at SCARL f o r the i n v a l u a b l e c o n s u l t a t i o n s w i t h the s t a t i s t i c a l aspects of the study, as w e l l as the a d d i t i o n a l help and the wonderful open-door p o l i c i e s of Frank Ho ( S t a t i s t i c s ) and Susan Mair (with the Telegraf p l o t s ) i n the Computer Science Department. X F i n a l l y , my love and admiration goes out to my family, the closest to me of course, my wife Risa, who has stood by me a l l t h i s time throughout a l l the f r u s t r a t i o n s and achievements with patience and love. To her I am forever g r a t e f u l . In addition, the love, support and confidence of the Korsch's, and my wonderful family back home i n Toronto has given me the strength to go on when i t a l l seemed u p h i l l . 1 1.0 I n t r o d u c t i o n One of the many issues s t i l l not completely resolved i n cardiac r e h a b i l i t a t i o n i s the ef f e c t of chronic exercise on the adaptation of the l e f t v e n t r i c l e (LV) i n patients who have suffered a myocardial i n f a r c t i o n (MI), with angina, or af t e r recovery from coronary artery bypass surgery (CABS). H i s t o r i c a l l y , the mechanisms responsible for the improved functional capacity, reduced symptoms of coronary i n s u f f i c i e n c y , and reduced frequency of electrocardiographic abnormalities u n i v e r s a l l y observed aft e r three to 12 months of endurance t r a i n i n g have been ascribed to mostly peripheral e f f e c t s occurring i n the exercised muscles- (Clausen and Trap-Jensen, 1970, Detry et a l . , 1971, Ferguson and Taylor, 1982, Ogawa et a l . , 1981, Sim and N e i l l , 1974). There i s however, rapidly accumulating data to suggest that there might be a component of central ( l e f t ventricular) adaptation which might occur as a response to prolonged and intense endurance t r a i n i n g i n these patients. While increased exercise t r a i n i n g c a p a b i l i t i e s and improvements i n aerobic capacity would no doubt be expected with improvements i n LV function, even more important prognostic s u r v i v a l variables could be also expected, according to the data of White et a l . , (1984). 2 Although the s t u d i e s which have demonstrated l a r g e increases i n maximal aerobic c a p a c i t y (VC^max) and p a r a l l e l improvements i n i n t r i n s i c LV f u n c t i o n are impressive (Ehsani et a l . , 1 9 8 6 , Ehsani et a l . , 1 9 8 2 , W i l l i a m s et a l . , 1 9 8 4 , Hagberg et a l . , 1 9 8 3 , Jensen et a l . , 1 9 8 0 ) , these are countered by other s t u d i e s which have shown e i t h e r no changes (Verani et a l . , 1 9 8 1 , Ditchey et a l . , 1 9 8 1 ) , or minimal changes ( F r o e l i c h e r et a l . , 1984) at e i t h e r r e s t or submaximal e x e r c i s e . I t has been suggested that the s t u d i e s which have demonstrated LV adaptations have i n c l u d e d subjects who were unusually motivated and minimally compromised and thus represented a sub-sample of post-MI p a t i e n t s which were capable of a c h i e v i n g very high e x e r c i s e t r a i n i n g frequencies ( 5 - 6 d/week) and i n t e n s i t i e s ( 7 5 % - 9 0 % of VC^max). Other confounding f a c t o r s i n these s t u d i e s i n c l u d e the v a r i a t i o n s i n the s i z e of the i n f a r c t e d area of myocardium, the use of d i f f e r i n g techniques f o r measuring LV f u n c t i o n , the r o l e s of v a r y i n g medications on LV performance, the heterogeneity of the p a t i e n t s s t u d i e d (post-MI vs. CABG, angina, a n g i o p l a s t y , e t c . ) , and the modes of e x e r c i s e t r a i n i n g employed. Nevertheless, the question remains whether myocardial hypertrophy, a l t e r a t i o n s i n chamber s i z e , and general improvements i n i n t r i n s i c LV c o n t r a c t i l e f u n c t i o n , which have been observed r o u t i n e l y i n healthy normals post- 3 t r a i n i n g (Barnard et a l . , 1979), can be achieved i n the average post-MI p a t i e n t , even c o n s i d e r i n g n e c r o s i s - r e l a t e d decreases i n myocardial compliance and the amount of v i a b l e remaining myocardium. One method of i s o l a t i n g and uncovering the c o n t r i b u t i n g c e n t r a l and p e r i p h e r a l e f f e c t s of h a b i t u a l e x e r c i s e i s t o t r a i n one limb, and then subsequently t e s t the unt r a i n e d limb. I t has long been understood t h a t the e f f e c t s of e x e r c i s e t r a i n i n g are l a r g e l y s p e c i f i c to the muscle groups t r a i n e d , but tha t i n some cases, improvements i n the VT^max or maximal work, l o a d achieved i n the un t r a i n e d limb ( b a r r i n g h a b i t u a t i o n e f f e c t s ) , or reductions i n the heart r a t e and blood pressure response at an equivalent work load, would imply a c e n t r a l t r a i n i n g e f f e c t by v i r t u e of a gre a t e r c a r d i a c output and hence, O 2 d e l i v e r y . This c l a s s i c a l experimental design has been used numerous times w i t h normal su b j e c t s , w i t h general divergence of r e s u l t s . Clausen et a l . , (1973) found a small ( 10% improvement) i n arm VT^max a f t e r t r a i n i n g of the l e g s , and concluded a c e n t r a l e f f e c t , as d i d McKenzie et a l . , (1978), by demonstrating lower submaximal heart r a t e s f o r the unt r a i n e d limbs. S a l t i n et a l . , (1976) a l s o observed increases i n VT^ntax i n the u n t r a i n e d legs a f t e r one-leg c y c l e t r a i n i n g w i t h no 4 evidence of peripheral t r a i n i n g e f f e c t s (mitochondrial enzyme changes). These authors concluded that the e f f e c t was not due to improvements i n cardiac output, but rather to the greater e f f i c i e n c y of other organs to oxidize l a c t a t e a f t e r t r a i n i n g . Other general findings r e l a t i n g to the transfer e f f e c t suggest that the i n i t i a l l e v e l of f i t n e s s , t r a i n i n g frequency, i n t e n s i t y and duration determine the extent of cross-over of t r a i n i n g e f f e c t s (Lewis et a l . , 1980, Franklin, 1985) . It has been only recently that t h i s research model has been extended to the cardiac patient. This i s because t r a d i t i o n a l l y , walking and jogging was the only mode of t r a i n i n g considered appropriate for t h i s population, with fears that upper body exercise was largely s t a t i c i n nature, and would place excessive hemodynamic loading on the myocardium and dangerously elevate myocardial oxygen consumption. Today, i t i s well documented that programs u t i l i z i n g a combination of upper and lower body aerobic t r a i n i n g are not only safe hemodynamically, but e f f e c t i v e i n increasing functional capacity of muscle groups used i n occupational and l e i s u r e settings (Hellerstein, 1977, LaFontaine and Brackerhoff, 1987, Magder et a l . , 1981, Ben- A r i et a l . , 1987). This has resulted i n the formulation of a new research model to uncover central vs. peripheral t r a i n i n g mechanisms i n cardiac patients. 5 Only a few s t u d i e s have t r a i n e d the arms or legs and t e s t e d the u n t r a i n e d limbs i n coronary a r t e r y disease (CAD) p a t i e n t s . Increases i n the untraine d limb (arm) VC^max a f t e r l e g t r a i n i n g has been reported to range from 8% (Thompson et a l . , 1981) t o 13% (Wrisley et a l . , 1983), i n a d d i t i o n to decreases i n the HR x s y s t o l i c blood pressure product (RPP) at a matched submaximal workload (Ben-Ari et a l . , 1987). While a l l these s t u d i e s report improvements i n achieved work load, RPP, HR, and VC^max, none have u t i l i z e d techniques able t o q u a n t i f y d i r e c t changes i n the c e n t r a l component t o determine whether the adaptations were i n t r i n s i c t o the myocardium, or i s o l a t e d to the periphery. Therefore, the o b j e c t i v e of t h i s i n v e s t i g a t i o n was t o apply the t r a i n i n g s p e c i f i c i t y model to determine the c o n t r i b u t i o n of p e r i p h e r a l vs. c e n t r a l components before and a f t e r s i x months of e x e r c i s e t r a i n i n g i n average CAD p a t i e n t s . S p e c i f i c a l l y , the research goals i n t h i s study were t o : 1. Determine the c r o s s - t r a i n i n g p o t e n t i a l between p a t i e n t s e x e r c i s i n g the whole body (arms + legs) i n an aerobic c i r c u i t t r a i n i n g program, and p a t i e n t s e x e r c i s i n g only the lower e x t r e m i t i e s (walking/jogging), by t e s t i n g the legs and arms i n both groups using standard open c i r c u t gas a n a l y s i s arm and c y c l e ergometry. Observing an increase i n arm 6 f i t n e s s i n the w a l k i n g / j o g g i n g group would i m p l y f a c t o r s o t h e r than m u s c l e - s p e c i f i c ( p e r i p h e r a l ) mechanisms t o e x p l a i n the t r a i n i n g e f f e c t . 2 . To q u a n t i f y the above i m p l i e d c e n t r a l ( c a r d i a c ) component o f t r a i n i n g a d a p t a t i o n s i n b o t h groups , by u s i n g n u c l e a r i s o t o p e imaging t e c h n i q u e s d u r i n g r e s t and e x e r c i s e . 3. To de termine i f l i p i d p r o f i l e s and body c o m p o s i t i o n measures are a l t e r e d by e x e r c i s e t r a i n i n g by e i t h e r c i r c u i t or w a l k i n g and j o g g i n g t r a i n i n g methods. 4. To compare the e f f i c a c y o f whole body v s . l e g s o n l y modes o f c a r d i a c r e h a b i l i t a t i o n e x e r c i s e t r a i n i n g i n terms o f o v e r a l l t r a i n i n g a d a p t a t i o n s . 7 2.0 Methodology 2.1 Subject Recruitment Prospective patients were i d e n t i f i e d through r e f e r r a l from c a r d i o l o g i s t s i n the Greater Vancouver area. Patients were screened for the usual medical contraindications to exercise t r a i n i n g (American College of Sports Medicine, 1986). For the purposes of the study, additional c r i t e r i a were established. These included: (1) Resting l e f t v e n t r i c u l a r ejection f r a c t i o n of no less than 30%. (2) Subjects had sustained a MI documented by ECG and enzyme changes, or had recovered from CABS or angioplasty no sooner than 4 months p r i o r to entry into the study. (3) Subjects had no musculoskeletal l i m i t a t i o n s to exercise. (4) Subjects had either no supraventricular arrythmia or were otherwise c o n t r o l l e d by medication. (5) Subjects had no a o r t i c regurgitation or s i g n i f i c a n t m i t r a l valve abnormalities. (6) Subjects were w i l l i n g to exercise a t o t a l of 4-5 days per week for the study period, and the walking/jogging (WJ) group agreed not to perform any dynamic and prolonged arm or torso exercise during l e i s u r e a c t i v i t i e s or work, including swimming, nordic skiing, rowing, and c a l i s t h e n i c s (permitted arm a c t i v i t i e s included golf and household a c t i v i t i e s only). 8 A l l subjects signed a waiver and consent form before entering the study, which was approved by the University of B r i t i s h Columbia's Human Experimentation Ethics Committee. The subjects were permitted to continue with t h e i r regularly prescribed medications (see Table 3.1 i n Results section for patients' i n d i v i d u a l medications) both throughout the t r a i n i n g and t e s t i n g periods. They were asked to n o t i f y the experimentors i f a change i n medications occurred. A withdrawl and/or change i n medication resulted i n the exclusion of that patient's data i n the experimental analysis due to changes i n metabolic and hemodynamic function that would follow. 2.2 Exerc ise T ra in ing The subjects were randomized into one of two t r a i n i n g modalities, WJ (YMCA) or aerobic c i r c u i t t r a i n i n g (CT) (Hospital-based) programs. A low-intensity exercising control group (LC) of 7 patients unwilling to continue attendance at regular sessions, as determined by examination of t r a i n i n g logs from both the WJ and CT programs, were i d e n t i f i e d at the three-month period, and included i n the study. The c r i t e r i a for t h e i r selection were f a i l u r e to maintain t h e i r target heart rate above that representing 60% of V02Peak, and f a i l u r e to attend three consecutive weeks of 9 less than 2 sessions/week. They were maintained on low-level walking, c y c l i n g or c i r c u i t t r a i n i n g exercise programs (less than 3 sessions per week and an in t e n s i t y less than the heart rate equivalent to 60% VO^peak) for the duration of the study. Some of the WJ subjects declined attendance at a regular program, and they were followed on a c a r e f u l l y designed home program, s i m i l a r to that offered at the YMCA. Since true s t a t i s t i c a l randomization was not possible due to the few numbers of available subjects, the most fe a s i b l e method of subject recruitment employed was based upon geographical proximity to the centres. Of the t o t a l 40 patients i n i t i a l l y recruited, 13 were assigned to the CT, and 20 were assigned to the WJ programs, respectively. Both the WJ and CT programs u t i l i z e d a standard 10 minute warm-up period consisting of generalized l i g h t calesthenics and stretching exercises, followed by 30 to 45 minutes of endurance t r a i n i n g and a 5 to 10 minute concluding cool-down period. The aerobic phase i n the WJ program consisted of walking progressing to walking/jogging i n t e r v a l s at the predetermined target intensity, as described by Kavanagh et a l . (1973, 1975). Outdoor c y c l i n g and cycle ergometry was permitted i n t h i s group as supplements to walking and 10 jogging. The CT group u t i l i z e d a variety of aerobic exercise equipment, randomly assigned upon each session to achieve a balance between upper and lower body f i t n e s s by including a minimum of one upper extremity exercise s t a t i o n . Each session included 3 X 10 minutes of either treadmill walking, s t a i r climbing, rowing, cycle ergometry, arm ergometry, wall pulleys, medicine b a l l throwing, and a cross country s k i simulator at the previously determined target i n t e n s i t y . Subjects were required to move rapidly to the next station, to maintain the pulse i n the target range. In t h i s group, outdoor c y c l i n g and walking/jogging was also permitted as a supplement. The frequency of exercise t r a i n i n g was held at 3/week for the f i r s t three months, and then was increased to 4 - 5 for the next 3 months. Since both WJ and CT programs included only 3 sessions/week, subjects were instructed to supplement 1- 2 extra (stationary c y c l i n g or walking/jogging) sessions at home. Training durations and frequencies were matched between the two groups. The LC group trained 1 - 2/week for 20 .- 30 minutes per session at a heart rate equal to 50 to 60% of VC^peak with either l i g h t walking or cycle ergometry, or with c i r c u i t t r a i n i n g i n the case of three non-complying subjects o r i g i n a l l y randomized to the CT group. Exercise i n t e n s i t y was determined by recognized methods 11 (American C o l l e g e of Sports Medicine, 1986, Karvonen et a l . , 1957), based on r e s u l t s of the i n i t i a l c y c l e ergometry t e s t s , s i g n s and symptoms. An i n i t i a l t r a i n i n g i n t e n s i t y r e p r e s e n t i n g 60 - 70% HRpeak re s e r v e , and the h e a r t r a t e r e p r e s e n t i n g 70% of VC^peak, or i n the case of angina- l i m i t e d p a t i e n t s w i t h or without beta b l o c k i n g medications, a HR j u s t below the a n g i n a l t h r e s h o l d was a s s i g n e d . R e s t i n g HR was determined d u r i n g the 10 minute r e s t i n g p e r i o d i n the n u c l e a r medicine e v a l u a t i o n s (See 2.4.2 Gated Blood Pool E x e r c i s e S t u d i e s ). Over a 3 month p e r i o d , or as e x e r c i s e t o l e r a n c e improved, e x e r c i s e i n t e n s i t y was g r a d u a l l y i n c r e a s e d t o 75-80% HRpeak, b a r r i n g s i g n s and symptoms. Because maximal HR a c h i e v e d on c y c l e ergometry i s 5 - 7% below t h a t of t r e a d m i l l t e s t i n g (Wicks et a l . 1978), the i n t e n s i t y was a d j u s t e d upward i n p a t i e n t s who achieved a t r u e VC^max (plateau of V O 2 , r e s p i r a t o r y exchange r a t i o (RER) > 1.15) d u r i n g c y c l e t e s t i n g by t h i s amount f o r the WJ group s u b j e c t s . Upper body e x e r c i s e i n t e n s i t i e s f o r the CT group were a l s o determined by these methods, y i e l d i n g t r a i n i n g HR's 50 - 70% o f t h a t a t t a i n e d f o r c y c l i n g and walking ( F r a n k l i n , 1985) . The energy expenditure of each s e s s i o n f o r the WJ and CT groups was. e s t i m a t e d t o ensure t h a t each group was p e r f o r m i n g the same amount of work per s e s s i o n . Based upon a 70kg s u b j e c t e x e r c i s i n g at an average t a r g e t i n t e n s i t y , the t o t a l energy expenditure per s e s s i o n f o r the CT group was 1184.4 k j , and 12 1146.6 k j f o r the WJ group ( e q v i v a l e n t t o 273 and 282 k c a l , r e s p e c t i v e l y ) i n c l u d i n g the 10 minute warm-up f o r b o t h g r o u p s . The c a l c u l a t i o n ' o f energy e x p e n d i t u r e f o r the CT group was based upon an average o f two l o w e r - e x t r e m i t y and one upper e x t r e m i t y 10 minute s e s s i o n s p e r c l a s s . C a l c u l a t e d t r a i n i n g h e a r t r a t e s f o r the groups were as f o l l o w s : WJ: month 0 to 3: 100 - 105 bpm, months 3 t o 6: 111 - 118 bpm. C T : month 0 to 3: 109 - 112 bpm, months 3 t o 6: 110 - 115 bpm. L C : month 0 t o 3: 97 - 103 bpm, months 3 t o 6: 94 - 97 bpm. In the CT group , p r e - t r a i n i n g t r e a d m i l l maximum t e s t s (Bruce p r o t o c o l w i t h o u t gas a n a l y s i s ) were per formed as a requ irement f o r a t tendance at t h a t program. The d a t a from these t e s t s i s not i n c l u d e d i n t h i s s t u d y , but was used t o de termine t r a i n i n g ' i n t e n s i t e s a l o n g w i t h the o t h e r methods d e s c r i b e d above (75 - 85% o f s y m p t o m - l i m i t e d HRmax). A l l s u b j e c t s r e c o r d e d i n - c l a s s and at-home e x e r c i s e s e s s i o n s on l o g s h e e t s . These sheets were examined r e g u l a r l y by the i n v e s t i g a t o r s and i n d i v i d u a l program s t a f f , and i n c l u d e d i n f o r m a t i o n on e x e r c i s e p u l s e , d u r a t i o n and symptoms. D i e t a r y and b e h a v i o r m o d i f i c a t i o n e d u c a t i o n was not i n c l u d e d i n the s t u d y . In the case o f p a r t i c i p a n t s on a home w a l k i n g program, c o n t a c t was m a i n t a i n e d by r e g u l a r t e l e p h o n e c a l l s , b i - w e e k l y m a i l - i n o f l o g s , and s e v e r a l v i s i t s t o the 13 exercise laboratory for low-level submaximal exercise t e s t i n g for the purposes of monitoring and exercise p r e s c r i p t i o n updating. 2.3 Exercise Testing 2.3.1 Maximum Oxygen Uptake The following t e s t i n g procedures were performed i n the exact order for both pre and post-testing. After avoiding food and caffeine for 3 hours, subjects reported to the lab, where basal measurements of body mass and height were f i r s t obtained. Subjects were prepared for 12-lead ECG, and f i r s t performed a graded arm ergometry test with open c i r c u i t gas analysis. A f t e r c a l i b r a t i o n , the arm ergometer (Monarch Rehab Trainer) was adjusted so that during the phase of maximum reach, a s l i g h t bend i n the elbow occurred, and a l i n e between the crank arm and the olecranon was i n a l i n e p a r a l l e l to the f l o o r (Franklin, 1985). After an i n i t i a l warm-up work load of 0 W, increments of 6.25 W were applied every 2 minutes at 50 RPM (paced by a metronone) u n t i l termination of the t e s t . Subjects were continuously monitored by ECG using an oscilloscope, and 12- lead recordings were made i n the l a s t 15 seconds of each work load. Blood pressure was not recorded during arm ergometry tests due to the pot e n t i a l unreliable nature of p o p l i t e a l artery blood pressure determinations, and the need 14 f o r a continuous t e s t p r o t o c o l f o r d e t e r m i n a t i o n of v e n t i l a t o r y t h r e s h o l d s ( d i s c u s s e d i n the f o l l o w i n g s e c t i o n s ) . C r i t e r i a f o r determining the t e r m i n a t i o n p o i n t of the t e s t are d e s c r i b e d i n g r e a t e r d e t a i l elswhere (American C o l l e g e of Sports Medicine, 1986, E l l e s t a d , 1975), but b r i e f l y i n c l u d e d : 1. F a i l u r e t o maintain the d e s i r e d p e d a l i n g cadence, 2. Muscular f a t i q u e , 3. Syncope, 4. P a l l o r , 5. Nausea, 6. F a i l u r e t o i n c r e a s e VO2 when work i s i n c r e a s e d , 7. RER > 1.15, 8. Attainment of a g e - p r e d i c t e d maximal HR, 9. F a i l u r e t o i n c r e a s e HR w i t h i n c r e a s i n g work, 10. ECG a b n o r m a l i t i e s ( i n c l u d i n g > 2 mm h o r i z o n t a l or downsloping ST-segment d e p r e s s i o n or e l e v a t i o n ) , 11. Grade 3+ angina, and 12. e x h a u s t i o n . S u b j e c t s breathed through a two-way Hans Rudolf v a l v e (Volume = 70 ml) i n t o a SensorMedics H o r i z o n MMC f o r continuous measurement of e x p i r e d gases. The MMC was c a l i b r a t e d p r i o r t o the t e s t s with gases of known c o n c e n t r a t i o n , and was a l s o c a l i b r a t e d f o r temperature, b a r o m e t r i c p r e s s u r e , and volume a c c o r d i n g t o the manufactuer's s p e c i f i c a t i o n s . The t e s t p r o t o c o l was continuous i n nature, a l l o w i n g f o r d e t e r m i n a t i o n of v e n t i l a t o r y t h r e s h o l d (Wasserman and M c l l r o y , 1968, Skinner and McLellan, 1980), i n a d d i t i o n t o the peak oxygen consumption (VC^peak), minute v e n t i l a t i o n ( V E ) , volume of 15 e x p i r e d CO2 ( V C O 2 ) / r e s p i r a t o r y e x c h a n g e r a t i o (RER), e n d - t i d a l p a r t i a l p r e s s u r e o f CO2 ( P E T C O 2 ) , a n d e n d - t i d a l p a r t i a l p r e s s u r e o f O2 ( P E T O 2 ) . V e n t i l a t o r y t h r e s h o l d (VT) was d e f i n e d as a b s o l u t e w o r k l o a d ( W a t t s ) o r VO2 ( a b s o l u t e o r r e l a t i v e p e r c e n t o f V C ^ p e a k / m a x ) w h e r e t h e r e l a t i o n s h i p b e t w e e n V E a n d VO2 b e c o m e s a l i n e a r (Wasserman e t a l . , 1973, K i n d e r m a n e t a l . , 1979, D a v i s e t a l . , 1976, S k i n n e r a n d M c L e l l a n , 1980) . V T ' s w e r e d e t e r m i n e d b y t h e same o b s e r v e r , a n d no r e l i a b i l i t y / v a l i d i t y s t u d i e s w e r e p e r f o r m e d on t h e d e t e r m i n a t i o n s o f V T ' s . Due t o l a c k o f a v a i l a b l e l a b o r a t o r y t i m e w h i c h w o u l d h a v e e n a b l e d arm a n d l e g t e s t i n g on s e p a r a t e d a y s , a r e s t p e r i o d o f 60 m i n u t e s b e t w e e n t h e arm a n d c y c l e t e s t s was i n c l u d e d , w i t h t h e c y c l e t e s t a l w a y s f o l l o w i n g t h e arm t e s t i n a n a t t e m p t t o m i n i m i z e s u b j e c t f a t i g u e b y f i r s t t e s t i n g t h e s m a l l e r m u s c l e mass f i r s t . The c y c l e e r g o m e t e r t e s t was p e r f o r m e d b y u t i l i z i n g a m a g n e t i c a l l y - b r a k e d e r g o m e t e r ( Q u i n t o n U n i w o r k M o d e l 245) . The e r g o m e t e r was i n d i v i d u a l l y a d j u s t e d so t h a t u p o n l e g e x t e n s i o n t h e r e was a 5^ f l e x i o n a t t h e k n e e . I n i t i a l p e d a l l o a d was 32.7 W, a n d i n c r e a s e d 16.3 W e v e r y 2 m i n u t e s u n t i l t e r m i n a t i o n . T w e l v e - l e a d ECG was r e c o r d e d a t t h e e n d o f e a c h s t a g e . T h e o b s e r v e d a n d d e r i v e d g a s e x c h a n g e i n d i c e s a n d c a l i b r a t i o n p r o c e d u r e s d e s c r i b e d f o r t h e arm e r g o m e t r y t e s t , a s w e l l a s t e r m i n a t i o n c r i t e r i a (but w i t h t h e a d d i t i o n o f t h e f a i l u r e o f s y s t o l i c 16 blood pressure to increase) , were repeated for the cycle t e s t . Subjects were instructed to maintain a pedal rate of 70-80 RPM to minimize l o c a l quadriceps fatique, and blood pressure was determined at the second minute of every exercise l e v e l . Subjects were asked to not v o l u n t a r i l y hold t h e i r arm up for the experimenter during blood pressure measurement, and were requested not to gri p the handlebars t i g h t l y while c y c l i n g to minimize changes i n blood pressure. 2.3.2 Body Composition The Third E d i t i o n of the Canadian Standardized Test of Fitness body composition protocol (1986) was u t i l i z e d to characterize changes i n fatness/muscularity, and fat d i s t r i b u t i o n patterns over the 6 month period i n these patients. A f t e r determining landmarks, the following measurements were recorded: tr i c e p s , subscapular, biceps, s u p r a i l i a c and medial c a l f skinfolds, and waist, g l u t e a l (hip) g i r t h s . Derived variables from these raw measurements included: Body Mass Index (BMI) {kg/m^}, Sum of 5 skinfolds (SOS), Waist/Hip g i r t h r a t i o (WHR), and Sum of two trunk skinfolds {subscapular + suprailiac} (SOTS). 2.3.3 Blood Lipid Analysis Within 2 - 5 days of maximal testing, patients reported to the lab a f t e r an overnight (14 hr.) fast and abstinence from 17 alcohol. Blood was drawn for analysis of t o t a l cholesterol, high and low-density l i p o p r o t e i n cholesterol subtractions (HDL-C, LDL-C), and t r i g l y c e r i d e s (TG) using an enzymatic method (Kodak Ektachem, Seragen Diagnostics, Indiana), ( A l l a i n et a l . 1974). This was repeated a f t e r 6 months of exercise t r a i n i n g . 2.4 N u c l e a r Imaging 2 .4 .1 Sup ine R e s t i n g L e f t V e n t r i c u l a r F u n c t i o n Within 1-3 days of maximal testing, subjects reported to the Nuclear Medicine Laboratory i n the morning; they were asked to avoid food and caffeine for 3 hours before t e s t i n g . After administration of stannous f l u o r i d e to prepare the red blood c e l l s for in-vivo l a b e l i n g by the tracer, subjects were placed i n the supine position, and a gamma camera (Picker dyna 4/15) with a p a r a l l e l hole collamator was placed i n the l e f t anterior oblique (LAO) 40° pos i t i o n over the chest. Technesium-99m ( 9 9 mTc) (370 MBq combined with 0.5ml saline) was injected as a bolus into the b a s i l i c vein, and imaged on-line by a Picker gamma camera interfaced to an ADAC DPS- 2 800 computer. Dynamic images of the heart with the camera i n the LAO 4 0° projection were obtained at a framing rate of 0.6 seconds per image for a t o t a l of 128 images. The images were saved on a Winchester hard disc on a 64 x 64 x 8 matrix. Immediately a f t e r a c q u i s i t i o n of the dynamic images, a 1 18 minute s t a t i c blood pool image of the heart was obtained on a 64 x 64 x 16 matrix, also saved for subsequent analysis. Resting cardiac output (CO) was calculated using processing software (ADAC version 2.0). The software determined CO by d i v i d i n g the injected a c t i v i t y by the area under the f i r s t pass curve (excluding re-c i r c u l a t i o n ) according to the basic indicator d i l u t i o n therapy (Alazracki et a l . , 1975, Fouad et a l . , 1979). The CO program determines the i n i t i a l a c t i v i t y by r e l a t i n g equilibrium count rate to blood volume, and excludes r e c i r c u l a t i o n from the f i r s t pass curve by extrapolation of the downslope of that curve. The program assures a good f i t s t a t i s t i c a l l y to the downslope and performs integration to determine the area under the curve. (Appendix II) . In addition to CO, cardiac index and stroke volume (SV) were calculated (CO HR). The remaining 370 MBq and saline was then injected to bring the t o t a l a c t i v i t y to 740 MBq, and allowed to reach e q u i l i b r a t i o n for 10 minutes for the in-vivo l a b e l i n g of autologous red blood c e l l s . 2 . 4 . 2 G a t e d B l o o d P o o l E x e r c i s e S t u d i e s Immediately a f t e r the supine imaging studies, and allowing for maximum la b e l i n g of the red blood c e l l s with ^^ mTc, subjects were f i t t e d onto the cycle ergometer (Collins 19 Pedalmate c o n t r o l l e r , Atomic Products Corporation elecromagnetic ergometer) i n the semi-erect p o s i t i o n . A s c i n t i l a t i o n camera (Siemens LEM 6607) equiped with a low energy 140 KEV all-purpose p a r a l l e l - h o l e collimator was positioned over the patient's chest i n the LAO 40° p o s i t i o n for best v e n t r i c u l a r separation. Some deviation from t h i s angle was required to optimally v i s u a l i z e the v e n t r i c l e s i n some patients. Count data was obtained i n a frame mode of 16 frames per R-R i n t e r v a l of the ECG i n a 64 X 64 p i x e l matrix, and processed using a CDA MicroDelta computer/terminal and software for manual c a l c u l a t i o n of Global and regional l e f t v e n t r i c u l a r ejection f r a c t i o n (LVEF). The LVEF was calculated as: LVEF = [(EDBC - ESBC)/EDBC] X 100 1.0 Where EDBC = End-Diastolic Background-Corrected Counts. ESBC = End-Systolic Background-Corrected Counts. The computer automatically displayed frames representing the end-diastolic and end-systolic phases of the cardiac cycle, and l e f t - v e n t r i c u l a r end-systolic and end-diastolic regions of i n t e r e s t (ROI) were then manually drawn with a joy s t i c k . A background region was manually drawn 2 p i x i e s l a t e r a l and i n f e r i o r to the LV ROI (Holman and Parker, 1981, Gerson, 1987) (See Appendix I I ) . Attenuation ( e - ^ ) of the a c t i v i t y of the isotope by chest 20 wall structures and distance to the camera was calculated using the formula: e"P d 2.0 Where -u i s the l i n e a r attenuation c o e f f i c i e n t of water (given at -0.15), d i s the distance from the centre of the LV to the s c i n t i l l a t i o n camera divided by s i n 40° , as measured and processed by a 1 minute a c q u i s i t i o n (after the exercise studies), i n the anterior p o s i t i o n with a labled marker positioned over the centre of the LV (Links et a l . , 1982). Left v e n t r i c u l a r end-diastolic volume (LVEDV) for each l e v e l of exercise was then subsequently calculated u t i l i z i n g a non-geometric method (Links et a l . , 1982, Slutsky et a l , 1979, Holman, and Parker, 1981). This method has been validated against standard contrast angiographic methods with r e l i a b i l i t y c o e f f i c i e n t s of .87 (LVESV) and .85 (LVEDV) for both rest and exercise. (Slutsky et a l . , 1979). Va l i d a t i o n studies c a r r i e d out i n the present t e s t i n g f a c i l i t y between angiographic vs. RNA - determined resting LVEF and SV yielded r e l i a b i l i t y c o e f f i c i e n t s of .83 ( P < .04) and .93 ( P < .006), respectively for r e s t i n g studies only, since exercise contrast angiography i s not performed at the present i n s t i t u t i o n . The count rate of blood i n the LV was calculated by drawing 21 two 5 ml s a m p l e s o f t h e p a t i e n t ' s b l o o d s o o n a f t e r e x e r c i s e , a n d i m a g i n g t h e s e i n p e t r i d i s h e s f o r 5 m i n . The c o u n t r a t e f o r t h e a v e r a g e o f t h e s e 2 b l o o d s a m p l e s , p l u s an a r e a d r a w n w i t h a j o y s t i c k f o r b a c k g r o u n d c o u n t s was p r o c e s s e d . To a c c o u n t f o r t h e d e c a y o f ^ ^ m T c o v e r t i m e , a s t a n d a r d t a b l e f o r d e c a y r a t e o f 9 9 m T c was u s e d t o a d j u s t t h e L V c o u n t r a t e f o r e a c h l e v e l o f e x e r c i s e b y m u l t i p l y i n g e a c h f a c t o r b y t h e r e c o r d e d t i m e o f e a c h e x e r c i s e a c q u i s i t i o n . L V E D V was c a l c u l a t e d a s : L V E D V = LV c o u n t r a t e / e ^ R d 5 ml c o u n t r a t e 3 .0 E x e r c i s e was p r e c e e d e d b y a 10 m i n u t e r e s t i n g a c q u i s i t i o n w h i l e t h e s u b j e c t s s a t q u i e t l y on t h e e r g o m e t e r . R e s t i n g b l o o d p r e s s u r e was r e c o r d e d a t t h e e n d o f t h i s p e r i o d . The e x e r c i s e l e v e l s w e r e d e t e r m i n e d b y t h e p r e v i o u s c y c l e maximum t e s t s , a n d were s e t a t 30, 50, 70 a n d 90% (WL -30 , WL -50, WL -70, WL-90) o f t h e m a x i m a l w o r k r a t e a n d / o r c o r r e s p o n d i n g HR a t t h a t w o r k l o a d . P e d a l i n g r a t e was m a i n t a i n e d a t 70 RPM a n d t h e l e v e l s w e r e c o n t i n u o u s . E a c h l e v e l c o n s i s t e d o f 1 m i n u t e t o a c h i e v e a s t e a d y - s t a t e , a n d 2 m i n u t e s o f a c q u i s i t i o n f o r a t o t a l o f 3 m i n u t e s a t e a c h l e v e l . The ECG was c o n t i n u a l l y m o n i t o r e d a n d b l o o d p r e s s u r e was r e c o r d e d a t t h e e n d o f t h e f i r s t a n d s e c o n d m i n u t e s o f a c q u i s i t i o n (2nd a n d 3 r d m i n u t e s ) . B e c a u s e t h e s e m i - e r e c t 2 2 p o s i t i o n n e c c e s s a r y f o r g a t e d b l o o d p o o l i m a g i n g , t h e b i o m e c h a n i c s d i f f e r e d f r o m t h a t o n t h e s t a n d a r d e r g o m e t e r . T h i s o c c a s i o n a l l y r e q u i r e d a d j u s t m e n t s o f t h e w o r k l o a d d o w n w a r d s i n s o m e p a t i e n t s i f i t w a s n o t i c e d t h a t t h e e n e r g y a n d H R r e q u i r e m e n t s w e r e a b o v e t h e s e l e v e l s . I n t h i s c a s e , a t a r g e t H R c o r r e s p o n d i n g t o t h e w o r k l o a d r e p r e s e n t i n g t h e s e p e r c e n t a g e s w a s u s e d t o g a u g e t h e w o r k l o a d s e t t i n g , a n d t h e w o r k l o a d w a s n o t e d . U p o n p o s t - t e s t i n g , t h e i d e n t i c a l p r o c e d u r e s w e r e u t i l i z e d , e x c e p t i n t h e c a s e o f d e t e r m i n i n g t h e w o r k l o a d s . D e p e n d i n g u p o n t h e e x t e n t o f i m p r o v e m e n t i n t h e c y c l e m a x i m u m t e s t , t h e s u b j e c t s p e d a l e d a t t h e s a m e a b s o l u t e w o r k l o a d s r e p r e s e n t i n g 3 0 , 5 0 , 7 0 , a n d 90% ( W L - 3 0 , W L - 5 0 , W L - 7 0 , W L - 9 0 ) o f t h e p r e - t e s t i n g m a x i m u m , a n d t h e n t w o a d d i t i o n a l l e v e l s r e p r e s e n t i n g t h e n e w 7 0 a n d 90% ( W L - 7 0 p o s t a n d W L - 9 0 p o s t ) o f ( r e l a t i v e ) m a x i m u m . T o m i n i m i z e i n v e s t i g a t o r b i a s e f f e c t s d u r i n g t h e p r o c e s s i n g a n d d r a w i n g o f t h e R O I ' s , t h e i n v e s t i g a t o r w a s b l i n d e d t o t h e i d e n t i t y o f t h e s u b j e c t s b y a s s i g n i n g c o d e n u m b e r s t o e a c h i n d i v i d u a l . M e a s u r e d p a r a m e t e r s a t e a c h l e v e l o f r e s t a n d e x e r c i s e w e r e a s f o l l o w s : L V E F ( c a l c u l a t e d a u t o m a t i c a l l y ) , L V E D V , d e r i v e d S t r o k e V o l u m e ( S V ) : L V E F X L V E D V , L e f t - V e n t r i c u l a r E n d - s y s t o l i c v o l u m e ( L V E S V ) : L V E D V - S V , a n d C a r d i a c O u t p u t (CO) : S V X H R . R a t e - p r e s s u r e p r o d u c t ( R P P ) (HR X S y s t o l i c b l o o d p r e s s u r e X l O - ^ ) w a s c a l c u l a t e d a t e a c h e x e r c i s e 23 l e v e l , as was t o t a l peripheral resistance (TPR), calculated by: TPR = MAP 4.0 CO " where MAP i s mean a r t e r i a l blood pressure calculated as d i a s t o l i c blood pressure + .33 ( s y s t o l i c - d i a s t o l i c blood pressure). TPR i s expressed as Peripheral Resistance Units (PRU), where 1 PRU = 1 l/min _ 1/mmHg _ 1 (Burton, 1972). I n t r i n s i c myocardial performance parameters were also estimated by u t i l i z i n g the calculated parameters expressed as S y s t o l i c Blood Pressure/End-Systolic Volume Ratio (P/V Ratio) (Sagawa et a l . , 1977, Iskandrian et a l . , 1983) as: P/V Ratio = SBP 5.0 LVESV' Where SBP = s y s t o l i c blood pressure ( an estimation of LV end-systolic pressure), and LVESV = l e f t v e n t r i c u l a r end- s y s t o l i c volume. Left v e n t r i c u l a r stroke work (LVSW, g • m) was calculated as SV X MAP X .0136 (Kragenbuehi, 1985). 2.5 S t a t i s t i c a l Analysis Data was analyzed by SAS ( S t a t i s t i c a l Analysis Systems Inc., Cary Id.) software on The University of B r i t i s h Columbia's 24 48-megabite Amdahl 58 60 mainframe computer using the Michigan Terminal System. Metabolic, body composition, and blood l i p i d data were analyzed using a 3 X 2 General Linear Model of Analysis of Variance design for unbalanced c e l l data, for mean differences of scores from pre to post t r a i n i n g . Students paired t - t e s t s were u t i l i z e d for some analysis for pre-vs. post differences of scores within groups. Upon finding a s i g n i f i c a n t F r a t i o , post-hoc tests using Scheffe's test was u t i l i z e d to determine the between groups differences. The minimum of a 0.05 l e v e l of sign i f i c a n c e was used as the c r i t e r i a to determine a s t a t i s t i c a l l y s i g n i f i c a n t difference. To minimize the p r o b a b i l i t y of excessive type I and II experimentwise error rates due to the extent of the data c o l l e c t e d i n t h i s project, for many of the data, only the WL-70, WL-90, and WL-90post exercise l e v e l s were quant i t i v e l y analyzed i n t h i s t h e s i s . Some data not s t a t i s t i c a l l y analyzed does appear i n figures (resting, WL- 30 and WL-50). Pearson Product Moment Correlation proceedure was used to estimate the r e l a t i o n of one phy s i o l o g i c a l variable to another. The 0.05 l e v e l of significance was used. Plotted c o r r e l a t i o n a l data was generated using SAS plot proceedure. 25 Plotted data for figures (See L i s t of Figures, page vi) were computer-generated by Tell-a-Graf Version 5.0 software on The University of B r i t i s h Columbia's mainframe computer using raw data input. A QMS p r i n t e r was used to produce camera-ready p l o t s . 26 3.0 Results 3.1 Physical C h a r a c t e r i s t i c s of Subjects Twenty-nine of the o r i g i n a l 40 subjects completed the t r a i n i n g study. Of the 11 drop-outs, 3 were f o r non-medical reasons, and 8 were f o r medical reasons. None of the remaining p a t i e n t s were smokers. D e s c r i p t i o n of the p h y s i c a l and medical c h a r a c t e r i s t i c s of the p a t i e n t s are l i s t e d i n Table 3.1. 3.1.2 Exercise Training T h i r t e e n p a t i e n t s comprised the walking/jogging (WJ) group, 9 i n the c i r c u i t t r a i n i n g (CT) group, w i t h 7 remaining i n the l o w - i n t e n s i t y e x e r c i s e c o n t r o l (LC) group. A l l t e s t i n g proceeded without event except i n two cases of hypoglycemia, where a d m i n i s t r a t i o n of f r u i t j u i c e immediately p r i o r t o the t e s t i n g r e s o l v e d the problem. In one a d d i t i o n a l p a t i e n t , t e s t i n g was postponed due to an episode of acute unstable angina immediately p r i o r t o the RNA e x e r c i s e procedure. 27 Subjects i n the CT and WJ groups trained an average of 3.8 ± 1.0 d/week, and the LC exercised 2.0 ± 0.5 d/week. Exercise t r a i n i n g durations were i n i t i a l l y set at 20 min. and progressed to 40 to 60 min/sesion for the CT and WJ groups. No incidents or cardiac events took place during exercise t r a i n i n g . Exercise t r a i n i n g d i a r i e s were monitored for each patient to maintain compliance. Exercise i n t e n s i t i e s (target HR, calculated by Karvonen's (1957) formula) for the three groups were as follows: WJ month 0 - 3 : 100 to 105 bpm, months 3 - 6 : 111 to 118 bpm. CT month 0 - 3 : 109 to 112 bpm, months 3 - 6 : 110 - 115 bpm. LC month 0 - 3 : 97 to 103 bpm, months 3 - 6 : 94 to 97 bpm. 3.2 Body Composition and Lip i d s Body weight did not change for any of the groups before or aft e r t r a i n i n g , nor did body mass index (BMI) , waist-hip r a t i o (WHR) or sum of f i v e skinfolds (SOS) . The t o t a l cholesterol to HDL cholesterol r a t i o and HDL cholesterol (HDL-C) d i d not demonstrate any changes due to t r a i n i n g i n either group (Table 3.2). 28 No s i g n i f i c a n t correlations for any of the body compositon or blood l i p i d s were found, including any of the metabolic va r i a b l e s . Only when the complete pre-testing data (n=4 0) was analyzed did s i g n i f i c a n t correlations r e s u l t between WHR and HDL-C (r = -.74, P < .03). BMI and HDL-C were not correlated (r = -.18, P < .32). The best c o r r e l a t i o n obtained between l i p i d s and body composition was BMI and LDL-C (r = -.25, P < .18). There was a mild but s i g n i f i c a n t c o r r e l a t i o n between HDL-C and VC^peak for a l l 4 0 pre-test data (r = .45, P < . 01) . 29 Table 3.1 Physical C h a r a c t e r i s t i c s of Subjects Subject Group Sex Age Hx Height (cm) Weight (ka) Medicatioi LD CT F 37 MI 160.8 54.7 As C I L AH CT F 68 MI 166.0 67.4 C AM CT M 60 MI,CABS 172.2 90.1 B I MR CT M 51 MI,CABS 175.1 91.9 As GW CT M 50 MI 177.0 74.7 As JE CT M 68 MI 177.0 78.0 As B C N DP CT M 54 MI 178.4 78.5 As C N HG CT M 55 A, MI 177.9 76.8 B D S JR CT M 55 MI 175.2 95.4 As C N S EP WJ F 47 MI 159. 9 54.2 C D N JM WJ M 51 MI,CABS 175.1 91.9 As RR WJ M 52 MI, BA 170.5 62.7 C D S GE WJ M 46 MI,TPA 180.9 88.4 As B PH WJ M 64 A 175.2 97. 9 C N KS WJ M 48 MI 163.5 66.3 B C N GW WJ M 52 MI 165.0 64.8 B GG WJ M 34 MI 183.5 83.2 B C L N EP WJ M . 47 MI. 159. 9 • 54.2 C D N SR WJ M 54 MI 182.4 100.0 BB WJ M 39 MI 172 . 0 54.2 B L N DH WJ M 53 MI 171.5 66.2 As B JG WJ M 50 MI 178.0 90.6 B LB LC M 57 MI 178.6 86.8 C N DP LC M 46 MI 173.5 95. 6 As B D PH LC M 53 MI 178.2 79.7 B AA LC M 63 MI 167.2 68.7 A r N JP LC M 57 MI 168.4 70.4 As B C D LN LC M 63 MI 172.9 88.2 B JP LC M 55 CABS 175.0 73.2 As L Mean 53.5 167.11 77.33 SD 8.46 32.14 13.40 M I - M y o c a r c i a l I n f a r c t i o n A-Angina B A - B a l l o o n A n g i o p l a s t y CABS-Coronary A r t e r y Bypass S u r g e r y TPA-Tissue P l a s m i n o g e n A c t i v a t o r Treatment A s - A s p i r i n / P l a t e l e t I n h i b i t o r A r - A n t i - A r r h y t h m i c B-Beta B l o c k a d e C-Calcium Channel B l o c k a d e D- D i u r e t i c I - I n o t r o p i c Agent L - L i p i d L o w e r i n g Agent N- N i t r a t e S - S e d a t i v e WJ-walk/jog group C T - c i r c u i t t r a i n i n g group L C - l o w - i n t e n s i t y c o n t r o l group. 30 3.3 Aerobic Capacity 3.3.1 Lower Extremity Aerobic Capacity The maximal external workload for the WJ and CT t r a i n i n g groups increased from 131.95 ± 33.64 to 144.30 ± 36.73 and 134.28 ± 19.84 to 147.32 ± 48.60 Watts, r e s p e c t f u l l y (P < .04). There was no s i g n i f i c a n t change for the LC group. Table 3.2 Body Composition and Lip i d s A f t e r Exercise Training Variable Group Pre (mean, SD) Post (mean, SD) Body Mass (kg) WJ 75.1 15.6 75.4 15.5 CT 78.6 12.8 78.9 11.8 LC 79.9 10.7 81.4 10.1 BMI (kg/m2) WJ 25.0 3.9 24.9 3.6 CT 26.3 3.7 26.5 3.1 LC 26.9 2.8 27.3 2.7 SOS (mm) WJ 60.2 18.8 61.6 21.2 CT 71. 0 23.4 71. 9 12 .0 LC 63. 6 16.2 65.4 12.3 T-Chol/HDL-C WJ 6.07 1.3 6.04 0. 99 Ratio CT 5.50 1.9 5. 68 0.98 LC 5.12 1.3 5.31 1.08 HDL-C (mg/100 ml) WJ 37.6 6.23 36.7 6.14 CT 41.1 9.42 40.3 8.10 LC 40.6 6. 60 41.5 8.80 WJ Walking/Jogging Group CT LC Low-Intensity Control C i r c u i t Training Group VC^peak i n c r e a s e d s i g n i f i c a n t l y f o r the two groups by 13% (1.93 ± 0.51 t o 2.22 ± 0.54 1-min" 1 ) and 9.7% (1.96 ± 0.58 t o 2.17 ± 0.70 l - m i n - 1 ) f o r the WJ and C T . groups r e s p e c t i v e l y (P < . 0 0 4 ) . The LC g r o u p ' s VC^peak was reduced by 6% a f t e r the 6 months t r a i n i n g . Both the WJ and CT groups were s i g n i f i c a n t l y d i f f e r e n t than the LC on p o s t - t e s t i n g d i f f e r e n c e s i n s c o r e s , but t h e r e was no d i f f e r e n c e between the WJ and CT group (Table 3 . 3 , F i g u r e 3 . 1 a ) . There was no d i f f e r e n c e i n VO^peak between the groups on p r e - t e s t i n g . To v e r i f y t h a t the i n c r e a s e d V 0 2 p e a k v a l u e s were due t o r e a l e x e r c i s e t r a i n i n g e f f e c t s and not t o h a b i t u a t i o n or m o t i v a t i o n , a n a l y s i s was per formed on the RER at maximal e x e r c i s e . There was no s i g n i f i c a n c e f o r p r e t o pos t d i f f e r e n c e s f o r a l l t h r e e groups ( P < .32 ) . Maximal RPP i n c r e a s e d s i g n i f i c a n t l y i n the WJ and CT groups a f t e r t r a i n i n g from 21.57 t o 24.35 mmHg/HR x 10~ 3 (P < .05 ) and 22.35 t o 23.29 mmHg/HR x 1 0 - 3 (P < . 0 4 ) , r e s p e c t i v e l y (Table 3 . 3 ) . When the d a t a i n the t h r e e groups was p o o l e d (n=2 9)., VC^peak was s i g n i f i c a n t l y c o r r e l a t e d w i t h RPP (r = .69 , P < . 0 0 1 ) . 32 T he g r o u p s d i f f e r e d u p o n p r e - t e s t i n g , h o w e v e r f o r m a x i m a l w o r k l o a d (P < . 0 3 ) , RPPmax (P < . 0 5 ) , a n d HRmax (P < . 0 5 ) . T h e r e w e r e no d i f f e r e n c e s i n m a x i m a l HR due t o t r a i n i n g i n a n y g r o u p , h o w e v e r , t h e L C g r o u p h a d s i g n i f i c a n t l y l o w e r m a x i m a l HR t h a n t h e WJ a n d CT g r o u p s a t b o t h p r e a n d p o s t - t e s t i n g (P < .05) . 33 T a b l e 3 . 3 L o w e r E x t r e m i t y A e r o b i c C a p a c i t y a f t e r S i x M o n t h s o f E n d u r a n c e T r a i n i n g Variable Group Pre (Mean, SD) Post (Mean, SD) Workload Max (Watts) WJ CT LC 131.95 33.64 ¥ 144.30 36.73 134.28 35.30 ¥ 147.05 48.60 116.70 19.84 114.32 32.69 * P < .04 ¥ P > .03 pre vs. post t r a i n i n g pre-testing vs. LC. V0 2peak (1 •min--'- WJ CT LC 1.93 1.96 1.83 0.51 0.58 0.36 2.22 2 .17 1.73 0.54 * 0.70 * 0.55 RER (VC0 2/V0 2) P < .004 pre vs. post t r a i n i n g , vs. LC WJ CT LC 1.02 0.99 0. 97 0.06 * 0.08 0.11 04 04 06 0.06 * 0.09 0.09 P < .32 WJ vs. CT, LC. RPPmax (mmHgXHRxlO 3) WJ 21. 57 4.86 ¥ 24, .34 CT 22. 35 6.34 ¥ 23, .29 LC 18. 66 3.69 18 , .28 * P < .05 pre vs. post * * p < .04 pre ¥ P < .05 vs. LC. Max HR (bpm) WJ 129 22.7 * 136 18 CT 133 37.1 * 136 31 LC 119 26.1 117 20 3.66 ¥ 7.04 * 4.41 >. post 6 * 9 * * P < .05 WJ, CT vs. LC. 3 4 2- i 1.75- Rgure 3.1a Arm Peak 0 Uptake Before and After Training c E i"-5- S 1.25-o > 0.75- 2.5- Rgure 3.1b Leg Peak 0 Uptake Before and After Training if- P-=.0O3 # P<-05 1.75- O > fr ~ - - - T 1 • WJ • CT • LC _ * P -e.004 Pre-test Post-test Testing Periods 35 3.3.2 Lower Extremity V e n t i l a t o r y Threshold A f t e r Training Break points i n the deviation from l i n e a r i t y i n the V E vs. V0 2 and V E/V0 2 curves were i d e n t i f i a b l e i n 27 of the 2 9 patients, with one patient (LC group) stopping exercise prematurely due to ischemic symptoms and associated ECG changes. The other patient's plotted metabolic data was lo s t due to disk and software problems encountered on that t e s t i n g date on the MMC Horizon System. SAS calculates data only on pairs of data, leaving out missing data pairs from calculations, and hence, these data are based on n=27. The VT occurring at an absolute V0 2 increased s i g n i f i c a n t l y only i n the WJ group, from 1.38 ± 0.33 to 1.76 ± 0 . 4 0 l * m i n - 1 ( P < .001), but was not s i g n i f i c a n t l y d i f f e r e n t from the CT • or LC groups (Table 3.4, Figure 3.2). When expressed as percent of V0 2peak, the changes were non- s i g n i f i c a n t for a l l groups despite a trend towards sign i f i c a n c e , increasing from 70.18 to 80.65 and from 66.37 to 7 6.96 percent of V0 2peak i n the WJ and CT groups respectively. VT expressed as a percentage of HRmax increased s i g n i f i c a n t l y i n the WJ group only, from 79.86 + 5.97 to 85.08 ± 5.42% after t r a i n i n g ( P < .05 ). 36 T a b l e 3 . 4 L o w e r E x t r e m i t y ( C y c l e ) V e n t i l a t o r y T h r e s h o l d A l t e r a t i o n s A f t e r E n d u r a n c e T r a i n i n g Variable Group Pre (Mean, SD) Post (Mean, SD) VT lC^-min - 1 WJ 1.38 0.33 1.76 0.40 * ¥ CT 1.31 0.33 1.59 0.49 LC 1.22 0.37 1.29 0.33 * P < .001 pre vs. post ¥ P < .05 vs . CT, : LC VT %V0 2peak WJ 70.18 8.14 80.65 5.31 CT 66.37 9.72 76.96 10.37 LC 68.26 7.72 70.45 8 . 69 ns. VT %HRmax WJ 79.86 5. 97 85.08 5.42 * CT 81.56 7.17 85.06 11.08 LC 84 .76 5.43 84.20 7.80 * p < 05 pre vs. post 3 7 3 8 3.3.3 Upper Extremity Aerobic Capacity T h e f o l l o w i n g u p p e r b o d y m e t a b o l i c v a l u e s a r e r e p o r t e d i n T a b l e 3 . 5 . A r m e r g o m e t r y w a s c o m p l e t e d i n a l l s u b j e c t s w i t h o u t i n c i d e n t . S u b j e c t s i n b o t h t h e W J a n d C T g r o u p s i n c r e a s e d t h e m a x i m a l w o r k l o a d a c h i e v a b l e f r o m 4 1 . 7 0 ± 1 4 . 2 t o 4 5 . 8 7 ± 1 2 . 9 W ( P < . 0 0 3 ) a n d f r o m 3 6 . 8 3 ± 1 1 . 9 t o 4 5 . 8 7 ± 1 4 . 9 W ( P < . 0 0 2 ) , r e s p e c t i v e l y . T h e L C g r o u p i n c r e a s e d s i g n i f i c a n t l y f r o m 3 4 . 7 7 ± 1 1 . 9 t o 4 0 . 2 0 ± 7 . 9 0 W. V C ^ p e a k v a l u e s f o r a r m e r g o m e t r y i n c r e a s e d s i g n i f i c a n t l y f o r t h e W J a n d C T g r o u p s ; 1 . 3 5 ± 0 . 3 2 t o 1 . 4 5 ± 0 . 3 4 (P < . 0 5 ) , a n d f r o m 1 . 3 2 ± 0 . 4 2 t o 1 . 5 2 ± 0 . 4 7 l - m i n - 1 (P < . 0 0 3 ) , r e s p e c t i v e l y . T h e r e w a s n o s i g n i f i c a n t i n c r e a s e r e p o r t e d f o r t h e L C g r o u p . O n l y t h e C T g r o u p w a s s i g n i f i c a n l y d i f f e r e n t f r o m L C o n d i f f e r e n c e s o f p r e - p o s t s c o r e s (P < . 0 5 ) ( F i g u r e 3 . 1 b ) . M a x i m a l R E R v a l u e s p r e v s . p o s t w e r e n o t d i f f e r e n t f o r t h e W J a n d C T g r o u p s f o r a r m e r g o m e t r y , h o w e v e r , t h e L C g r o u p h a d a s i g n i f i c a n t i n c r e a s e i n p o s t - t e s t i n g R E R ( 0 . 9 5 t o 1 . 0 7 , P < . 0 5 ) . T h e r e w e r e a l s o n o c h a n g e s i n m a x i m a l H R e x c e p t f o r t h e C T g r o u p , w h o i n c r e a s e d f r o m 1 1 7 . 7 t o 1 2 5 . 0 b p m (P < . 0 5 ) . 3 9 T a b l e 3 . 5 U p p e r E x t r e m i t y E r g o m e t r y A e r o b i c C a p a c i t y a f t e r E x e r c i s e T r a i n i n g V a r i a b l e G r o u p P r e (Mean, SD) P o s t (Mean , SD) M a x i m a l W o r k - l o a d ( W a t t s ) W J 4 1 . 7 1 4 . 2 4 5 . 9 1 2 . 9 * * CT 3 6 . 8 1 1 . 9 4 5 . 9 1 4 . 9 * LC 3 4 . 8 1 1 . 9 4 0 . 2 7 . 9 0 ~ P r e v s . P o s t : * * P < . 0 0 3 * P < . 0 0 2 ~ P < . 0 5 4 V C ^ p e a k ( l - m i n - 1 ) W J 1 . 3 5 0 . 3 2 1 . 4 5 0 . 3 4 * * CT 1 . 3 2 0 . 4 2 1 . 5 2 0 . 4 7 * ¥ LC 1 . 2 3 0 . 4 2 1 . 3 1 0 . 3 5 * * P < . 0 0 1 * P < . 0 0 0 3 P r e v s . P o s t ¥ P < . 0 5 v s . LC R E R ( V C 0 2 / V 0 2 ) W J 1 . 0 4 0 . 0 6 1 . 0 4 0 . 0 7 CT 0 . 9 8 0 . 0 7 1 . 0 5 0 . 0 7 LC 0 . 9 5 0 . 0 6 1 . 0 7 0 . 0 7 * * P < . 0 5 p r e v s . p o s t H R m a x ( b p m ) W J 1 1 5 2 0 . 4 1 1 8 1 4 . 9 CT 1 1 8 2 9 . 6 1 2 5 2 5 . 5 * LC 1 1 1 2 8 . 8 1 1 8 2 3 . 2 * P < . 0 5 P r e v s . P o s t 40 3 . 3 . 4 V e n t i l a t o r y T h r e s h o l d a n d U p p e r E x t r e m i t y E x e r c i s e T r a i n i n g The VT as expressed i n absolute l - m i n - 1 0 2 increased s i g n i f i c a n t l y i n the WJ group, from 0.829 ± 0.21 to 1.075 ± 0.29 l - m i n - 1 (P < .001). The CT group s i g n i f i c a n t l y increased VT from 0.816 ± 0.25 to 1.093 ± 0 . 3 3 l - m i n - 1 (P < .001). There were only s l i g h t changes i n the LC for absolute VT (Table 3.6) (Figure 3.2). The CT group was s i g n i f i c a n t l y greater than the WJ, and both WJ and CT groups had higher absolute VT's than the LC group (P < .05). When expressed as percent of V0 2peak, s i g n i f i c a n t increases were observed i n the WJ and CT groups, from 62.43 ± 12.1 to 74.66 ± 10.46% (P < .05), and from 62.33 ± 10.1 to 72.48 ± 8.8% (P < .001) afte r t r a i n i n g , r e s p e c t f u l l y . Only the WJ group d i f f e r e d from the LC group on differences of scores (P < .05) . VT Expressed as a percent of maximal HR increased only i n the WJ group (76.48 ± 11.0 to 83.38 ± 7.5%, P < .02), and was s i g n i f i c a n t l y d i f f e r e n t from the LC group on differences of scores (P < .05). F u l l data for VT data i s presented i n Table 3.6. 41 T a b l e 3 . 6 A l t e r a t i o n s i n V e n t i l a t o r y T h r e s h o l d a f t e r U p p e r E x t r e m i t y T r a i n i n g V a r i a b l e G r o u p P r e (Mean, SD) P o s t (Mean, SD) A r m V T ( I O 2 - m i n - 1 ) WJ 0.829 0.21 CT 0.816 0.25 L C 0.894 0.27 1.075 0.29 * ¥ 1.093 0.33 * ¥ f 0.908 0.22 P < .001 p r e v s . p o s t ¥ P < .05 v s . L C , f v s . WJ A r m V T (%V0^peak) WJ 62.43 12.1 74 .66 10.5 * * * ¥ C T 62.33 10.1 72 .48 8.8 * L C 75.23 9.45 68 .46 5.83 * p < .001 p r e v s . p o s t * * p < .05 v s . L C ¥ P 05 WJ v s . C T A r m V T (%HRmax) WJ 76. .48 10 . 9 83. .38 7 . 54 * • * * CT 83. .71 4. 77 83. .90 7, .75 L C 84. .49 9. 54 77. .74 8. .89 * P < .02 p r e v s . p o s t * * P < .05 WJ v s . L C 42 The VT expressed i n l-min 0 2 was p o s i t i v e l y c o r r e l a t e d w i t h VC^peak f o r a l l groups pooled f o r arm ergometry (r = .87 P < .001) and f o r c y c l e ergometry ( r = . 91 P < .0001) (Figures 3.3, 3.4). The c o r r e l a t i o n s f o r V0 2peak w i t h VT, expressed as a percentage of HRmax or V0 2peak were weaker and i n v e r s e l y r e l a t e d , w i t h arm VT %V0 2peak (r = -.47 P < .01), and arm VT %HRmax (r = -.33 P < .07). Cycle VT %V0 2peak was al s o i n v e r s e l y c o r r e l a t e d w i t h V0 2peak (r = -.47 P < .007), as was VT %HRmax (r = -.64 P < .001). Arm V0 2peak was c o r r e l a t e d w i t h Cycle V0 2peak (r = .77 P < .003), as was arm VT w i t h Cycle VT when expressed i n l - m i n - 1 02 (r = . 68 P < .01). There was a s i g n i f i c a n t c o r r e l a t i o n between the Cycle V0 2peak and T o t a l P e r i p h e r a l Resistance (r = -.53 P < .002, Figure 3.5). Arm Ventilatory Threshold (1 • min" 1) FIGURE 3 .4 rH 25 • r l 6 • r H „ OO cd 75 p . CN o • > t 5 0 01 1 I—I a >-. O i 25 Cycle (Leg) VCVjpeak vs. Cycle V e n t i l a t o r y Threshold r = .91 P < 0001 0 . 5 0 . 6 ' 0 . 7 O.O 0 . 0 1.CJ 1.1 1.2 1.3 1.4 1 .5 1.G 1 .7 1 .8 1.9 2 . 0 Cycle Ve n t i l a t o r y Threshold (1 •min--'-) 45 TPR U n i t s 46 3 . 3 . 5 ST-Segment Alt e r a t i o n s A f t e r Training The l e v e l of ST-segment depression at peak cycle exercise increased n o n - s i g n i f i c a n t l y from 0.54 ± 0.51 mm to 0.67 ± 0.98 mm i n the WJ group and decreased from 0.94 ± 1.5 mm to 0.39 ± 0.60 mm i n the CT group ( P < .05). There was an increase i n ST-segment depression i n the LC group, from 0.57 ± 0.93 mm to 0.93 ± 1.5 mm aft e r the 6 month period (P < .05) . The ST-segment at maximal arm workload decreased i n both the WJ and CT groups aft e r t r a i n i n g , but n o n - s i g n i f i c a n t l y (0.15 ± 0.32 to 0.04 ± 0.14 mm, and 0.11 ±0.33 to 0.0 ± 0.0 mm, respectfully) . There was no change for the LC group (0.57 ± 1.1 to 0.50 ± 1.1 mm). 47 3 . 3 . 6 Submaximal Heart Rate Responses and Transfer E f f e c t s The heart rate recorded at absolute workloads of 65.4 W (400 kpm) on the cycle ergometer and 25 W on the arm ergometer were compared before and aft e r t r a i n i n g i n the three groups. These workloads were chosen because they represented low enough l e v e l s of work to be considered submaximal for most of the subjects. However, 2 of the subjects i n the LC group, one i n the CT group, and one subject i n the WJ group f a i l e d to reach these workloads on pre-testing, and t h e i r data i s not included i n t h i s analysis. Heart rate for cycle ergometery declined at 65.4 W by 6 and 5 bpm for the WJ and CT groups respectively (P < .05) . The LC group demonstrated no s i g n i f i c a n t reduction i n submaximal HR (-0.80 bpm). There was a reduction for both the WJ and CT groups for HR at 25 W arm during ergometry, with the magnitude of the change greater for the WJ group (-4 and -2 bpm resp e c t i v e l y ) , but the changes were non-significant. There was no change for the LC group (Table 3.7, Figure 3.6). 48 Table 3 . 7 Changes i n Submaximal Heart Rate f o r Arm and Leg Ergometry Variable Group Pre (Mean, SD) Post (Mean, Cycle HR @ 65.4 W WJ 98 ± 14.2 92 ± 1 6 . 4 * (bpm) CT 108 ± 19.5 102 ± 18.3 * LC 99 ± 19.9 98 ± 13.6 Arm HR @ 25 W WJ 90 ± 11.8 87 ± 12.1 CT 103 ± 25.0 100 ± 24.5 LC 94 ±21.6 94 ± 13.1 * P < .05 pre vs. post 4 9 Figure 3.6a Arm Crank HR Response at 25W 110-1 T . 105- X 8 0 - 75 - 7 0 - S Q. X I TO X 120 115 110- 105 100 95-( 90 8 5 - 8 0 - 75 70 Figure 3.6b Cycle Heart Rate Response at 65W pre-test post-test Testing Periods WJ • CT • LC _ • P < .05 50 3 .4 Cardiac Function and Exercise Training 3.4.1 F i r s t Pass Radionuclide Angiogram First-pass cardiac output radionuclide angiograms were available i n 24 of the 29 subjects. Technical problems i n one subject, i n a b i l i t y to e s t a b l i s h a good venous l i n e for the i n j e c t i o n , and poor bolus quality for subsequent analysis of the t i m e - a c t i v i t y curve were reasons for the remaining missing data. There was a s i g n i f i c a n t difference for a l l subjects i n resting SV from the supine p o s i t i o n using t h i s technique, to the semi-erect p o s i t i o n during gated bloodpool radionuclide angiograms (88.44 ± 19.24 vs. 62.28 ± 15.5 ml, P < .001). There was no difference however i n resting supine CO or SV a f t e r t r a i n i n g . Stroke volume demonstrated non-significant changes from 97.96 ± 18.79 to 99.22 ± 21.18, 81.20 ± 18.35 to 94.81 ± 21.32, and 78.65 ± 12.65 to 84.60 ± 11.72 ml for the WJ, CT, and LC groups, respectively. 51 3.4.2 Gated Bloodpool Radionuclide Angiogram Exercise Testing A l l Gated Bloodpool RNA's were completed s u c c e s s f u l l y , except i n two cases, where a l l the s u b j e c t s ' data s t o r e d on d i s k were a c c i d e n t a l l y erased. T h e i r data i s not i n c l u d e d i n the o v e r a l l a n a l y s i s of c a r d i a c f u n c t i o n , except f o r the remaining HR and b l o o d p r e s s u r e v a r i a b l e s . R e s t i n g HR, reco r d e d d u r i n g the 10 minute e r e c t p o s i t i o n Gated Bloodpool RNA demonstrated no changes a f t e r t r a i n i n g i n a l l groups. At the ab s o l u t e submaximal workload r e p r e s e n t i n g the p r e - t r a i n i n g 70% of maximal VO2 (WL-70), HR was reduced from 104 ± 16.8 t o 100 ± 16.0, 115 ± 28.0 t o 107 ± 22.5 (P < .05), and 100 ± 18.2 to 98 ± 13.8 bpm f o r the WJ, CT and LC groups r e s p e c t i v e l y . HR at the workload r e p r e s e n t i n g the p r e - t r a i n i n g 90% of maximal VO2 (WL-90) decreased s i g n i f i c a n t l y f o r only the WJ group (122 ± 22.2 t o 114 ± 19.0 bpm, P < .05). The CT group demonstrated HR decrease o f 126 ± 29.6 to 120 ± 29.5 bpm, ( n o n - s i g n i f i c a n t ) , w h i le the LC group had an i n c r e a s e i n HR at t h i s workload (Table 3.8, F i g u r e 3.7). 52 There were "no d i f f e r e n c e s i n RPP at WL-90 f o r a l l t h r e e groups, although t h e r e was a t r e n d f o r s m a l l e r v a l u e s f o r the WJ and CT groups on p o s t - t e s t i n g . At a WL r e p r e s e n t i n g 70% of p r e - t e s t i n g maximum, only the CT group demonstrated a decrease i n RPP from 17.57 ± 4 . 5 4 to 16.10 ± 3.27 mmHgXHR X 1 0 - 3 (P < . 0 5 ) . The l e v e l s o f s y s t o l i c b l o o d p r e s s u r e (SBP) were unchanged at WL 70 f o r a l l groups, but the l e v e l of peak SBP was s i g n i f i c a n t l y i n c r e a s e d a f t e r t r a i n i n g o n l y i n the WJ group (166.62 ± 18.23 to 184.62 ± 24.35 and 160.80 ± 30.45 t o 168.80 ± 34.60 mmHg, f o r WJ and CT, r e s p e c t f u l l y . The LC d i d not demonstrate an i n c r e a s e i n SBP at peak e x e r c i s e a f t e r t r a i n i n g . 53 Table 3 . 8 Heart Rate and Blood Pressure Responses During Gated Bloodpool RNA Exercise Testing Variable Group Pre (Mean, SD) Post (Mean, SD) Resting HR (bpm) WJ 57 9.3 59 10. 6 CT 73 11.1 69 12. 8 LC 65 17.4 64 10. 7 HR WL-7 0 (bpm) WJ 104 16.9 101 16 .1 CT 116 27.9 107 22 .5 * LC 100 18.2 98 13 .8 * P < .05 pre vs. post HR WL-90 (bpm) WJ 122 22.1 114 18 .9 CT 126 29.6 120 29 .5 * LC 109 18.7 117 20 .5 * P < .05 pre vs. post SBP WL-70 (mmHg) WJ 166. 6 18.23 174 .5 24 . 96 CT 160.8 30.45 166 .4 28 . 90 LC 153.1 25.50 169 .0 9. 540 SBP peak WL WJ 166.6 18.23 184 .6 24 .35 * ¥ (mmHg) CT 160.8 30.45 168 .8 34 . 60 LC 153.1 25.50 153 .0 26 .13 * P < .02 ¥ P < .05 vs. LC • RPP WL-7 0 (mmHg x bpmXIO"3) WJ 16.40 4.02 16. 03 3. 87 CT 17.57 4.54 16. 10 3. 27 * LC 14.53 3.33 15. 15 1. 85 * P < .01 pre vs. post RPP peak WL (mmHg x bpmXIO-3) WJ 20.51 5.54 23. 44 19 .9 * CT 20.34 5. 99 21. 25 6. 84 LC 16. 64 4.05 15. 94 4. 80 * P < .01 pre vs. post Figure 3.7 Alterations in Submaximal Heart Rate After Training Rest WL-70pre Absolute Workload WL-90pre # P < 05 M2i WJ-pre 777X CT-pre ZZ} LC-pre C3 WJ-post C2 CT-post LC-post 55 3 . 4 . 3 E j e c t i o n Fraction and Absolute Cardiac Chamber Volumes A f t e r Exercise Training. R e s t i n g LVEF i n c r e a s e d s i g n i f i c a n t l y i n the WJ group from 46.4 ± 0.08 to 52.7 ± 0.09% (P < . 0 0 1 ) . There were a l s o s i g n i f i c a n t d i f f e r e n c e s between the WJ group w i t h CT and LC groups wi t h r e s p e c t t o r e s t i n g LVEF (P < .05) . At the same abs o l u t e workload r e p r e s e n t i n g the p r e - t r a i n i n g 90% l e v e l (WL 90) , only the WJ group i n c r e a s e d LVEF; upon p o s t - t e s t i n g , at t h i s submaximal e x e r c i s e l e v e l , LVEF was 65.8 ± 0.11% compared wit h 53.3 ± 0.11% at t h i s same WL p r e - t r a i n i n g (P < . 0 0 1 ) . The CT group a l s o i n c r e a s e d LVEF at WL- 90, but the change was not s i g n i f i c a n t (Table 3 . 9 , F i g u r e 3 . 8 ) . Peak LVEF i n c r e a s e d i n both the WJ and CT groups, wi t h the magnitude of change g r e a t e r f o r the WJ group (53.3 ± 0.11 t o 64.8 ± 0.10%, and 50.7 ± 0.12 to 55 .3 ± 0.11%, P < .001, and P < .02 , r e s p e c t i v e l y ) . When Peak LVEF was p l o t t e d a g a i n s t peak SBP, t h e r e was an upward and r i g h t s h i f t f o r the WJ and CT groups, but not f o r the LC group, i n d i c a t i n g improved c a r d i a c f u n c t i o n when an estimate o f a f t e r l o a d (using SBP) i s taken i n t o account (Figure 3 . 9 ) . There was no s i g n i f i c a n t c o r r e l a t i o n between peak LVEF and VC^peak f o r the groups combined (r = . 2 3 ) . 56 Table 3 . 9 Changes i n Ejection Fraction a f t e r Exercise Training Variable Group Pre (Mean, SD) Post (Mean, SD) LVEFrest (%) WJ 46.4 0.08 52.7 0.09* ¥ CT 44 .4 0.11 45.2 0.09 LC 43.0 0.08 40.0 0.06 * p < .001 pre vs. post ¥ P < .05 vs. LC LVEF-WL 90 ( %) WJ 53.3 0.11 65.8 0.11 '* ¥ CT 50.7 0.12 54.1 0.12 LC 47.9 0.01 45.0 0.06 * P < .001 pre vs. post ¥ P < .05 vs. CT, : LC LVEFpeak (%) WJ 53.3 0.11 64.8 0.10 * f CT 50.7 0.12 55.3 0.11 ¥ LC 47.9 0.08 46.7 0.09 * P < .001, ¥ P < .02 pre vs. post f P < .05 v s . CT, LC Data for SV (rest, WL-90, WL-90post), CO (WL-90post), LVESV, and LVEDV (WL-90, WL-90post) are presented i n Table 3.10. Resting CO (Figure 3.10) increased, but non- s i g n i f i c a n t l y i n the WJ and CT groups a f t e r exercise t r a i n i n g , with the LC group demonstrating no change. (3.43 ± 0.58 to 4.68 ± 1.02, 4.23 ± 1.06 to 5.16 ± 0.73, and 4.15 ± 1.51 to 4.23 ± 0.70, res p e c t i v e l y ) . 57 Submaximal CO (WL-90) was i n c r e a s e d a f t e r t r a i n i n g f o r only the WJ group from 12.20 ± 3.27 to 15.54 ± 4.54 l - m i n - 1 , (P < .05) and was g r e a t e r than the CT group, and s t a t i s t i c a l l y g r e a t e r than the LC group. At peak e x e r c i s e (WL-90post v s . WL-90) ,. CO i n c r e a s e d s i g n i f i c a n t l y f o r both the WJ and CT groups t o 15.54 ± 4.45 and 14.27 ± 6.37 l - m i n - 1 (P < .03) (Figure 3.10). CO at WL-90 and WL-90post were s i g n i f i c a n t l y c o r r e l a t e d w i t h TPR (r = -.67, P <. 0001, and r = -.66, P < .0007) . 58 Table 3.10 Changes i n L. Ven t r i c u l a r Volumes Af t e r Exercise Training Variable Group Pre (Mean, SD) Post (Mean, SD) SV Rest (ml) WJ 62.80 . 11.9 80.52 - 19.9 * CT 59.84 18.9 77.72 18.9 LC 64.53 17.9 67.61 12.8 * P < .05 pre vs . post SV WL-90 (ml) WJ 101.23 22.6 ¥ 127.87 42.9 * CT 88.10 36.9 109.59 49.0 LC 89.60 34.0 79.20 51.9 * P < .02 pre vs . post ¥ P < .05 vs. CT, LC SV peak (ml) WJ 101.23 22.6 125.71 34.4 * (WL-90post CT 88.10 36.9 118.21 46.9 * vs. WL-90pre) LC 89.56 34.1 86.03 34 . 4 * P <• .02 pre vs . post CO peak (l-min - 1) WJ 12.20 3.27 ¥ 15.54 4.45 * (WL-90post vs. CT 11.03 5.06 14 .27 6.37 * WL-90pre) LC 9.88 4.62 8.60 3.74 * P < .05 pre vs . post ¥ P < .05 vs. LC LVESV WL-90 (ml) WJ 93. 97 40.6 70.11 35.80 CT 84 .17 32.8 86. 64 20.20 LC 103.10 41.9 88.93 51.35 * P < .01 pre vs . post LVESV peak (ml) WJ 93. 98 40.6 72.39 33.40 (WL-90post vs. CT 84.17 32.8 91.06 , 25. 90 WL-90pre) LC 103.10 41. 9 95. 94 38.40 * P < .03 pre vs . post LVEDV WL-90 (ml) WJ 195.20 51.5 197.97 66.1 CT 172.27 54.4 196.24 54.6 LC 192.62 72.8 168.10 102.9 LVEDV peak (ml) WJ 198.20 51.5 198.10 59.0 (WL-90post vs. CT 172.27 54.4 209.30 64 .7 WL-90pre) LC 192.60 72.8 182.00 64 .4 59 Stroke volume was s i g n i f i c a n t l y greater at a l l l e v e l s (rest, WL-90, peak) i n the WJ group after t r a i n i n g , with only peak SV s t a t i s t i c a l l y greater after t r a i n i n g i n the CT group. The LC group did not display any changes at any l e v e l . Resting SV increased from 62.8 ± 11.99 to 80.50 ± 19.9 ml (P < .02) in the WJ group, and non-s i g n i f i c a n t l y i n the CT group ( 59.84 ± 18.87 to 77.72 ± 18.9 ml). At WL-90, SV increased i n the WJ group from 101.23 ± 22.6 to 127.87 + 42.9 ml (P < .02), and t h i s change was greater than for the CT and LC groups (P < .05). At peak exercise le v e l s (WL-90post), the WJ group decreased from the value at . pre-training (WL-90) (125.71 ± 34.4 vs. 127.87 ± 42.9) but was s t i l l s i g n i f i c a n t l y greater than pre- t r a i n i n g peak leve l s (125.71 ± 34.4 vs. 101.23 ± 22.60 ml (P < .02). The CT group increased peak SV from 88.10 ± 36.95 to 118.21 ± 46.98 ml (P < .02). When an i n d i r e c t estimate of afterload (TPR) was plotted against changes i n peak and submaximal SV from pre to post-training, the curves s h i f t e d upwards and to the right for the two t r a i n i n g groups (Figures 3.11, 3.12), suggesting improved c o n t r a c t i l e function. TPR (WL-90) however, s i g n i f i c a n t l y correlated with WL-90 SV (r = -.69, P < .003, Figure 3.13). When plot t e d against TPR for rest, WL-70, WL-90post, SV s h i f t e d upwards and to the l e f t for each group except the LC group at peak exercise (Figure 3.14). 60 There were no s t a t i s t i c a l l y s i g n i f i c a n t r e d u c t i o n s i n LVESV at WL-7 0 f o r any group, but at WL-90 and peak l e v e l s , LVESV decreased s i g n i f i c a n t l y i n only the WJ group a f t e r t r a i n i n g (93.97 ± 40.6 t o 70.11 ± 35.8 ml at WL-90 [P < .01], and 93:98 ± 40.55 t o 72 .39 ± 33.42 ml at WL-90post [P < .03]). Peak TPR was m i l d l y c o r r e l a t e d t o peak LVESV f o r combined groups (r = -.42, P < .05). The p l o t of changes i n LVESV a g a i n s t SBP demonstrated a s h i f t upwards and t o the l e f t f o r the WJ group, i n d i c a t i n g an improvement i n v e n t r i c u l a r emptying a g a i n s t a g r e a t e r a f t e r l o a d (Figure 3.15).. L V E D V i n c r e a s e d from r e s t t o peak e x e r c i s e at p o s t - t e s t i n g f o r the WJ group only (154.70 ± 33.4 t o 198.10 ± 59.0 ml, P < .002). There was no change i n L V E D V at WL-90 e x e r c i s e l e v e l s f o r the WJ group (195.20 ± 51.5 vs. 197.97 ± 6 6 . 1 0 ml or at the new peak l e v e l (WL-90post) 198.10 ± 59.0 v s . 198.20 ± 51.5. The CT group however, d i s p l a y e d a t r e n d towards i n c r e a s i n g L V E D V at these two l e v e l s of e x e r c i s e (172.27 ± 54.4 v s . 196.24 ± 54.6 ml (WL-90), and 172.27 ± 54.4 v s . 209 .30 ± 64.7 ml (WL-90post) (P < .07). TPR at both l e v e l s o f e x e r c i s e (WL-90 and peak) was s i g n i f i c a n t l y and n e g a t i v e l y c o r r e l a t e d w i t h LVEDV (r = -.67, P < .0004, r = - .69, P < . 0003) . In F i g u r e 3.16, LVEDV f o r r e s t and t h r e e e x e r c i s e l e v e l s i s p l o t t e d a g a i n s t LVSW to assess the c o n t r i b u t i o n s of the F r a n k - S t a r l i n g Mechanism t o v e n t r i c u l a r performance. <x> 70 66 60 66- U. 60- LU >, 45 40 35 30 WJ group Figure 3.8 Ejection Fraction Before After Exercise Training CT group o p < 05<vs.CT, LC) • P < .001 • P < .02 LC group a pre • post 62 Figure 3.9 Peak Ejection Fraction vs. Peak Systol ic BP After Exercise Training 70- 6 0 - >, 50 C L 40 30 130 140 150 160 170 180 190 Systol ic BloodPressure (mmHg) 200 . P • P p < .001 05 vs.CT, LC WJ • CJ 0 LC _ : 02 c.05 (SBP) 20 n F i g u r e 3 . 1 0 C a r d i a c O u t p u t B e f o r e a n d A f t e r E x e r c i s e T r a i n i n g 18H e p < . 0 5 v s . W L - 9 0 p r e +. p < .05 v s . L C Rest WL-50 WL-70pre Workload WL-90pre WL-90post WJ pre • WJ post • CT pre O CT post A LC pre X LCj>ost 64 Figure 3.11 Change in Submaximal Stroke Volume vs. Systolic Blood Pressure 180-, » P •= .02 (SV ) * P < 05 vs. CT, LC 65 Figure 3.12 Changes in Stroke Volume vs. Systolic Blood Pressure Before, After Training 190-1 180 X E E CO CD Q . D_ CO. CO 170 160 1 5 o ^ 140 -20 -10 10 SV (ml) 20 30 • WJ • CT • LC _ # P < . 0 2 ( S V ) * P < . 0 2 ( S B P ) P < . 0 5 ( S B P ) FIGURE 3.13 S t r o k e Volume (WL-90) v s . T o t a l P e r i p h e r a l R e s i s t a n c e (WL-90) 0 . 0 0 . 1 0 . 2 0 . 3 O.t 0 . 5 0 . 6 0 . 7 0 . 8 0 . 9 1.0 1.1 1.2 1.3 1.4 I . G T o t a l P e r i p h e r a l R e s i s t a n c e (TPR U n i t s ) Figure 3.14 Changes in Stroke Volume vs. Total Peripheral Resistance After Exercise Training 140-| 1 3 0 - 120 - 110- E ioo- o > a) o i _ •t—' CO 90H 80- 70- 60- If. + P < .02 + P < .05 (vs. LC) 5 0 - 1 — r i — i — i — i — i — i —r~ 0 . 8 0 . 9 1 1.1 1.2 1.3 1.4 1.5 1.6 Rest i i i i i i i i i i i i O.23.aD.4D.83.60.70.a3.9 1 1.11.21.3 WL-90pre TPR — i — i — T — i — i — i — i — i — i — r 0 .10.20.30.40.B0.60.70.80.9 1 WL-90post • yvj • CJ • LC _ 68 Figure 3.15 Changes in End-Systolic Volume vs. Systolic Blood Pressure at Peak Exercise 210-i 200 190 E 180- £ CD <D D. 170-0_ CO. CO 160 150 140 + P <= .05 (SBP) * P < .03 (LVESV) E WJ 30 I -20 I I I -10 0 10 LVESV (ml) i 20 • • CT LC _ 69 3 . 4 . 4 Derived Measures of L. Ven t r i c u l a r Function; E f f e c t s of Exercise Training S y s t o l i c Blood Pressure/LVESV r a t i o (P/V Ratio) WL-90 increased but non-s i g n i f i c a n t l y i n the WJ group from 2.19 ± 0.88 to 3.53 ± 1.08 mmHg/ml"1 (P < .08) af t e r t r a i n i n g . There were no changes for the CT or LC groups (Table 3.11, Figure 3.17). At WL-90post, P/V r a t i o declined i n a l l groups, with the WJ group demonstrating a non-significant increase i n t h i s variable pre vs. post (Peak P/V r a t i o = 2.19 ± 0.88 to 3.48 ± 2.78 (P < .06). Left V e n t r i c u l a r Stroke Work (LVSW) increased s i g n i f i c a n t l y at the WL-90 l e v e l i n the WJ group (154.45 ± 34.76 to 196.41 ± 72.51 g-m, P < .04), and increased, but no n - s i g n i f i c a n t l y in the CT group ( 136.38 ± 71.70 to 168.98 ± 92.83 g-m ), with the . LC group demonstrating a decline i n LVSW at peak exercise a f t e r low-intensity t r a i n i n g . Comparison of pre vs. post peak LVSW, demonstrated s i g n i f i c a n t improvements for both the WJ and CT groups with a decline i n the LC group. The WJ group improved at peak exercise (WL-90post) from 154.45 ± 34.6 to 200.35 ± 54.4 g-m (P <.001), with the CT group improving to a lesser extent from 136.38 ± 71.7 to 183.33 ± 90.91 g-m (P < .01) (Figure 3.16). TPR was rela t e d to LVSW at both WL-90 and WL-90post exercise l e v e l s ( r = - .58, P < .001, r = -.62, P < .002) (Figure 3.18). 70 An i n d i r e c t measure of c o n t r a c t i l e f u n c t i o n , E j e c t i o n Rate (ER) was improved only i n the WJ group at WL-90 (2.81 ± 0.67 vs. 3.06 ± 0.59 EDV/Sec. - 1), but n o n - s i g n i f i c a n t l y . There were no changes i n ER a f t e r t r a i n i n g i n e i t h e r the CT or LC group. At peak e x e r c i s e l e v e l s a f t e r t r a i n i n g , o n l y the WJ group demonstrated a s i g n i f i c a n t change i n ER (2.81 ± 0.67 vs. 3 \ 3 3 ± 0.90 EDV/Sec - 1 (P < .01), which was a l s o s i g n i f i c a n t l y g r e a t e r than the CT group (P < .05). The LC group demonstrated a s i g n i f i c a n t l y r e d u c t i o n i n ER from 2.26 ± 0.55 t o 1.98 ± 0.64 EDV/Sec - 1 (P < .05). For a l l groups pooled, ER at WL-90 was p o s i t i v e l y c o r r e l a t e d w i t h LVEF WL- 90 (r = .85, P < .0001), as was SV at t h i s e x e r c i s e l e v e l ( r = .50, P < .02) . The e s t i m a t i o n o f d i a s t o l i c f i l l i n g , F i l l i n g Rate (FR) i n c r e a s e d m a r g i n a l l y at WL-90 f o r only the WJ group a f t e r t r a i n i n g (3.15 ± 0.99 vs. 3.45 ± 1.03 E D V / S e c - 1 ) , and i n c r e a s e d s i g n i f i c a n t l y at peak e x e r c i s e pre v s . post (WL-90 vs . WL-90post) i n only the WJ group (3.15 ± 0.99 v s . 3.72 ± 1.33 EDV/Sec - 1 (P < .01). P/V R a t i o was c o r r e l a t e d w i t h FR WL-90 and FR peak ) r = .55, P <.007). T o t a l P e r i p h e r a l R e s i s t a n c e (TPR) was reduced with i n c r e a s i n g l e v e l s of e x e r c i s e f o r a l l groups, but r e v e r s e d s l i g h t l y at peak e x e r c i s e l e v e l s . At the WL-90 l e v e l a f t e r t r a i n i n g , the WJ and CT groups demonstrated reduced TPR; 0.558 ± 0.13 t o 0.485 ± 0.13 and 0.678 ± 0.34 t o 0.551 ± 0.13 PRU's f o r WJ and CT groups, (P < .02, P < .05) 71 respectively) (Table 3.12). TPR was also reduced at peak exercise post-training (WL-90 vs. WL-90post) i n the WJ and CT groups; 0.558 ± 0.13 to 0.466 ± 0.12 (P < .03), and 0.678 ± 0.34 to 0.496 ± 0.15 ( P < .09), and 0.722 ± 0.27 to 0.941 ± 0.74 PRU for the WJ, CT, and LC groups, respectively (Table 3.12) . Table 3.11 Alt e r a t i o n s i n Total Peripheral Resistance: E f f e c t of Exercise Training Variable Group Pre (Mean, SD) Post (Mean, SD) TPR WL-90 WJ 0.558 0. 13 0.485 0.13 * f (PR units) CT 0.678 0. 34 0 .551 0.13 * f LC 0.722 0. 27 1.22 1.16 * P < .02 pre vs. post f P < .05 vs. LC• TPR peak WJ 0.558 0. 13 0.466 0.12 * (WL-90post CT 0.678 0. 34 0.496 0.15 vs. WL-90) LC 0.722 0. 27 0.941 0.74 (PR units) * P < .03 pre vs. post 72 Table 3.12 Derived L. Ven t r i c u l a r Function Variables; E f f e c t of Exercise Training Variable Group Pre (Mean, SD) Post (Mean, SD) P/V Ratio WL-90 WJ 2.19 0.88 3.53 0.08 (mmHg/ml) CT 2.25 1.03 2.07 0.83 LC 1.97 0.94 2.87 2.41 P/V Ratio peak WJ 2.19 0.88 3.48 2.78 (mmHg/ml) CT 2.25 1.03 2.04 0. 97 LC 1.97 0.94 2.13 1.71 LVSW WL-90 WJ 154.45 34.8 196.41 72 .5 * (g-m-'i) CT 136.38 71.7 168.98 92 .8 LC 130.29 47.9 117.91 77 .2 * P < . 04 pre vs. post LVSW peak WJ 154.45 34. 6 200.35 54 .4 * (g-m J) CT 136.38 71.7 183.33 90 .1 ¥ LC 130.30 47.9 124.00 53 .43 * P < .001 ¥ P < .01 pre vs. post Peak Ejection Rate (EDV/Sec - 1) WJ 2.81 0.67 3.33 0.90 * f CT 2.85 0.81 2.71 0.93 LC 2.26 0 .55 1.98 0.64 ¥ * P '< .01, ¥ P < .05 pre vs. post f P < .05 vs. CT, : LC. Peak F i l i n g Rate (EDV/Sec - 1) WJ 3.15 0.99 3.72 1.33 * ¥ CT 2.88 0.81 2.95 0.87 LC 2.37 0.51 2.01 0.59 * P < .01 pre vs. post ¥ P < .05 vs. LC. Figure 3.16 Changes in Stroke Work and LVEDV After Exercise Training r- 220- 200- 180- 160- E 6) co > 140- 120- 100- 80- 80- 40- wl-90post - ' 90 •*«mv(i ' • q w i - hwl -70 4 I / ^flwl-90 • • w l - 9 0 p o s t oWl-90 Qwl-70 4 , p -= .001 vs.wl-90pre(LVSW) • P < .002 v s . r p o s t (LVEDV) • P < .04 vs wl-90 p r e (LVSW) • P -c .01 vs wl-90 p r e (LVSW) 20- 130 150 170 190 210 WJ group — I 1 1 1 1 1 1— 120 140 160 180200220240 CT group LVEDV (ml) 120 140 160 180 200 220 LC group • pre • post Figure 3.17 Systolic Blood Pressure/LVESV Ratio After Exercise Training • p < .06 vs. WL-70 * p - c .06 vs. VVL-90p r e p < .06 vs.WL-90pre Exercise Workloads .lOPc ,90P • WJ pre • WJ post • CJ pre 0 CTjjost A LC pre X LC post  76 4 . 0 Discussion 4 . 1 Body Composition The f a i l u r e to lower body fat lev e l s contrasts with the majority of the l i t e r a t u r e i n t h i s area (Kavanagh et a l . , 1973, H e l l e r s t e i n , 1973) . A lowering of body fat would reduce the external work required during work or exercise, and thus lower myocardial 0 2 consumption for the same given l e v e l of work. In theory, t h i s concept i s p h y s i o l o g i c a l l y correct, providing there i s a p o t e n t i a l for considerable body fat loss i n i t i a l l y . This group of subjects however, displayed average body fat leve l s compared to large populations at pre-testing, and thus further reductions i n body fat might have been u n r e a l i s t i c for subjects who could have achieved most of the p o t e n t i a l body fat losses immediately aft e r the MI due to changes i n d i e t / l i f e s t y l e . On WHR scores, the data reveals that a l l the subjects ranked i n the top 90 to 9 5 t n percentile for the 50 to 50 age-group (Mean for the three groups at pre-testing = .79). The mean sum of 5 skinfolds (SOS) for a l l groups on pre-testing was 64.9 mm, i n the 3 5 t n percentile for the general population, but outside the "health r i s k zone", where increased r i s k for CAD and diabetes i s most correlated (Lapidus et a l . , 1984). 77 Other f a c t o r s t o c o n s i d e r i n the f a i l u r e of body composition t o change are the time frame from MI or surgery t o the onset of e x e r c i s e t r a i n i n g ; many changes i n body composition can take p l a c e d u r i n g h o s p i t a l stay (mainly an i n c r e a s e i n f a t to muscle mass r a t i o ) due to c h r o n i c bed r e s t . I f p r e - t e s t i n g measurements are taken at t h i s p o i n t , the apparent body f a t l o s s e s c o u l d be h i g h l y exaggerated. Secondly, the e x e r c i s e t r a i n i n g programs, although s u f f i c i e n t t o provoke i n c r e a s e s i n a e r o b i c f i t n e s s , were probably too sh o r t i n d u r a t i o n / s e s s i o n t o a f f e c t weight l o s s i n a group of p a t i e n t s w i t h a l r e a d y normal body f a t l e v e l s . Impressive f a t l o s s e s have only been recorded i n CAD p a t i e n t s who t r a i n e x t e n s i v e l y , such as marathon running (Blessey et a l . , 1981, Kavanagh et a l . , 1974). 4 . 2 Blood L i p i d s A l t e r a t i o n s i n c h o l e s t e r o l and i t s s u b f r a c t i o n s has been w e l l documented i n the h e a l t h l y p o p u l a t i o n , but a l s o i n e x e r c i s i n g c a r d i a c p a t i e n t s . The p a t i e n t s i n t h i s study had t o t a l c h o l esterol/HDL-C r a t i o s above what would be c o n s i d e r e d d e s i r a b l e f o r t h i s p o p u l a t i o n (values below 4.5 r e p r e s e n t i n g reduced r i s k ) . The r e s u l t s o f t h i s study c o n f l i c t w i t h other s t u d i e s which have demonstrated i n c r e a s e s i n HDL-C and/or r e d u c t i o n s i n the T o t a l Cholesterol/HDL-C r a t i o . S t r e j a and co-workers (1979) 78 observed a s i g n i f i c a n t increase i n HDL-C, which has been associated with reduced CAD r i s k and linked with an a r t e r i a l plaque "scavenging" e f f e c t as well i n healthly and a t - r i s k populations. Their patients increased HDL from 35 to 39 mg/dL afte r 13 weeks of t r a i n i n g , which however, f a i l e d to induce a t r a i n i n g e f f e c t . None of the exercise groups i n t h i s study demonstrated an increase i n either HDL, or a decrease i n total-cholesterol/HDL r a t i o , and LDL-C, despite an increase i n f i t n e s s l e v e l s for the WJ and CT groups. Heath et a l . , (1983) also demonstrated a decrease (9%) and and increase (11%) i n LDL-C and HDL-C respectively, a f t e r t r a i n i n g , and the change i n LDL vs. change i n VC^peak was s i g n i f i c a n t l y related (r = -.73). In our patients, the rel a t i o n s h i p of VC^peak to HDL-C was not as strong, but s i g n i f i c a n t , (r = .45, P < .01), s t i l l i n d i c a t i n g that aerobic f i t n e s s i s related to HDL-C l e v e l s . A study by Erkelens et a l . , (1979) also demonstrated an increase i n HDL-C i n 83 t r a i n i n g CAD patients from 35 to 40 mg/dL, but found that a f t e r 6 months, there was no further increase i n HDL-C. As our patients were r e c r u i t e d 4 -6 months afte r MI, i t i s possible that maximal changes i n l i p i d s had already been attained by dietary changes that subsequent exercise and the lack of cont r o l l e d diet changes were unable to a f f e c t . Thus, these results seem to indicate that without dietary manipulation i n these patients, r e l y i n g 79 e n t i r e l y upon exercise to improve l i p o p r o t e i n p r o f i l e s seems to be i n e f f e c t i v e . There i s documentation however, of l i p i d s remaining unchanged, even i n normal individuals a f t e r exercise t r a i n i n g which produced an increase i n VC^max. (A l l i s o n et a l . , 1981). These authors linked the f a i l u r e of a HDL-C increase to a f a i l u r e of TG to also reduce. Upon further analysis, i t i s revealed that i n our patients, TG was reduced i n a l l groups (20% i n WJ, 6 % i n CT, and 20% i n LC). Thus i n our patients, the i n a b i l i t y for HDL-C to increase must be rela t e d to other factors which can influence HDL and LDL-C, namely alcohol intake, diet, exercise i n t e n s i t y , duration, and i n i t i a l f i t n e s s l e v e l . Some l i t e r a t u r e has linked the fat deposition and body composition to blood l i p i d changes (Ribeiro et a l . , 1984, Melish et a l . , 1978). In the f i r s t study, the authors demonstrated that only i n the CAD patients that recieved dietary counselling and exercise (vs. exercise only), did body fat leve l s and t o t a l cholesterol l e v e l s decline. However, i n t h e i r study, HDL-C leve l s were unchanged i n both groups a f t e r exercise. The Melish study demonstrated a s i g n i f i c a n t decline i n LDL-C in normals subjects, with a s i g n i f i c a n t r e l a t i o n s h i p between the^ change i n LDL-C and a decline i n adiposity. 80 In our group of subjects, Waist-Hip r a t i o was negatively related to HDL-C, in d i c a t i n g some degree of association with body composition. Thus, the mechanisms of t h i s l i n k between body fat and blood l i p i d s needs further i n v e s t i g a t i o n and research. An additional factor to consider i n evaluating the complex in t e r r e l a t i o n s h i p s between l i p i d s , diet and exercise, i s that there exists s i g n i f i c a n t r e l i a b i l i t y and v a r i a b l i l i t y problems i n the measurement procedures (Superko et a l . , 198 6) . Any s i g n i f i c a n t changes i n HDL-C could be masked by the wide i n t e r and intra-laboratory measurement and qual i t y control measures which have not been adequately standardized in Canada and the U.S. F i n a l l y , i t must be emphasised that the actual measures themselves are s t i l l c ontroversial; the subfractions of HDL, HDL2 and HDL3 have been i d e n t i f i e d recently, and have d i f f e r i n g metabolic r o l e s . The HDL2 unit has been i d e n t i f i e d as the cardioprotective unit, with the HDL3 unit being non- protective, but p o s i t i v e l y correlated with alcohol consumption. Also, the apolipoproteins associated with HDL and LDL (Apo A-I, A-II) have been recently i d e n t i f i e d more strongly with atherogenisis r i s k than the lipoproteins themselves (Superko et a l . , 1986). The u n a v a i l a b i l i t y of the measurements of these l i p o p r o t e i n subfractions and t h e i r 81 r e l a t e d a p o l i p o p r o t e i n s renders t h i s a l i m i t a t i o n i n t h i s aspect o f the study. 82 4.3 Lower and Upper Extremity Aerobic Capacity 4.3.1. Lower Extremity Changes i n Aerobic Capacity The values obtained for peak VO2 for the arm and cycle ergometry are probably 7-8% lower than what would be found for treadmill work, due to less muscle mass involved (Shephard, 1984). However, the variations i n e f f i c i e n c y for c y c l i n g demonstrates a much lower value than for treadmill walking, eliminating any bias that might have occurred for the CT group, since they were the only group that performed cycle ergometry during t r a i n i n g . The advantages of cycle ergometery t e s t i n g are more e a s i l y measured and r e l i a b l e s y s t o l i c blood pressures, and equal RPP for the two modes (Wicks et a l . , 1978), suggesting that the patients responses could be v a l i d l y compared and equated to t h e i r medical and ph y s i o l o g i c a l status. The increases i n cycle VC>2peak i n both the WJ and CT groups i s consistent with changes found i n the l i t e r a t u r e a f t e r exercise t r a i n i n g . A search of the l i t e r a t u r e demonstrates that d i r e c t l y measured VC^peak values increase from 0 (Sullivan et a l . , 1985) to 46% (Hagberg et a l . , 1983), with the 13.1 and 9.7% (for WJ and CT groups, respectively) increases for the two groups of patients i n t h i s study representing an average increase i n functional capacity. 83 Detry et a l . , (1971) demonstrated 21% improvements, as d i d groups of p a t i e n t s from the Toronto R e h a b i l i t a t i o n Centre (Kavanagh et a l . , 1973). A s e l e c t group of marathoning CAD/Post-MI p a t i e n t s from Kavanagh's p a t i e n t program have r e p o r t e d v a l u e s o f 43.5 m l ' k g - 1 - m i n - 1 , wi t h up t o 55% i n c r e a s e s , but u s i n g estimated VC^max (using a nomogram). I t i s noteworthy t h a t the s t u d i e s t h a t were p r i m a r i l y intended t o demonstrate i n t r i n s i c changes i n c a r d i a c f u n c t i o n a f t e r t r a i n i n g a l s o demonstrated the l a r g e s t i n c r e a s e s i n VO2 (Ferguson et a l . , : 41%, Hagberg et a l . , : 46%) . To ensure t h a t VC^max as opposed t o VC^peak has s i g n i f i c a n t l y improved however, RER and other p h y s i o l o g i c a l v a r i a b l e s must a l s o be c o n s i d e r e d i n the e x e r c i s e t e s t r e s u l t s (Roberts et a l . , 1984, T a y l o r et a l . , 1963). I t i s u n c e r t a i n i n some s t u d i e s whether RER and other i n d i c i e s of t r u e attainment of VC^max have been reached. CAD p a t i e n t s , p a r t i c u l a r l y those w i t h ischemic symptoms, w i l l o f t e n a t t a i n a h i g h e r VO2 upon r e - t e s t i n g due t o m o t i v a t i o n a l and p a t i e n t - p h y s i c i a n / t e s t e r i n t e r a c t i o n s (Taylor et a l . , 1963). Measurement of RER at peak e f f o r t w i l l o f t e n d i f f e r e n t i a t e between a t r u e VC^max or VC^peak. However, h i g h e r RER v a l u e s upon r e - t e s t i n g a f t e r a p e r i o d o f e x e r c i s e t r a i n i n g should not always r u l e out attainment of t r u e t r a i n i n g e f f e c t s ; some p a t i e n t s who have h i g h e r peak RER v a l u e s at p o s t - 84 t e s t i n g might have i n c r e a s e d t h e i r m y o c a r d i a l oxygen consumption c a p a b i l i t i e s , and thus are abl e t o work c l o s e r t o t h e i r t r u e VO^max be f o r e t e r m i n a t i o n of e x e r c i s e . On the other hand, some p a t i e n t s might be l i m i t e d by an e a r l y onset of anaerobic metabolism i n the working muscles, i n c r e a s i n g excess CO2 p r o d u c t i o n , and thereby i n c r e a s i n g RER at low e x e r c i s e i n t e n s i t i e s . However, i t would f o l l o w t h a t i n t h i s case, h i g h RER va l u e s would not be acccompanied by an attainment of a g e - p r e d i c t e d HRmax and a p l a t e a u i n g o f VO2 • C l e a r l y , i t i s apparent from t h i s d i s c u s s i o n t h a t t h i s i s s u e has not adequately been r e s o l v e d i n the c a r d i a c r e h a b i l i t a t i o n l i t e r a t u r e , and needs f u r t h e r examination. I t can be seen from the present data t h a t the t r u e c r i t e r i a f o r attainment o f VX^max (RER 1.15, a p l a t e a u i n g o f VO2 w i t h i n c r e a s i n g workload, a g e - p r e d i c t e d HRmax) were not accomplished due t o the u s u a l reasons a s s o c i a t e d w i t h t h i s medical c o n d i t i o n , and agreeing w i t h other data ( T a y l o r et a l . , 1963). However, the RER va l u e s were s i g n i f i c a n t l y unchanged at pre and p o s t - t e s t i n g , i n d i c a t i n g t h a t the m o t i v a t i o n l e v e l and p h y s i o l o g i c a l s t r e s s at peak e x e r c i s e d u r i n g both t e s t i n g s i t u a t i o n was s i m i l a r . Other parameters (maximal workload achieved, and RPPmax) a l s o i n d i c a t e a t r a i n i n g e f f e c t i n the WJ and CT groups, and an absence o f any e f f e c t i n the LC group. However, the LC group had lower v a l u e s f o r maximal WL, HR, and RPP at p r e - 85 t e s t i n g , s u g g e s t i n g t h a t they might have r e p r e s e n t e d a d i f f e r e n t group of p a t i e n t s . T h e i r i n c l u s i o n i n t o the LC group based upon the above l i s t e d c r i t e r i a (See Methods s e c t i o n ) c o u l d have been due t o a p r o g r e s s i o n o f t h e i r d i s e a s e , i n i t i a l l y poorer f u n c t i o n a l c a p a c i t y due t o more e x t e n s i v e myocardial d i s e a s e , or a g r e a t e r number and/or extent of coronary v e s s e l o c c l u s i o n . Since more d e t a i l e d medical r e c o r d s were not a v a i l a b l e on these p a t i e n t s , c o r r e l a t i n g i n f o r m a t i o n on the extent of coronary o c c l u s i o n and/or pe r c e n t of LV a f f e c t e d by the MI, t o c u r r e n t group c l a s s i f i c a t i o n was not p o s s i b l e . The o b s e r v a t i o n t h a t the s l i g h t l y g r e a t e r i n c r e a s e i n V 0 2 p e a k i n the WJ v s . the CT group i s probably a r e f l e c t i o n o f the g r e a t e r time spent performing lower limb t r a i n i n g i n the WJ group, compared to the CT group, who spread the t r a i n i n g time between the upper and lower e x t r e m i t i e s . I t i s i n t e r e s t i n g i n t h a t , although the CT group on the average spent between o n e - t h i r d and t w o - t h i r d s of the t r a i n i n g on lower e x t r e m i t y t r a i n i n g compared t o the WJ group, the i n c r e a s e i n VO2 f o r the WJ group was not s i g n i f i c a n t l y g r e a t e r . I t i s s p e c u l a t e d t h a t the s p e c i f i c i t y of walking and j o g g i n g became uncovered d u r i n g c y c l e t e s t i n g i n the WJ group, o f f s e t t i n g the reduced lower limb t r a i n i n g time f a c t o r . O v e r a l l , the p h y s i o l o g i c a l changes demonstrated are 86 consistent with improved functional capacity a f t e r exercise t r a i n i n g i n these patients. The fact that ST-segment depression at peak exercise did not decrease i n the WJ group, but did i n the CT group (.94 to .39 mm) would also suggest an exercise s p e c i f i c i t y e f f e c t , and a f a i l u r e i n the WJ group to increase peak myocardial oxygen consumption, using electrocardiography alone as a basis for t h i s i n t e r p r e t a t i o n . However, maximal RPP (as were many cardiac function parameters discussed later) was increased i n both groups, which would however indicate that a higher external workload and metabolic rate, and hence, an increased myocardial oxygen demand was indeed successfully achieved aft e r t r a i n i n g . It must be recognized that there e x i s t s a high fa l s e p o s i t i v e and fa l s e negative rate i n ECG evaluation, and these results i n i s o l a t i o n of other p h y s i o l o g i c a l variables, should be viewed with caution. Although the ST-segments were generally not depressed at submaximal work loads, reports of angina were also reduced at a given submaximal exercise l e v e l i n the two t r a i n i n g groups, thus agreeing with the c l a s s i c e f f e c t s of reduced myocardial O2 demand and symptoms of ischemia at a given external workload previously reported i n the l i t e r a t u r e (Clausen et a l . , 1969, Detry and Bruce, 1971, and Sim et a l . , 1974). Ventilatory threshold for c y c l i n g demonstrated improvements, 87 but only i n the WJ group when expressed as a b s o l u t e l-min 0 2 (Table 3.4). These f i n d i n g s are i n c o n t r a s t w i t h those by S u l l i v a n (et a l . , 1985), who f a i l e d t o demonstrate an a l t e r a t i o n o f VT a f t e r 12 months of e x e r c i s e t r a i n i n g , whether expressed as V E vs. VO2 or v e n t i l a t o r y e q u i v a l e n t f o r 02 - However, u n l i k e the present f i n d i n g s , the authors a l s o f a i l e d t o demonstrate an improvement i n VC^peak a f t e r e x e r c i s e t r a i n i n g i n t h e i r s u b j e c t s . Although the VT as expressed as percentage o f VC^peak or HRmax f a i l e d t o improve t o the same extent as expressed as ab s o l u t e V O 2 , the v a r i a b i l i t y of the measures c o u l d have rendered these changes n o n - s i g n i f i c a n t . As the m a j o r i t y of these p a t i e n t s were on some form o f Beta a d r e n e r g i c blockade medication, the VT's o c c u r r e d at r e l a t i v e l y h i g h e r percentages of HRmax than i s u s u a l l y found f o r normal or even a t h l e t i c s u b j e c t s . Increases i n VT have been p r e v i o u s l y documented i n normal middle-age males (Davis et a l . , 1979) (44% improvement i n ab s o l u t e VT) , but not i n e x e r c i s i n g CAD p a t i e n t s . Since the VT (absolute VO2) was c o r r e l a t e d w i t h VC^peak (r = .87), i t seems t h a t VT i s a parameter which a c c u r a t e l y d e s c r i b e s a e r o b i c f i t n e s s without the p i t f a l l s o f r e l y i n g upon "maximal" p h y s i o l o g i c a l v a l u e s . However, the r e l a t i o n s h i p becomes a l t e r e d , and i s flawed when percentages of HRmax and V 0 2 P e a k are compared, probably r e f l e c t i n g the a l t e r e d HR response due t o medi c a t i o n s . Since HRmax v a l u e s 88 are low due t o B e t a - a d r e n e r g i c b l o c k i n g medications, the p a t i e n t s w i t h the h i g h e s t r e l a t i v e VT's are those t h a t have a low VC^peak, (who t erminate the e x e r c i s e t e s t e a r l y ) and the p a t i e n t s w i t h the h i g h e s t f u n c t i o n a l c a p a c i t i e s (and VC^peak), have the lower r e l a t i v e VT's, s i n c e they t e r m i n a t e e x e r c i s e l a t e r . Thus i n e v a l u a t i n g the e f f e c t of e x e r c i s e t r a i n i n g on VT i n CAD p a t i e n t s on B e t a - a d r e n e r g i c blockade, only the VT expressed as an a b s o l u t e HR or VO2 s h o u l d be compared. 4.3.2 Changes i n Upper Extremity Aerobic Capacity Arm VC>2Peak f o r the groups r e p r e s e n t e d between 65 and 70% of l e g VC^peak. T h i s agrees with data from F r a n k l i n (1985), and A s t r a n d et a l . , (1965), who found s i m i l a r percentages i n t e s t i n g arms and l e g s i n both normal and c a r d i a c p o p u l a t i o n s . Schwade et a l . , (1977) found t h a t maximal arm workloads r e p r e s e n t e d approximately 41% t h a t of the l e g . We found t h a t t h i s percentage was lower, w i t h arms r e p r e s e n t i n g only 33% of l e g maximal workload. The s m a l l but s i g n i f i c a n t improvements i n arm ergometry VC^peak and workload were demonstrated i n the WJ group who d i d not t r a i n the arms (Table 3.5). The s m a l l r e d u c t i o n s i n submaximal HR f o r l e g e x e r c i s e a f t e r l e g t r a i n i n g was observed f o r both the WJ and CT groups, s i n c e they both t r a i n e d the l e g s . However, (although the d i f f e r e n c e s were 89 non-significant), a s l i g h t l y greater r e l a t i v e decrease i n submaximal arm HR at 25 W for the WJ group than that for the CT group, who did t r a i n the arms (Figure 3.6) was observed. It i s speculated that since the WJ group demonstrated the greater o v e r a l l t r a i n i n g e f f e c t (greater cycle VG^pea'k af t e r training) than the CT group, t h i s was r e f l e c t e d i n the greater but small transfer e f f e c t to the untrained limbs. The CT group's t r a i n i n g stimulus, spread over three r e l a t i v e l y discontinuous 10 minute sessions, each on a d i f f e r e n t apparatus, might not represent enough of a metabolic stress to uncover changes at submaximal workloads. McKenzie et a l . , (1978) and Savard et a l . , (1987) have suggested that the transfer e f f e c t i s greater from the trained, larger muscle mass to the' smaller untrained muscle mass than the reverse. It i s speculated that since i n the present study the WJ group spent a greater percentage of time t r a i n i n g with the larger muscle mass than the CT group, t h i s could have expedited t h i s transfer e f f e c t . The p o s s i b i l i t y that the WJ group could have derived some upper extremity t r a i n i n g e f f e c t due to the more vigourous use of the arms during walking and jogging can be ruled out, since the r e l a t i v e contribution of these limbs to the t r a i n i n g e f f e c t would be negligable i n active i n d i v i d u a l s at t h i s phase of r e h a b i l i t a t i o n . In addition, the CT group supplemented t h e i r t r a i n i n g with walking/jogging, and they too would therefore have benefited equally. 90 Another factor to consider i n explaining the r e l a t i v e l y small submaximal arm HR responses found i n t h i s study compared to other i n d i c i e s of arm f i t n e s s i s that many of these patients were on Beta-adrenergic and/or Calcium antagonist medications. This contrasts to most studies, where the patients were weaned o f f t h e i r medications during t e s t i n g . This most l i k e l y resulted i n lower absolute changes i n HR from rest to exercise and hence, would explain the f a i l u r e to uncover these changes at submaximal le v e l s of work. Nevertheless, the CT group s t i l l demonstrated the greater absolute increase i n arm VC>2Peak (13.2%) vs. the smaller but s i g n i f i c a n t transfer e f f e c t for the WJ group (7.0% increase i n arm VC^peak). These re s u l t s generally agree with other l i t e r a t u r e . The improvement i n arm VC^peak i n the CT group i s s i m i l a r to that found i n other studies. Wrisley (et a l . , 1983) found that patients who also balanced t r a i n i n g of the arms and legs improved arm and leg VC>2Peak 11 and 13%, respectively. Lewis et a l . , (1980) found a 9% transfer e f f e c t to the untrained arms in healthy normal subjects, as did ROsler et a l . , (1985). Clausen et a l . , (1973), found a 10% transfer e f f e c t to the untrained arms. Thompson and Cullinane (1981), studying t h i s possible transfer e f f e c t i n CAD/Post-MI patients, revealed an 8% improvement i n arm cranking a f t e r cycle t r a i n i n g only, but the t r a i n i n g e f f e c t 91 f o r the group who had the arms t e s t e d a f t e r arm e x e r c i s e t r a i n i n g was only 10%. The s p e c u l a t e d mechanisms f o r these t r a n s f e r e f f e c t s have been i n c r e a s e s i n c a r d i a c ( c e n t r a l ) f u n c t i o n , s u p p l y i n g a g r e a t e r c a r d i a c output t o the u n t r a i n e d limbs, changes i n catecholamines, a l t e r a t i o n s i n TPR, and most o f t e n c i t e d , i n c r e a s e s i n l a c t a t e (H +) u p t a k e / o x i d a t i o n by i n a c t i v e but t r a i n e d s k e l e t a l muscle, heart and kidney ( S a l t i n et a l . , 1976). ROsler et a l . , (1985) has argued t h a t the c e n t r a l h y p o t h e s i s can be r u l e d out s i n c e p o s t - t e s t i n g arm VC^peak i s o f t e n lower than p r e - t e s t i n g l e g VC>2, and t h e r e f o r e even b e f o r e t r a i n i n g , the c a r d i o v a s c u l a r system i s a l r e a d y able to support an i n c r e a s e d arm a e r o b i c c a p a c i t y . T h i s would agree wi t h the data i n t h i s study. In a d d i t i o n , the authors a l s o demonstrated no evidence f o r l o c a l b i o c h e m i c a l / u l t r a s t r u c t u r a l changes i n the u n t r a i n e d limbs. U n f o r t u n a t e l y , none of the aformentioned s t u d i e s have measured changes i n c a r d i a c f u n c t i o n a f t e r t r a i n i n g of e i t h e r the arms or l e g s . Reports on the p r e s e n t study's f i n d i n g s r e l a t i n g t o c a r d i a c f u n c t i o n appear i n a l a t e r s e c t i o n of t h i s d i s c u s s i o n . For arm ergometry, both the WJ and CT groups demonstrated improvements i n VT expressed as a b s o l u t e l e v e l of O2 consumption, as a percent of V 0 2 p e a k or as a percent of HRmax (Table 3.6). The demonstration of an i n c r e a s e i n arm 92 ergometry VT f o r the WJ group p a r a l l e l s the p r e v i o u s l y noted i n c r e a s e i n arm VC^peak, and f u r t h e r r e i n f o r c e s the f i n d i n g of a t r a n s f e r e f f e c t from the t r a i n e d t o the u n t r a i n e d l i m b s . The r e l a t i v e l y l a r g e r i n c r e a s e i n VT expressed as a b s o l u t e l - m i n - ! O2 f o r the CT group i s c o n s i s t e n t w i t h t h e i r g r e a t e r t r a i n i n g e f f e c t f o r arm e x e r c i s e , and r e p r e s e n t s the concept of s p e c i f i c i t y of e x e r c i s e t r a i n i n g . A l i m i t a t i o n i n t h i s study i n completely understanding the t r a i n i n g e f f e c t s of arm e x e r c i s e and the t r a n s f e r of f i t n e s s to the u n t r a i n e d limbs i n CAD p a t i e n t s , i s the l a c k of b l o o d p r e s s u r e measurements d u r i n g arm e x e r c i s e . As a r e s u l t , s y s t o l i c b l o o d p r e s s u r e , which would have g i v e n i n s i g h t s i n t o RPP and hence an i n d i r e c t estimate of m y o c a r d i a l oxygen consumption d u r i n g arm e x e r c i s e , was not p o s s i b l e . I t was f e l t t h a t the measurements u s i n g the p o p l i t e a l a r t e r y , or u t i l i z i n g a d i s c o n t i n u o u s t e s t p r o t o c o l were cumbersome, or p r e v e nted VT measurements, r e s p e c t i v e l y . F u r t h e r s t u d i e s s h o u l d i n v e s t i g a t e the p o s s i b l e use of newer microprocessor/automated BP u n i t s (which were u n f o r t u n a t e l y u n a v a i l a b l e f o r t h i s study) when t e s t i n g arm responses t o e x e r c i s e . 93 4.4 Cardiac Function 4.4.1 F i r s t Pass Radionuclide Angiography The data from t h i s study are consistent with the c l a s s i c finding that there are postural changes i n cardiac volumes from the supine to erect p o s i t i o n (Bevgard et a l . , 1960); SV decreased from 88 to 62 ml from supine to the erect p o s i t i o n . Owing to increased venous return due to reduction in the e f f e c t s of gravity, stroke volume i s enhanced i n the supine p o s i t i o n . As a result, there were no changes i n CO or SV i n t h i s p o s i t i o n due to the exercise t r a i n i n g intervention, since any changes i n cardiac performance would be masked by t h i s position, which would increase SV to near maximal values. 4.4.2 Gated Bloodpool Radionuclide Angiography Exercise: Submaximal Hemodynamic and HR Responses The f a i l u r e of resting HR to decline due to the t r a i n i n g e f f e c t c o n f l i c t s with some of the l i t e r a t u r e (Ehsani et a l . , 1986, Clausen et a l . , 1970, Kasch and Boyer, 1969). It should be emphasized however, that i n most studies, patients have been taken o f f beta adrenergic medication. Thus the p o t e n t i a l for demonstrating a resting bradycardia i s l i m i t e d i n these patients who have already blunted heart rate responses. Although some authors have demonstrated reduced 94 re s t i n g HR i n patients on Beta-blockade (Froelicher et a l . , 1985, Wilmore et a l . , 1985), i t has also been demonstrated i n many populations that VC^max i s poorly correlated with HR reduction at rest (Astrand and Rodhal, 197 6). The demonstration however of s i g n i f i c a n t (-5%) reductions i n HR at the submaximal exercise lev e l s at the pre-testing 70 and 90% of maximal leve l s (WL-70, WL-90) agrees with other findings, but i s less than commonly observed i n other l i t e r a t u r e (Hagberg et a l . , 1983, Sim and N e i l l , 1974, Detry et a l . , 1971, Fric k and K a t i l a , 1968). The 90% l e v e l might have represented too high a stress, even a f t e r t r a i n i n g to uncover greater changes i n HR for the two t r a i n i n g groups. The fact that only the CT group demonstrated a reduction i n RPP and HR at WL-70 probably r e f l e c t s t h e i r greater adaptive response due to the s p e c i f i c i t y of cycling, which the WJ group did not perform. On the other hand, the ov e r a l l increases i n fi t n e s s were s l i g h t l y greater for the WJ group, as previously documented. The greater peak RPP recorded af t e r t r a i n i n g r e f l e c t s t h i s adaptive response, despite the fact that t h i s group did not t r a i n using cycle ergometers. The increase i n maximal RPP agrees with findings of Sim and N e i l (1974), and Hagberg et a l . , (1983), and would suggest that the myocardial oxygen consumption has been augmented. Since i t has already been established that the increases i n VC^peak were not 95 a r t i f a c t u a l , these i n c r e a s e s ' i n RPPmax f o r the WJ group are due p r i m a r i l y t o i n c r e a s e s i n SBPmax, and would appear ( i n the absence o f f u r t h e r c a r d i a c data) t o re p r e s e n t changes i n the myocardial fj^supply/demand r e l a t i o n s h i p . T h i s data agrees w i t h i n c r e a s e d RPPmax found by Ehsani and co-workers (1981), who found h i g h l y s i g n i f i c a n t i n c r e a s e s , but a l s o w i t h accompanying i n c r e a s e s i n ischemic t h r e s h o l d and reduced ST-segment d e p r e s s i o n at peak e x e r c i s e l e v e l s . 4 . 4 . 3 Gated Bloodpool Angiography: R e l i a b i l i t y and V a l i d i t y The c o r r e l a t i o n s f o r de t e r m i n a t i o n o f LVEF and SV u s i n g standard c o n t r a s t angiography v s . RNA's found f o r t h i s study ( .85, .93 , r e s p e c t i v e l y ) agree with others (Hindman and Wallace, 1981, L i n k s et a l . , 1982, S l u t s k y et a l . , 1979) . R e l i a b i l i t y s t u d i e s were not undertaken, but s t u d i e s i n v e s t i g a t i n g the t e s t - r e t e s t r e l i a b i l i t y of r a d i o n u c l i d e - d e r i v e d LVEF and abs o l u t e c a r d i a c volumes have r e p o r t e d a c c e p t a b l e t e s t - r e t e s t r e l i a b i l i t y . Hindman and Wallace r e p o r t e d v a l u e s of .89 , .89 , and .94 f o r e x e r c i s e LVEDV, LVEF, and CO, r e s p e c t f u l l y . C a l d w e l l (1981) found e x e r c i s e LVEF had an i n t r a o b s e r v e r v a r i a b l i l i t y o f 1 - 3%. Ehsani and co-workers (1986) found b e t t e r r e p r o d u c i b i l i t y f o r e x e r c i s e LVEF (1.7 ± 0.9% , r = . 9 2 ) , and LVEDV. (7 ± 3 ml, r = . 9 2 ) . Drawing i n c o r r e c t r e g i o n s of i n t e r e s t about the v e n t r i c u l a r 96 borders and the background r e g i o n s ( d e s p i t e b u i l t - i n computer a l g o r i t h m s t o check e r r o r s ) can c o n t r i b u t e t o s m a l l e r r o r s which can r e s u l t i n i n c r e a s e d LVEF and v o l u m e t r i c data i f performed by a b i a s e d or u n s k i l l e d o p e r a t o r . To minimize these e f f e c t s , only one experimentor was used t o draw these r e g i o n s a f t e r p r a c t i c i n g on u n r e l a t e d data. Furthermore, b l i n d i n g the i d e n t i t y of the s u b j e c t s reduced the b i a s e f f e c t . 4.4.4 L e f t V e n t r i c u l a r E j e c t i o n Fraction The b a s e l i n e l e v e l s of r e s t i n g LVEF (46, 44, 43% f o r WJ, CT and LC groups r e s p e c t i v e l y ) r e p r e s e n t v a l u e s commonly found i n p a t i e n t s w i t h CAD or p r e v i o u s MI (Values f o r normal range between 60 and 80%) (Nivatpumin et a l . , 1979). The i n c r e a s e i n r e s t i n g LVEF i n the WJ group a f t e r e x e r c i s e t r a i n i n g i s not commonly found i n the l i t e r a t u r e , even i n the s t u d i e s which demonstrated g r e a t e r m e t a b o l i c and c a r d i a c f u n c t i o n a d a p t a t i o n s than t h i s p r e s e n t study (Ehsani et a l . , 1986, W i l l i a m s et a l . , 1984). Only V e r a n i et a l . (1981) found an i n c r e a s e i n r e s t i n g LVEF a f t e r only 3 months of t r a i n i n g . I t i s s p e c u l a t e d t h a t the s i g n i f i c a n t f i n d i n g s i n r e s t i n g LVEF i n t h i s study were due t o d i f f e r e n c e s i n RNA p r o c e s s i n g techniques from other s t u d i e s , combined wi t h the t r a i n i n g e f f e c t s i n the two t r a i n i n g groups, and the f a c t 97 that our patients remained on t h e i r medications, augmenting v e n t r i c u l a r function by decreasing systemic resistance. Consistent with the greater o v e r a l l aerobic f i t n e s s adaptations i n the WJ group was the observation of s i g n i f i c a n t (19 and 18%, respectively) improvements i n LVEF at the pre-testing 90% l e v e l (WL-90) and at peak l e v e l s . This r e s u l t i s s i m i l a r to those by other investigators (Ehsani et a l . , 1986 and Williams et a l . , 1984,). Williams and co-workers reported peak LVEF to increase from 50 to 54%, while Ehsani et a l . (1986) reported an increase i n the intensely trained group from 52 to 58%. Our findings of changes from 53 to 64% (WJ) and 51 to 55% (CT) are s l i g h t l y larger changes, despite the lower exercise t r a i n i n g i n t e n s i t i e s than the former study, whose subjects trained for 12 months for up to 1 hour per session, f i v e sessions per week, at up to 90% of V02max. The known v a r i a b l i l i t y of LVEF measures, coupled with the use of a d i f f e r e n t method of LVEF determination used by the above authors could explain i n part, the greater changes i n LVEF found i n the present study. However, a more probable cause i s that Ehsani's patients had higher pre-testing r e s t i n g LVEF than our patients (53 vs. 46, 44 and 43% for the WJ, CT and LC groups, and thus our patients displayed a greater p o t e n t i a l adaptive response. Also, i t i s uncertain whether the authors' patients were studied at the same l e v e l 98 of s t r e s s as our p a t i e n t s . T h e i r p a t i e n t s were s t u d i e d at r e s t and "peak" e x e r c i s e . However, i t would be d i f f i c u l t t o o b t a i n t r u e peak e x e r c i s e l e v e l s d u r i n g RNA's w i t h CAD p a t i e n t s , as at l e a s t 2 minutes of s t e a d y - s t a t e a c q u i s i t i o n i s r e q u i r e d f o r enough count data f o r r e l i a b l e LVEF and v o l u m e t r i c data. Our p a t i e n t s e x e r c i s e d at 90% of VC^peak, a l e v e l t h a t most p a t i e n t s c o u l d accomplish s a f e l y . I t i s s p e c u l a t e d t h a t at the 90% of VC^peak workload, r a t h e r than a "peak" workload, our p a t i e n t s achieved h i g h e r and more r e l i a b l e LVEF v a l u e s than the Ehsani et a l ' s p a t i e n t s because they had not yet decreased LVEF, which would occur at peak e x e r c i s e due to ischemia. A l s o , the authors' e x e r c i s e d t h e i r p a t i e n t s i n the supine p o s i t i o n , which might have d i m i n i s h e d e j e c t i o n f r a c t i o n and other v o l u m e t r i c v a l u e s due t o the e f f e c t of g r a v i t y on venous r e t u r n ; i n the supine p o s i t i o n as p r e v i o u s l y d i s c u s s e d , LVEDV and SV are thought be be near maximal at r e s t . F i n a l l y , i t i s suggested t h a t s i n c e the p a t i e n t s remained on C a ^ + - a n t a g o n i s t and Beta-blockade medications d u r i n g t e s t i n g , t h i s r e s u l t e d i n a net augmention of LV performance due the g r e a t e r drop i n systemic r e s i s t a n c e than d e p r e s s i o n of c o n t r a c t i l i t y , which these drugs would a l s o cause. Other s t u d i e s have f a i l e d t o demonstrate changes i n LVEF i n CAD and Post-MI p a t i e n t s a f t e r endurance t r a i n i n g . Cobb (et 99 a l . , 1982) found no improvements i n LVEF at any l e v e l of r e s t or e x e r c i s e . S i m i l a r l y , 12 months of t r a i n i n g f a i l e d t o r e s u l t i n s i g n i f i c a n t improvements i n LVEF i n a l a r g e group of p a t i e n t s , d e s p i t e a demonstration of f a v o r a b l e p e r i p h e r a l a d a p t a t i o n s and an 18% improvement i n VC^peak ( F r o e l i c h e r et a l . , 1984). The l a t t e r study, however, measured p a t i e n t s i n the supine p o s i t i o n d u r i n g e x e r c i s e f o r the RNA procedures, and a f a i l u r e t o d e t e c t any s i g n i f i c a n t LV performance improvements c o u l d have been due to t h i s f a c t o r . F o s t e r et a l . , (1984) and Hung et a l . , (1984) a l s o f a i l e d t o d e t e c t any changes i n LVEF a f t e r t r a i n i n g , d e s p i t e o t h e r f a v o u r a b l e submaximal changes i n e x e r c i s e c a p a c i t y . As shown i n F i g u r e 3.8, although LVEF i s i n c r e a s e d at WL-90 f o r the WJ group, LVEF f a i l e d t o i n c r e a s e , and a c t u a l l y decreased ( n o n - s i g n i f i c a n t l y ) at the new peak workload. T h i s would i n d i c a t e t h a t a c r i t i c a l l e v e l o f myocardial 0 2 consumption supply/balance r a t i o had been exceeded. At t h i s new peak l e v e l , the ischemic t h r e s h o l d (now e l e v a t e d from the p r e - t e s t i n g peak), has been again reached. As d e f i n e d , LVEF i s a r a t i o o f SV t o LVEDV. Although i t i s a u s e f u l and popu l a r c l i n i c a l t o o l t o e v a l u a t e o v e r a l l c a r d i a c f u n c t i o n , i t can be g r e a t l y i n f l u e n c e d by the p e r i p h e r a l l y - mediated l o a d i n g c o n d i t i o n s p l a c e d upon the h e a r t from beat t o beat. E v a l u a t e d alone, LVEF can l e a d t o a m i s i n t e r p r e t a t i o n of the e f f e c t o f e x e r c i s e t r a i n i n g on LV 100 performance (Nivatpumin et a l . , 1979). To account for other factors which could influence LVEF, some measure of the contribution of afterload and preload conditions should be included i n the inter p r e t a t i o n of central vs. peripheral exercise t r a i n i n g e f f e c t s . Nivatpumin (et a l . , 1979) has presented data to confirm that patients with seemingly normal LVEF's have i n fact poor LV function when other parameters are evaluated to account for these factors. Only a few studies have incorporated the simultaneous evaluation of LVEF with measurements of s y s t o l i c blood pressure or RPP as an estimation of impedance to LV emptying (afterload). When submaximal and peak LVEF were plo t t e d against changes i n LVEF, Ehsani and co-workers (198 6) found that there was an upward and right s h i f t i n the relation s h i p , leading the authors to conclude that since LVEF s i g n i f i c a n t l y increased i n the face of s i g n i f i c a n t increases i n SBP, i n t r i n s i c improvements i n LV performance was suggested. Our data, demonstrating s i g n i f i c a n t . i n c r e a s e s in SBP and Peak LVEF i n the CT and WJ groups (Figure 3.9) agrees with t h e i r findings. 4 . 4 . 5 Cardiac Output and Absolute L. Ve n t r i c u l a r Volumes There were s i g n i f i c a n t increases i n CO for the WJ and CT groups at submaximal exercise l e v e l WL-90 and peak exercise l e v e l s on post-testing (WL-90post vs. WL-90) (Figure 3.10). 101 These re s u l t s agree with data from Hagberg et a l . (1983), however, they found no increases i n CO at the same absolute workloads, but did observe increases at r e l a t i v e percents of post- t r a i n i n g VC^peak. Since HR was reduced at these lev e l s of exercise, SV must have increased to account for the increased CO at these exercise l e v e l s . Stroke volume was increased at rest (63 to 80 ml) and each exercise l e v e l (101 to 127 ml at WL-90) for the WJ group. The increases i n resting SV compare favorably to data from Hagberg et a l . , (1983) who found increases from 66 to 81 ml af t e r t r a i n i n g , and from 100 to 120 ml at the peak exercise l e v e l tested (approximately 65% of pre-testing V02Peak) but disagrees other studies who found no changes i n SV (Froelicher et a l . , 1985, Rousseau et a l . , 1973). It can be observed that only at peak exercise l e v e l s (WL-90 post) , does SV f a i l to further increase, and i n fact f a l l s non-signif i c a n t l y (128 to 125 ml i n the WJ group) . This finding agrees with other data which suggests that SV f a i l s progressively up to maximal exercise i n CAD and normal subjects. These data however c o n f l i c t with reports of SV f a i l i n g to increases past about 40% of peak capacity (Rousseau et a l . , 1973, Astrand et a l . , 1964); the CT group was actually able to increase SV from the WL-90 l e v e l to the new WL-90post workload (109 to 118 ml). The i n t e r a c t i o n of beta-adrenergic blockade and calcium channel blocking 102 medications could have combined to maximally decrease peripheral resistance by the vasodilatory properties of these drugs to allow SV to increase at these high workloads i n compromised subjects. This e f f e c t should be persued with t h i s p a r t i c u l a r population by further i n v e s t i g a t i o n . U t i l i z i n g the measurement of SBP (a non-invasive estimation of afterload) to examine whether these changes i n SV were actually due to i n t r i n s i c improvements i n LV c o n t r a c t i l i t y , Figure 3.11 and 3.12 demontrates the upward and right s h i f t i n the curves for the two t r a i n i n g groups, which would suggest, s i m i l a r l y to others (Ehsani et a l . , 1986), that c o n t r a c t i l i t y has improved at submaximal and (near) maximal exercise l e v e l s . However, calculated TPR (not determined i n the l a t t e r study,) was found to be s i g n i f i c a n t l y lower at both submaximal and near maximal workloads (WL-90 and WL-90post, re s p e c t f u l l y , Table 3.13) aft e r t r a i n i n g . When the change i n SV from pre to post-training i s plotted against TPR (Figure 3.14), the curve s h i f t s upwards and to the l e f t , i n d i c a t i n g that for any absolute SV, systemic vascular resistance i s correspondingly reduced, except for the LC group, where i t i s increased as power output i s increased, (suggesting some increased intramuscular tension at high work rates for t h i s group). This data c o n f l i c t s with that from Hagberg et a l . , (1983) who demonstrated an increased SV at the same measured 103 systemic resistance a f t e r t r a i n i n g . However, the above authors measured SV at only 35, 45, and 65% of "VC^max", perhaps too low an i n t e n s i t y to greatly reduce TPR. It would appear that from our SV data, the f a l l i n g of TPR at the higher workloads (90% VC^peak) increased SV by enabling greater v e n t r i c u l a r emptying. It i s also speculated that the s i g n i f i c a n t drop i n TPR i n the patients was further augmented by the peripheral vasodilation e f f e c t s of Ca^ + and Beta-blockade medications which they remained on during t r a i n i n g and t e s t i n g . In agreement with the data from Hagberg et a l . , (1983), S i c o n o l f i et a l . , (1984) f a i l e d to demonstrate the expected drop i n TPR with increasing exercise l e v e l s , and found no co r r e l a t i o n with t r a i n i n g e f f e c t s , leading these authors to conclude that central e f f e c t s due to t r a i n i n g are possible, and are not always due to reductions i n aft e r l o a d and systemic resistance. This finding however, c o n f l i c t s with many i n the l i t e r a t u r e and our data, which supports the finding that systemic vascular resistance decreases as V0 2 increases (r = -.69, Figures 3.5, 3.13). The changes i n LVESV were the most pronounced for the WJ group, which was the only t r a i n i n g group to decrease LVESV at a greater afterload (estimated by SBP) at peak exercise a f t e r exercise t r a i n i n g from 94 to 70 ml (Table 3.10, Figure 3.15). This r e s u l t i s sim i l a r to that of Ehsani et a l . 104 (1986), who demonstrated a s i m i l a r s h i f t , but i n p a t i e n t s who t r a i n e d more i n t e n s e l y than those i n the c u r r e n t study. Again, the same adaptive responses found w i t h a l e s s i n t e n s e e x e r c i s e program c o u l d be due t o the c h a r a c t e r i s t i c s of the p a t i e n t sample, t e s t i n g p r o t o c o l s , t e s t i n g p o s t u r e , medications (with t h e i r a s s o c i a t e d g r e a t e r decreases i n TPR), and i n t e n s i t i e s chosen d u r i n g RNA a c q u i s i t i o n s . F r o e l i c h e r et a l . , (1984), u t i l i z i n g t r a i n i n g i n t e n s i t i e s s i m i l a r t o the p r e s e n t study however, found no improvements i n LVEF and SV a f t e r t r a i n i n g , but a l s o demonstrated a g r e a t e r LV emptying (reduced LVESV) wi t h no change i n a f t e r l o a d . The authors however, t e s t e d p a t i e n t s i n the supine p o s i t i o n . The CT group had i n c r e a s e s i n a f t e r l o a d at WL-90, but f a i l e d t o decrease LVESV at t h i s workload at p o s t - t e s t i n g , i n d i c a t i n g a d e c l i n i n g LV c o n t r a c t i l i t y at t h i s new l e v e l of e x t e r n a l work compared to the WJ group. T h i s i s c o n s i s t e n t w i t h the l e s s e r improvements i n VC^peak and LVEF i n t h i s group' compared wi t h the WJ group. In a d d i t i o n , the LC group f a i l e d t o i n c r e a s e SBP at t h i s workload, and decreased LVESV n o n - s i g n i f i c a n t l y , which i s c o n s i s t e n t w i t h t h e i r o v e r a l l f a i l u r e t o i n c r e a s e a e r o b i c c a p a c i t y , as p r e v i o u s l y demonstrated. Accompanying the decrease i n LVESV f o r the WJ t r a i n i n g group however, was a low but s i g n i f i c a n t c o r r e l a t i o n between TPR 105 and LVESV (r =-.42), su g g e s t i n g t h a t although the decrease i n LVESV a f t e r t r a i n i n g might be due to i n t r i n s i c c a r d i a c a d a p t a t i o n s , the drop i n systemic v a s c u l a r r e s i s t a n c e , a p e r i p h e r a l e f f e c t , might a l s o i n f l u e n c e t h i s i n t e r p r e t a t i o n . The pumping a b i l i t y of the l e f t v e n t r i c l e can be i n f l u e n c e d by e x t r a - c a r d i a c e f f e c t s , such as p r e l o a d , i n a d d i t i o n to other i n t r i n s i c f a c t o r s . Measurement of LVEDV d u r i n g e x e r c i s e t e s t i n g enables the i n v e s t i g a t o r t o uncover the c o n t r i b u t i o n of the F r a n k - S t a r l i n g Mechanism t o i n c r e a s i n g SV and CO. E n d - D i a s t o l i c Volume has been equated to the magnitude of venous r e t u r n (Katz, 1977, Guyton, 1976) and compliance of the v e n t r i c u l a r w a l l s (Port et a l . , 1980). The p o s s i b l e mechanisms u n d e r l y i n g d i a s t o l i c f u n c t i o n are not completely understood, but might be r e l a t e d t o f a c t o r s such as age, p r i o r m y o cardial damage ( r e l a t i n g t o w a l l t e n s i o n and d i s t e n s i b i l i t y ) , p e r i p h e r a l v e n o c o n s t r i c t i o n , and b l o o d volume. R o d e f f e r et a l . , (1984) has suggested t h a t i n the aged, SV as w e l l as LVEDV assumes an i n c r e a s i n g l y important r o l e i n m a i n t a i n i n g CO i n the face of d e c r e a s i n g HR with age. The i n c r e a s e i n LVEDV wit h t r a i n i n g , and the change i n t h i s c a r d i a c volume from r e s t t o e x e r c i s e i s not c l e a r . I s k a n d r i a n et a l . , (1981) found t h a t LVEDV changed m i n i m a l l y 106 from r e s t t o e x e r c i s e , as d i d Ehsani et a l . , (1986). The l a t t e r group however found t h a t LVEDV i n c r e a s e d at r e s t and e x e r c i s e a f t e r h i g h - i n t e n s i t y t r a i n i n g . Our data i n d i c a t e s a s l i g h t i n c r e a s e s i n LVEDV f o r the WJ and CT groups at both r e s t and peak e x e r c i s e l e v e l s a f t e r t r a i n i n g , but the i n c r e a s e s were n o n - s i g n i f i c a n t due to the wide range of v a l u e s . T h i s c o n t r a s t s with Ehsani et a l . , who found a l t e r a t i o n s i n LVEDV a f t e r t r a i n i n g . I t i s suggested t h a t t h e i r s u b j e c t s r e p r e s e n t e d a subset o f p a t i e n t s w i t h i n i t i a l l y l e s s myocardial damage, and hence g r e a t e r v e n t r i c u l a r compliance. However, u n l i k e the . r e s u l t s from Ehsani et a l . (1986), the p a t i e n t s i n the WJ group s i g n i f i c a n t l y i n c r e a s e d LVEDV from r e s t t o e x e r c i s e at the WL-90 l e v e l on p o s t - t e s t i n g (Figure 3.16), from 153 t o 196 ml. Although l e f t v e n t r i c u l a r s t r o k e work was s i g n i f i c a n t l y i n c r e a s e d i n both the WJ and CT groups a f t e r t r a i n i n g at WL- 90 p o s t - t e s t i n g , (Table 3.11, F i g u r e 3.16), s i n c e LVEDV a l s o i n c r e a s e d , the r o l e of the F r a n k - S t a r l i n g mechanism and both p e r i p h e r a l and c e n t r a l mechanisms i n s u p p o r t i n g the improved c e n t r a l f u n c t i o n must be c o n s i d e r e d i n t h i s response. T h i s r e s u l t d i f f e r s from those of Ehsani et a l . , (1986) who found s i g n i f i c a n t i n c r e a s e s i n LVSW without the augmentation of the F r a n k - S t a r l i n g mechanism (no changes i n LVEDV from r e s t t o e x e r c i s e ) . T h i s c o n c l u s i o n i s strengthened by the o b s e r v a t i o n o f a s i g n i f i c a n t c o r r e l a t i o n between LVEDV and 107 TPR o f -.67 i n the present study, s u g g e s t i n g i n c r e a s e d venous r e t u r n p o s s i b l y l e a d i n g t o the g r e a t e r v e n t r i c u l a r f i l l i n g (Table 3.11) . T h i s would i n c r e a s e s t r o k e volume and c a r d i a c output p a r t i a l l y by the F r a n k - S t a r l i n g mechanism. Since we have no data t o c o r r e l a t e the extent of LV damage to d i a s t o l i c compliance and thus f i l l i n g c h a r a c t e r i s t i c s i n the s u b j e c t s , the r o l e of LVEDV i n the. c a r d i a c response t o e x e r c i s e t r a i n i n g i n these p a t i e n t s remains unanswered. Furthermore, the a l t e r a t i o n s i n b l o o d volume, which i n c r e a s e s w i t h endurance t r a i n i n g i n h e a l t h y s u b j e c t s (Covertino et a l . , 1980), has not been examined wi t h r e s p e c t to i t s r e l a t i o n t o c a r d i a c f u n c t i o n and e x e r c i s e t r a i n i n g i n t h i s p o p u l a t i o n . The measurement of the LV S y s t o l i c P r e s s u r e / E n d - S y s t o l i c Volume (P/V) r a t i o has been examined by Sagawa and co- workers (1977) i n animal models as a v a l i d index of myocardial c o n t r a c t i l i t y which i s independent of p r e l o a d and a f t e r l o a d . The use of the P/V r a t i o has been v a l i d a t e d i n the human model with c o n t r a s t v e n t r i c u l o g r a p h y (Nivatpumin et a l . , 1979) and r e c e n t l y , w i t h RNA techniques, u t i l i z i n g a standar d sphygmomanometer f o r s y s t o l i c b l o o d p r e s s u r e measurements and c a l c u l a t e d LVESV (Iskandrian et a l . , 1983). Although both the WJ and CT s u b j e c t s i n c r e a s e d the P/V r a t i o at submaximal and peak e x e r c i s e l e v e l s a f t e r t r a i n i n g , the 108 changes only approached significance due to the large standard deviations i n the data (Figure 3.17) . Examination of the raw data revealed a wide scatter of values; one subject (WJ group) had very small LVESV and high SBP values upon post-testing, r e s u l t i n g i n values i n excess of 11.0. Since P/V (expressed as a ratio) might contribute more s t a t i s t i c a l variance as measure than separate examination of SBP and SV, etc., i t might not represent a sens i t i v e enough measure for examination with a r e l a t i v e l y heterogenious sample as found i n t h i s study. Despite s t a t i s t i c a l non-significance, the data however suggests improvement i n t h i s variable due to exercise t r a i n i n g , and suggests that peak c o n t r a c t i l e function i s attained at submaximal workloads, with impairment of c o n t r a c t i l i t y at the new peak exercise l e v e l s . Thus, the f a i l u r e of P/V r a t i o to s i g n i f i c a n t l y increase aft e r t r a i n i n g , i n contrast to other investigations, might: 1. be a function of i t greater s e n s i t i v i t y as a measure than p l o t t i n g a f t e r l o a d estimates vs. a central function variable, or 2., represent a sensi t i v e measure only with data that displays less v a r i a t i o n than that found i n t h i s study. The larger differences that were found i n the present study in SV and LVESV afte r t r a i n i n g vary from that found i n studies where the exercise i n t e n s i t y was s u b s t a n t i a l l y greater (Ehsani et a l . , 1986, Hagberg et a l . , 1983, Ehsani et a l . , 1982) can also be explained by the posture during 109 e x e r c i s e t e s t i n g . The l a t t e r i n v e s t i g a t o r s u t i l i z e d the supine p o s i t i o n d u r i n g RNA's, which would d i m i n i s h the changes i n a b s o l u t e LV volumes from r e s t t o e x e r c i s e . In a d d i t i o n , most other s t u d i e s have observed the e x e r c i s e t e s t responses without any i n o t r o p i c or c h r o n o t r o p i c m e d i c a t i o n s . The s u b j e c t s i n t h i s study were on a v a r i e t y o f medications (Table 3.1), and were maintained on t h e i r m e dications throughout the t e s t i n g p e r i o d s . Although i t has been demonstrated t h a t t r a i n i n g w h i l e on b e t a - a d r e n e r g i c blockade does not prevent attainment o f a t r a i n i n g e f f e c t ( F r o e l i c h e r et a l . , 1985), the e f f e c t can i n c e r t a i n circumstances be at t e n u a t e d i f the me d i c a t i o n i s not c a r d i o s e l e c t i v e (Wilmore et a l . , 1985). S k l a r et a l . , (1982) found t h a t VT and VC^peak were unchanged i n CAD p a t i e n t s whether on or o f f these m e d i c a t i o n s . K a l i s c h e r et a l . , (1984) have demonstrated some d e p r e s s i o n i n LV f u n c t i o n and volumes w i t h p r o p r a n o l o l , p a r t i c u l a r l y at r e s t . The P/V r a t i o was depressed at r e s t , however LVEF and P/V r a t i o were unchanged at e x e r c i s e . T h i s would account f o r the lower r e s t i n g LVEF found i n these p a t i e n t s compared t o others (Ehsani et a l . , 1986, W i l l i a m s et a l . , 1984, and F o s t e r et a l . , 1984) and the g r e a t e r p o t e n t i a l f o r the l a r g e r i n c r e a s e s i n LVEF t h a t have been observed i n t h i s study. Calcium a n t a g o n i s t medications a l s o reduce myocardial O2 110 demand, and can a f f e c t LV f u n c t i o n , but not t o the extent of the B e t a - a n t a g o n i s t m e d i c a t i o n s . (Lowenthal, 1987). Few s t u d i e s have examined the i n f l u e n c e of these medications on the t r a i n i n g response i n CAD and Post-MI p a t i e n t s , p a r t i c u l a r l y l e f t v e n t r i c u l a r f u n c t i o n . However s i n c e these medications decrease coronary as w e l l as p e r i p h e r a l v a s c u l a r r e s i s t a n c e by i n h i b i t i n g smooth muscle C a ^ + f l u x , a l t e r a t i o n s i n venous r e t u r n c o u l d have accounted f o r the changes i n LVEDV, LVESV and SV i n t h i s study, i n a d d i t i o n t o the decreased TPR w i t h i n c r e a s e d l e v e l s of e x e r c i s e . Since o n l y a r e l a t i v e l y s m a l l number o f s t u d i e s have demonstrated c a r d i a c involvement i n c a r d i a c p a t i e n t s a f t e r e x e r c i s e t r a i n i n g , based on the present f i n d i n g s , e x t r a - c a r d i a c f a c t o r s must s t i l l be c o n s i d e r e d . One p o s s i b l i l i t y which would account f o r the f i n d i n g s of c a r d i a c a d a p t a t i o n i n t h i s and other s t u d i e s u s i n g h i g h e r e x e r c i s e s t i m u l i (Ehsani et a l . , 1986, Hagberg et a l . 1983) i s the f i n d i n g of an a t t e n u a t i o n of plasma catecholamines at r e s t and any g i v e n l e v e l of e x e r c i s e a f t e r t r a i n i n g i n CAD/Post-MI p a t i e n t s (Ehsani et a l . , 1984). The r e d u c t i o n i n sympathetic tone serves t o reduce myocardial O2 demand at any g i v e n l e v e l of submaximal e x e r c i s e , e n a b l i n g a g r e a t e r LVEF and volume response b e f o r e ischemia o c c u r s . The p a t i e n t s i n the p r e s e n t study have t h i s accomplished by t h e i r b e t a - a d r e n e r g i c blockade medication, and so t h i s e f f e c t might be I l l l e s s n o t i c a b l e , thus a f f e c t i n g many of the c e n t r a l and p e r i p h e r a l f u n c t i o n s d u r i n g e x e r c i s e . 112 5.0 Conclusions In c o n c l u s i o n , the r e s u l t s o f t h i s study support the f i n d i n g s o f some but not a l l i n v e s t i g a t i o n s i n t h a t : 1. A s m a l l degree of t r a n s f e r of f i t n e s s t o the u n t r a i n e d limbs as judged by i n c r e a s e s i n VC^peak and VT occurs as a response t o 6 months of endurance t r a i n i n g i n uncomplicated and medicated CAD/Post-MI p a t i e n t s . 2. These t r a i n i n g e f f e c t s are both c e n t r a l l y and p e r i p h e r a l l y - m e d i a t e d , with a p o r t i o n of the c a r d i a c e f f e c t s due t o changes o c c u r r i n g i n the p e r i p h e r y which augment l e f t v e n t r i c u l a r performance, d e s p i t e other p h y s i o l o g i c a l measurements which would i n d i c a t e independent i n t r i n s i c c a r d i a c a l t e r a t i o n s had o c c u r r e d . 3. The mode of t r a i n i n g u t i l i z i n g a e r o b i c c i r c u i t t r a i n i n g as opposed t o continuous walking and j o g g i n g i s l e s s e f f e c t i v e i n producing a g e n e r a l i z e d t r a i n i n g e f f e c t . T h i s i s pro b a b l y due t o the l i m i t e d d u r a t i o n spent at each s t a t i o n per s e s s i o n , and\or the g r e a t e r muscle mass u t i l i z e d d u r i n g walking and jog g i n g . i 4. The f a i l u r e t o i n c r e a s e a e r o b i c c a p a c i t y and c a r d i a c f u n c t i o n i n the group of l o w - i n t e n s i t y c o n t r o l p a t i e n t s 113 probably r e f l e c t s an o v e r a l l l a c k of t r a i n i n g s t i m u l i , as judged by the low e x e r c i s e i n t e n s i t i e s and f r e q u e n c i e s per week. However, d e t e r i o r a t i o n i n t h e i r medical c o n d i t i o n by p r o g r e s s i o n o f CAD l e a d i n g t o these r e s u l t s cannnot be r u l e d out, and would a l s o e x p l a i n the poor e x e r c i s e performance, i n i t i a l p r e - t e s t i n g d i f f e r e n c e s on many c e n t r a l and p e r i p h e r a l i n d i c i e s , and t h e i r poor compliance w i t h e x e r c i s e t r a i n i n g . 5. F a v o r a b l e improvements i n c e n t r a l and p e r i p h e r a l a d a p t a t i o n s t o endurance t r a i n i n g i n the WJ and CT p a t i e n t s were not accompanied by expected a l t e r a t i o n s i n l i p i d p r o f i l e s and body composition. The f a i l u r e t o e x p e r i m e n t a l l y manipulate the d i e t , the f a i l u r e t o measure a p o l i p o p r o t e i n s , and the p r e v i o u s l y d i s c u s s e d v a r i a b i l i t y and u n r e l i a b i l i t y of l i p o p r o t e i n measurements c o u l d e x p l a i n these r e s u l t s . Regarding the c i r c u i t t r a i n i n g group, o v e r a l l balance o f upper t o lower e x t r e m i t y f i t n e s s might be d e s i r a b l e w i t h t h i s type o f t r a i n i n g , as demonstrated by the s l i g h t l y g r e a t e r improvement i n arm ergometry VC^peak and c y c l e e r g o m e t r y - s p e c i f i c improvements i n t h i s group. However, due to the e x t r a equipment, c o s t s , and dependence upon a h o s p i t a l or f a c i l i t y , c i r c u i t t r a i n i n g might not be as f e a s i b l e a t r a i n i n g mode as w a l k i n g / j o g g i n g . The l a t t e r form of t r a i n i n g i s more convenient and seems t o c o n f e r g r e a t e r p h y s i o l o g i c a l t r a i n i n g b e n e f i t s , as judged by the t r a n s f e r 114 of f i t n e s s t o the u n t r a i n e d arms i n the WJ group and g r e a t e r o v e r a l l LV a d a p t a t i o n i n t h i s group. I t s hould be emphasized however t h a t f o r s p e c i a l groups who need t o c o n d i t i o n s p e c i f i c muscle groups f o r p a r t i c i p a t i o n i n work or l e i s u r e a c t i v i t i e s , a e r o b i c c i r c u i t t r a i n i n g i s e f f i c a c i o u s i n p r o v i d i n g moderate t r a i n i n g e f f e c t s . However, t h i s i s p r o v i d i n g t h a t the t r a i n i n g i n t e n s i t i e s , f r e q u e n c i e s per week and d u r a t i o n s per mode are s u f f i c i e n t and e q u i v a l e n t t o t h a t o f a graded w a l k i n g / j o g g i n g programs. More work needs t o be done t o q u a n t i f y these v a r i a b l e s i n a e r o b i c c i r c u i t t r a i n i n g i n c a r d i a c r e h a b i l i t a t i o n . The o b s e r v a t i o n t h a t a l o w - i n t e n s i t y / l o w - f r e q u e n c y program of endurance t r a i n i n g of l e s s than 1 t o 2 days per week at l e s s than 60% of VC^peak f a i l e d t o c o n f e r e i t h e r c e n t r a l or p e r i p h e r a l t r a i n i n g e f f e c t s i n the LC group i s c o n s i s t e n t w i t h other data. This group a c t u a l l y demonstrated a r e g r e s s i o n i n f i t n e s s . I t can be r u l e d out t h a t t h i s group d i d not perform s u f f i c i e n t l y d u r i n g t e s t i n g due to m o t i v a t i o n a l reasons, s i n c e t h e i r RER data i n d i c a t e d equal e f f o r t d u r i n g a l l e x e r c i s e t e s t s . The observed c e n t r a l t r a i n i n g e f f e c t s i n the two t r a i n i n g groups may have been due t o i n t r i n s i c c a r d i a c a d a p t a t i o n s ( p r e v i o u s l y e s t a b l i s h e d i n h e a l t h y p o p u l a t i o n s ) . T h i s f i n d i n g i s i n f r e q u e n t l y observed i n other s t u d i e s however, 115 due t o t e c h n i c a l l i m i t a t i o n s , t e s t i n g i n the supine p o s i t i o n , f a i l u r e t o study e x e r c i s e responses at m u l t i p l e and h i g h e r submaximal workloads, and withdrawing p a t i e n t s ' i n o t r o p i c and c h r o n o t r o p i c medications d u r i n g t e s t i n g . They however might a l s o be due to changes i n t o t a l p e r i p h e r a l r e s i s t a n c e , catecholamines, changes i n sympathetic tone, unknown e f f e c t s of medications, or changes i n b l o o d volume. The f a c t t h a t ST-segments f a i l e d decrease i n the group which d i s p l a y e d the g r e a t e s t c e n t r a l a d a p t a t i o n s (WJ) d e s p i t e s i g n i f i c a n t improvements i n many of the c e n t r a l c a r d i a c f u n c t i o n measures i n d i c a t e s t h a t p e r i p h e r a l f a c t o r s s t i l l form at l e a s t a s i g n i f i c a n t p r o p o r t i o n of the t r a i n i n g e f f e c t , and as a r e s u l t , i s not p o s s i b l e t o s t a t e c o n c l u s i v e l y t h a t maximal myocardial oxygen consumption might have been f a v o u r a b l y a f f e c t e d by the t r a i n i n g regime. T r a n s f e r of f i t n e s s to the u n e x e r c i s e d arms i s demonstrated by the improvement i n arm VC^peak, maximal workload, and v e n t i l a t o r y t h r e s h o l d i n the WJ group f o r arm ergometry c o u l d a l s o be accomplished through e x t r a - c a r d i a c a l t e r a t i o n s . Recent i n v e s t i g a t i o n s i n l a c t a t e k i n e t i c s suggests t h a t the removal r a t e , b u f f e r i n g and o x i d a t i o n of H + i n n o n - e x e r c i s i n g but t r a i n e d s k e l e t a l muscle, l i v e r , h e a r t and kidney might occur a f t e r t r a i n i n g . T h i s c o u l d a l s o p a r t i a l l y e x p l a i n these f i n d i n g s . The f a i l u r e t o uncover decreases i n submaximal HR f o r the u n t r a i n e d arms d e s p i t e the other changes t h a t i n d i c a t e a t r a n s f e r e f f e c t c o u l d have been due t o the e f f e c t of B e t a - a d r e n e r g i c blockade and C a ^ + - channel b l o c k i n g drugs, which slow heart r a t e both at r e s t and at e x e r c i s e , e f f e c t i v e l y masking these changes. C l e a r l y , f u r t h e r r e s e a r c h u t i l i z i n g n e u r o p h y s i o l o g i c , b l o o d l a c t a t e , t r a c e r s t u d i e s , or NMR spectroscopy might shed f u r t h e r l i g h t on.these mechanisms i n t h i s p o p u l a t i o n . F i n a l l y , the o b s e r v a t i o n t h a t these improvements i n c e n t r a l and p e r i p h e r a l i n d i c a t o r s of endurance f i t n e s s can occur independently and i n the absence of body f a t r e d u c t i o n s and serum l i p i d a l t e r a t i o n s i s a s u r p r i s i n g f i n d i n g , and suggests other f a c t o r s are i n v o l v e d i n the t r a i n i n g e f f e c t i n t h i s p o p u l a t i o n . The measurement of serum l i p i d s , p a r t i c u l a r l y the l i p o p r o t e i n s u b f r a c t i o n s i s r e l a t i v e l y i m p r e cise, and complex. S t u d i e s measuring the e f f e c t s of e x e r c i s e t r a i n i n g on these parameters r e q u i r e the more s e n s i t i v e measures of HDL2 and a p o l i p o p r o t e i n s u b f r a c t i o n s . 117 6.0 Bibliography A l a z r a k i , N.P., S c h e l b e r t , H.R., and Verba, J.W. ( 1 9 7 5 ) . 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This i s despite a consistent trend towards lowered death rates recently reported across North America over the past two decades. The e f f o r t s to combat morbidity and mortality due to CAD have taken three basic i d e n t i f i a b l e d i r e c t i o n s i n modern medicine; the basic s c i e n t i f i c research designed to improve the understanding of the fundamental physiopathology and etiology, the immediate emergency and event-centred medical treatment, and the long-term prevention. and i n t e r d i s c i p l i n a r y team approach to r e h a b i l i t a t i o n of CAD. This f i r s t area represents basic s c i e n t i f i c laboratory-based investigations i n the mechanism of the genesis and p r o f l i f e r a t i o n of the coronary at h e r o s c l e r o t i c process (Gotleib, 1982) . Work i n t h i s area continues to strengthen the association of dietary constituents (Majno, et a l . , 1984, Eggen and Strong, 1987), psychoneurophysiological t r i g g e r s (Lee, 1985), and neuro-endocrine influences (Sirek, 137 et a l . , 1978) i n the i n i t i a l a r t e r i a l wall damage, followed by the gradual accumulation of atherosclerotic material i n the coronary a r t e r i e s . The second area of investigation concerns the acute and chronic medical treatment of CAD. This serves to reduce mortality, minimize morbidity, enhance early disease detection, and prevent recurrent myocardial i n f a r c t i o n . Modalities of treatment u t i l i z e d today consist of a plethora of resources: coronary bypass revascularization surgery, tranluminal angioplasty, streptokinase and tissue plasminogen activator administration, and advanced pharmacological, emergency, and coronary care unit management. The l a t t e r have often been i d e n t i f i e d as major reasons for the observed decreases i n short-term mortality from acute myocardial i n f a r c t i o n over the past few decades. The t h i r d area of intensive research, and more frequently, practice, involves prevention of i n i t i a l and reccurrent events through primary, secondary, and t e r t i a r y approaches (Froelicher and Brown, 1984), with the emphasis and techniques u t i l i z e d being determined by the population under consideration. The main q u a l i f y i n g difference from the medical approaches i s that prevention involves factors that can be a c t i v e l y altered by the i n d i v i d u a l , and that are related to " l i f e s t y l e " (ie., diet, stress, exercise). 138 Primary prevention i s the attempt to prevent the disease process from i n i t i a l l y e s tablishing i t s e l f i n the organism. This area, for example, involves p e d i a t r i c screening for f a m i l i a l l i p i d abnormalities, an emphasis on physical a c t i v i t y during childhood, and propagating of p o s i t i v e health behaviours throughout early childhood and towards adulthood. Secondary prevention relates to slowing and perhaps h a l t i n g the pathologic process already present, but which i s s t i l l i n a s u b - c l i n i c a l asymptomatic stage. Epidemiological invest i g a t i o n has convincingly documented the e f f e c t of diets low i n fats and cholesterol and l i f e s t y l e s which include > 2000 kcal/week of energy expenditure (either during work or purposeful l e i s u r e exercise pursuits) on subsequent development of symptomatic disease (Paffenbarger, 1986, Kannel, et a l . , 1986). Tert i a r y prevention has grown to be associated with r e h a b i l i t a t i o n a f t e r the sequlea of symptomatic disease, prevention of further progression of a r t e r i a l occlusion, and most o p t i m i s t i c a l l y , reversal of CAD through a combination of dietary, psychological, medical, pharmacological, and health behaviour modifications. Although i d e a l l y cardiopulmonary r e h a b i l i t a t i o n (CPR) encompasses a l l these aspects i n the achievement of a CAD patient's return to 139 productive l i f e , i t i s the physiological e f f e c t s of exercise t r a i n i n g i n t h i s population which i s currently undergoing major investigation, and which has formed the cornerstone of t h i s i n v e s t i g a t i o n . To date, the long-term e f f e c t s of exercise t r a i n i n g on mortality and recurrance of myocardial i n f a r c t i o n (MI) as studied by longitudinal t r i a l s have been generally dissapointing (Naughton, 1985) . Of the 7 t r i a l s that have been conducted, only one demonstrated a s t a t i s t i c a l l y s i g n i f i c a n t decrease i n recurrances i n the exercise t r a i n i n g group, but t h i s was the only study which used a multifaceted approach (counselling, diet intervention, as well as exercise training) (Kallio, . 1979) . Most of the t r i a l s suffered from inadaquate sample sizes, poor control of the exercise stimulus, and cross-over of the controls to the exercise group. Nevertheless, there i s a wealth of c l i n i c a l and s c i e n t i f i c information which contiues to overwhelmingly support the physiologic rationale for endurance (and more recently, upper body aerobic and resistance) t r a i n i n g i n patients recovering from MI, surgery, or with angina. It has been the understanding of the p h y s i o l o g i c a l adaptations which occur in both healthy humans as well as i n animals with a r t i f i c i a l l y - i n d u c e d coronary occlusions a f t e r chronic endurance exercise t r a i n i n g , where the rationale and 140 implimentation of graduated exercise t r a i n i n g for the CAD patient has evolved. Cardiorespiratory Function and Adaptation to Acute Endurance Exercise Regardless of the presence or absence of disease, during exercise of durations longer than 90 seconds, continuous supply of O2 i s required at the working muscle to combine with fuels and produce ATP for muscular contraction. The delivery of O2 to the muscles involves a linkage of ph y s i o l o g i c a l systems i n p a r a l l e l , and i s best described by the Fick Conductance Equation: V02max = CO. X A - V 0 2 A Where VC^max = Maximal O2 Uptake (1'inin or ml-kg -1'min -1) CO. = Cardiac Output (= Stroke Volume X Heart Rate) A-VO2A = Arteriovenous O2 difference. This famous expression summarizes the two general d i v i s i o n s of the oxygen transport and u t i l i z a t i o n process; systems which serve to d e l i v e r O2, (central) and systems which serve to u t i l i z e O2 (peripheral). This model can be further divided into more complex components, summarized i n order: 1. V e n t i l a t i o n ..mechanical exchange of O2 and CO2 with environment. Factors include pulmonary function, environmental content of O2 and C 0 2 • 2. D i f f u s i o n d i f f u s i o n of O2 and CO2 across the alveolar membrane. 141 3. Chemical combination with Hb chemical reaction binding O 2 and C O 2 to red blood c e l l s i n association with hemoglobin Factors include hemoglobin, number of red blood c e l l s , p a r t i a l pressure of water, O 2 , C O 2 , acid-base balance, temperature, and iron stores. 4. Transport and D i s t r i b u t i o n cardiac performance, blood volume and hydration, sympathetic stimulation, regulation of d i s t r i b u t i o n of cardiac output, t o t a l peripheral resistance, environmental temperatures. 5. U t i l i z a t i o n factors include p a r t i a l pressures of O 2 , C O 2 , myoglobin, mitochondrial number and oxidative enzyme l e v e l s , presence of fuels, number of cont- r a c t i l e units, metabolic a c t i v i t y of c o n t r a c t i l e units, acid-base balance, extra and i n t r a c e l l u l a r ion concentrations. It i s clear that when a human being increases his or her a c t i v i t y l e v e l , a l l these systems must operate e f f e c t i v e l y , and i n p a r a l l e l so that ultimately, i n t e r n a l c e l l u l a r homeostasis i s achieved i n the face of increases i n metabolic rate upwards of twenty times that at rest. At the onset of exercise i n the normal adult, i n t e r r e l a t e d factors come into play to adjust for the increasing metabolic rate of the muscles. Performed sporadically or infrequently, the response to an acute bout of either prolonged submaximal or rapidly incremental/maximal exercise r e s u l t s i n consistant and predictable p h y s i o l o g i c a l responses (Figure 7.1). Depending upon the i n i t i a l f i t n e s s 142 l e v e l of the subject, the presence or absence of disease, anatominc l i m i t a t i o n s , genetic endowment, and age, subjecting an i n d i v i d u a l to t h i s stress at frequent and regular periods constitutes habitual exposure, and w i l l r e s u l t i n adaptations i n most of the above systems for 0 2 transport and u t i l i z a t i o n . It i s the extent, time frame, and parameters of t h i s adaptation with which we are concerned and forms the basis for explorations i n the benefits that CAD patients accrue from exercise t r a i n i n g . 143 Figure 7.1 Normal Cardiorespiratory Responses to Acute Dynamic Exercise 180 0 300 600 900 Work-kg. m./min. From Berne and Levy, 1981, p 256. 144 Peripheral Components to Habitual Endurance Training As a consequence of h a b i t u a l e x e r c i s e , profound changes occur i n the u n t r a i n e d muscles which enables e x t e r n a l work to be performed at g e n e r a l l y l e s s c o s t t o the c a r d i o v a s c u l a r system. Clausen (1976) has examinined the r e l a t i o n s h i p of the p e r i p h e r a l and c e n t r a l components t o e x e r c i s e , and determined t h a t as e x e r c i s e i n t e n s i t y i n c r e a s e s , the p e r i p h e r a l r e s i s t a n c e (TPR) d e c l i n e s . In a d d i t i o n the d e c l i n e i n p e r i p h e r a l r e s i s t a n c e i s i n v e r s e l y p r o p o r t i o n a l t o the maximal oxygen uptake (VC^max) and muscle mass s i z e . As V0 2max i n c r e a s e s , the heart r a t e at any g i v e n l e v e l of e x e r c i s e decreases, and b l o o d flow t o t h a t muscle decreases. But what are the s p e c i f i c a d a p t a t i o n s t h a t occur which e x p l a i n these responses? Data from both m o r p h o l o g i c a l u l t r a s t r u c t u r a l s t u d i e s as w e l l as b i o c h e m i c a l and h i s t o l o g i c a l s t u d i e s have demonstrated s i g n i f i c a n t i n c r e a s e s i n c a p i l l a r i z a t i o n (Parizkova et a l . , 1971, Hermansen and Wachtlova, 1971, and B r o d a l et a l . , 1977) a f t e r prolonged t r a i n i n g i n mostly sl o w - t w i t c h f i b r e s . F u n c t i o n a l l y , t h i s p r o v i d e s g r e a t e r s u r f a c e area f o r exchange of Q>2, CO2/ f r e e f a t t y a c i d s , m e t a b o l i t e s , l a c t a t e and f u e l s . Of perhaps g r e a t e r s i g n i f i c a n c e are the a d a p t a t i o n s i n the c e l l u l a r b i o c h e m i c a l p rocesses which produce ATP. E a r l y 145 studies i n animals (Holloszy, 1967, Bengi et a l . , 1975) and subsequently i n humans (Gollnick and Sembrowich, 1977) have demonstrated the i n t r a c e l l u l a r increases i n mitochondrial mass, Electron Transport Chain co-enzymes, Krebs Cycle r a t e - l i m i t i n g enzymes and isoenzymes, mitochondrial shuttle enzymes, and s p e c i f i c myosin-ATPase's i n slow-twitch f i b r e s . For a more complete review of the s p e c i f i c enzymes involved, the reader i s referred to Holloszy's and Coyle's (1984) paper. The importance of the peripheral adaptations i n the general t r a i n i n g e f f e c t i s profound i n that not only i s maximal capacity improved by these adaptations; the duration factor (the a b i l i t y to perform prolonged submaximal exercise) i s increased. This i s accomplished by increasing the c e l l ' s capacity for fat metabolism, and thereby reducing the dependance upon the l i m i t e d intramuscular and l i v e r glycogen stores during exercise of 45 minutes or greater (Holloszy and Coyle, 1984). Exercise duration i s improved a d d i t i o n a l l y however by the complex interplay of the metabolic and cardiovascular responses a f t e r t r a i n i n g . The c l a s s i c response i s a sympathetically-mediated decrease i n muscle blood flow to the exercising and non-exercising tissue a f t e r t r a i n i n g , e s s e n t i a l l y r e d i s t r i b u t i n g the cardiac output for optimization of heat exchange by cutaneous vasodilation 146 (Rowell, 1974) . A summary of normal cardiovascular and metabolic adaptations as a consequence of endurance exercise t r a i n i n g i s outlined i n Table 7.1. 147 Table 7.1 Cardiovascular Adaptations A f t e r Endurance Training F a c t o r Rest Submaximal Peak Heart Rate Stroke Volume A-V02 D i f f e r e n c e C a r d i a c Output V 0 2 Work C a p a c i t y S y s t o l i c B.P. D i a s t o l i c B.P. Mean A r t e r i a l P res. TPR Coronary Blood Flow B r a i n Blood Flow V i s c e r a l Blood Flow 0 I n a c t i v e Muscle B.F. 0 A c t i v e Muscle B.F. 0 - Skin Blood Flow 0 Blood Volume + Plasma Volume + Red C e l l Mass 0 + Heart Volume + + 0 + 0 - 0 0 - 0 - 0 - 0 0 + + 0 0 0 0 0 0 0 + 0 0 0 0 - + + + + + 0 0 - 0 - 0 - + 0 0 0 + 0 Symbols: + i n c r e a s e - decrease not a p p l i c a b l e 0 no change Adapted from Brooks & Fahey, 1984, p. 326 148 Normal Cardiac Physiology: An Overview The heart muscle d i f f e r s from s k e l e t a l muscle from h i s t o l o g i c , metabolic and functional standpoints. These differences are . a manifestation of i t s challenging p h y s i o l o g i c a l requirements compared to s k e l e t a l muscle, which has the luxury of resting. The heart i s a four-chambered organ; the right side, (right atrium and ventricle) providing pulmonary c i r c u l a t i o n , and the L. atrium and v e n t r i c l e s providing systemic c i r c u l a t i o n . Both a t r i a are low-pressure reservoirs for venous and pulmonary venous return, and act more as primers for the ve n t r i c l e s . The v e n t r i c l e s are thicker muscled than t h e i r a t r i a , with the l e f t v e n t r i c l e demonstrating a more developed hypertrophy and smaller chamber compared to the Right v e n t r i c l e , which only requires a mean a r t e r i a l pressure of 15 mm/Hg to pump the cardiac output through the low-resistance pulmonary c i r c u l a t i o n . Left v e n t r i c u l a r pressures are t y p i c a l l y 120 and 70 mm/Hg s y s t o l i c and d i a s t o l i c , r e s p e c t f u l l y . The myocardium i s a v e r s a t i l e fuel user and myocardial f i b r e s are well endowed with mitochondria. The substrates that i t w i l l oxidize are i n proportion to t h e i r a r t e r i a l concentration. Although the heart i s unique i n that lactate can be u t i l i z e d as fue l , i t cannot be metabolized when the 149 heart i s hypoxic. In t h i s case, the heart w i l l break down glycogen. However, only 30 to 40% of the heart's oxygen consumption i s derived from the oxidation of glucose, the rest comprising of e s t e r i f i e d and non-esterified f a t t y acids (Katz, 1977, Berne and Levy, 1979). The myocardium's blood supply, the two coronary a r t e r i e s , t h e i r branches and c a p i l l a r i e s , d e l i v e r 200 ml/min at rest, and t h i s can increase to as much as 900 ml/min at maximal exercise (Berne and Levy, 1981). Invasive studies i n animals and i n humans have demonstrated that coronary venous blood i s almost f u l l y desaturated at rest (about 5 volume %, that found at the l e v e l of s k e l e t a l muscle mitochondria at maximal exercise). The importance of t h i s fact i s that when the myocardial metabolic (O2) demands are increased, for example during exercise, further increases i n myocardial O2 consumption must be met by increases i n coronary flow. In the healthy myocardium, t h i s i s accomplished successfully by a combination of mechanisms: 1. Increases i n a o r t i c pressure 2. Variation i n flow.during systole, d i a s t o l e 3. Increases/decreases i n coronary resistance with increasing/decreasing f i b r e metabolism 4. Increases i n sympathetic f i r i n g causing vasodilation and vasoconstriction 5. Local metabolites causing coronary vasodilation What then are the major determinants of cardiac function? 150 Most discussions of cardiac physiology have s i t e d four main factors i n the fundamental functioning of the heart. These are: 1. Afterload 2. Preload 3. C o n t r a c t i l i t y 4. Heart Rate 1. A f t e r l o a d Despite the fact that actual myocardial f i b r e shortening i s responsible for the ve n t r i c u l a r ejection of blood during systole, most of the myocardial oxygen consumption during the cardiac cycle i s attributed to increases i n pressure- work, as opposed to volume-work. An example of Pressure-work i s when s y s t o l i c blood pressure i s increased at a constant cardiac output (Katz, 1977). The exact periods of pressure work during the cardiac cycle are the isovolumetric contraction and rela.xtion phases, where a o r t i c pressure i s overcome by ve n t r i c u l a r pressure, and where v e n t r i c u l a r pressure i s overcome by a o r t i c pressure, respectively. The amount of pressure work that the heart has to perform during systole i s referred to as afterload, and can be estimated by ca l c u l a t i n g the t o t a l peripheral resistance (TPR) of a o r t i c outflow by: TPR = M.A.P./CO. Where M.A.P. i s mean a r t e r i a l pressure, and CO. i s Cardiac Output (Burton, 1972). 151 Afterload can be increased by s t r u c t u r a l abnormalities such as a o r t i c outflow defects, or by increases i n resistance i n the periphery, such as vasoconstriction. A f t e r l o a d can also be reduced by factors i n the periphery, such as vasod i l a t i o n . 2. Preload The amount and pressure of venous and pulmonary venous blood returning to the right and l e f t v e n t r i c l e s r e s p e c t f u l l y , w i l l d i c t a t e how much the chambers w i l l s tretch during diastole, how much poten t i a l energy w i l l be stored i n the myocardial f i b r e s when they stretch, and f i n a l l y , how much k i n e t i c energy they w i l l then contribute to systole. This e f f e c t was f i r s t demonstrated i n i s o l a t e d animal hearts preparations, and i s well known as the Frank-Starling Law of the heart (Figure 7.2). When venous return i s augmented, either by reinfusion of saline, increases i n blood volume, or by venoconstriction i n the periphery, the v e n t r i c l e s are stretched by the increased venous (right and l e f t a t r i a l ) pressure, and the next beat w i l l eject a greater stroke volume. 152 Figure 7.2 The Frank S t a r l i n g Law of the Heart 20 40 GO Time-sec. As right a t r i a l pressure (venous return i s increased, l e f t v e n t r i c u l a r volume i s increased (downward s h i f t i n top curve), leading to greater v e n t r i c u l a r emptying upon systole. • From Berne and Levy, 1981, p 158. 153 This mechanism allows the heart to eject any volume that i s delivered so that cardiac output i s regulated between the two sides of the heart. It also u t i l i z e s the basic c h a r a c t e r i s t i c s of myocardial f i b r e s to generate force upon stretch, according to the length/tension r e l a t i o n s h i p . Guyton, (1973) eloquently presents a series of curves which describe variations of venous return and the e f f e c t s on cardiac output i n normal and diseased hearts. These concepts have been regarded as basic to our understanding of cardiac performance i n cardiac f a i l u r e s i t u a t i o n s . The extent of cardiac f i l l i n g and stretch i s dependent upon factors which govern venous return (sympathetic and mechanically-induced venoconstriction), blood volume, and inherent d i s t e n s i b i l i t y of the cardiac chambers. Factors which can a l t e r v e n t r i c u l a r d i s t e n s i b i l i t y or compliance are age, myocardial calcium flux, heart rate, and extent of v e n t r i c u l a r scaring (Katz, 1977). 3. C o n t r a c t i l i t y During periods of increased metabolic a c t i v i t y , as found during exercise, the myocardium's c o n t r a c t i l i t y i s increased p r i m a r i l y by increases i n sympathetic f i r i n g . This process stimulates the adenylate cyclase system, a l t e r i n g calcium flux across the sarcolemal membrane (Katz, 1977) . Greater 154 calcium a v a i l a b i l i t y to the actual contraction machinery res u l t s i n greater cross-bridge formation and greater contraction v e l o c i t y , with the v e l o c i t y a function of i n t r a c e l l u l a r calcium concentration and the external load imposed upon the sarcomeres. C i r c u l a t i n g catecholamines also augment t h i s e f f e c t by increasing the permeability of calcium and therefore greater calcium inward flux during the plateau of the myocardial action p o t e n t i a l . The sum e f f e c t i s to enable the l e f t v e n t r i c l e to perform , more work for a given l e v e l of d i a s t o l i c pressure (Figure 7.3). 155 Figure 7.3 Intrinsic Cardiac Contractility 6 0 - Left Ventricular End Diastolic Pressure - cm.H 20 Infusion of norepinepherine i n the dog causes increased l e f t v e n t r i c u l a r performance due to enhanced c o n t r a c t i l i t y over control conditions. From Berne and Levy, 1981, p 161. 156 4. Heart Rate The frequency of cardiac contractions i s a function of increased sympathetic a c t i v i t y to the s i n o a t r i a l node to increase f i r i n g rate. The metabolic requirements of the body w i l l generally dictate the heart rate, and the heart rate i n turn, w i l l d i r e c t l y a f f e c t most of the heart's other performance determinants and oxygen consumption. The maximal heart rate possible i s l a r g e l y determined by age and present health, and to- a somewhat lesser extent, the state of physical f i t n e s s . Some important factors which take place during increases i n heart rate are the reduction i n the coronary flow period during the shortened dia s t o l e , and the impairment of cardiac f i l l i n g during' diastole (Astrand, 1976) . Much work has been undertaken to delineate methods whereby the work of the heart, or more s p e c i f i c a l l y , the oxygen consumption can be measured. The d i r e c t method i s cardiac catheterization which i s obviously invasive. However, more non-invasive methods have been used, which give close correlations to the d i r e c t methods, and u t i l i z e the above determinants of cardiac function. Gobel, et a l . (1978) have demonstrated that the product of HR and s y s t o l i c blood pressure (the Rate Pressure Product) i s a reasonable 157 estimate of myocardial oxygen consumption (MVO2)• Nelson et a l . (1974) found that the accuracy of using a blood pressure cuff or central a o r t i c catheter for s y s t o l i c blood pressure were equal when ca l c u l a t i n g RPP, producing correlations between invasive vs. non-invasive MVO2• of .85 and .88, r e s p e c t f u l l y . Other measures of cardiac function u t i l i z e d to describe cardiac function are the end-systolic pressure/volume r a t i o (Sagawa, et a l . , 1977, Nivatpumin et a l . , 1979), and l e f t v e n t r i c u l a r stroke work, a product of l e f t v e n t r i c u l a r s y s t o l i c pressure times stroke volume (Kragenbuehi, 1985). 158 Normal Cardiovascular Responses to Acute Exercise Even before the onset of dynamic exercise, heart rate and blood pressure r i s e i n a n t i c i p a t i o n of exercise, primarily mediated by c o r t i c a l a c t i v i t y . Upon i n i t i a t i o n of exercise, heart rate increases within 0.5 to 2 seconds, and r i s e s i n p a r a l l e l to metabolic needs. Steady-state heart rates are achieved within 1 to 2 minutes. Stroke volume i s larger, and close to maximal values at rest in the supine position, due to the lack of leg blood pooling e f f e c t s found i n the erect p o s i t i o n . As a re s u l t , stroke volume w i l l not increase appreciably with exercise i n the supine p o s i t i o n . In erect positions however, r e s t i n g stroke volume values are smaller, but w i l l increase at the onset of exercise. At lower i n t e n s i t i e s , stroke volume i s the major determinant of cardiac output, increasing approximately 20% from re s t i n g values to peak values (70 to 90ml, r e s p e c t i v e l y ) . Maximal lev e l s of stroke volume are reached early i n exercise, reportedly from as low as 25 to 30% of VC^max (Berne and Levy, 1979) to up to 60% V02max (Astrand and Rohdal, 1976), or even up to 70% i n young subjects ( Shephard, 1984). After these percentages of maximum are reached, further increases i n cardiac output must be achieved by increases i n heart 159 rate, and to a large extent, by decreasing l e v e l s of peripheral resistance. It has been observed that stroke volume values are dependent upon the type of exercise and the t o t a l muscle mass u t i l i z e d i n the a c t i v i t y . The finding that maximal stroke volumes for arm ergometry < cycle ergometry < treadmill running i s consistent with the concept that the smaller the muscle mass, the greater peripheral resistance, and hence the greater the obstacle for cardiac pumping. Cardiac output, the product of stroke volume X heart rate i s sim i l a r at rest and at submaximal leve l s of exercise between trained and untrained individuals, with r e s t i n g values of 5.6 to 6.4 l i t r e s • min - 1. Peak cardiac output values are t y p i c a l l y 18 to 25 i n healthy normals, and can reach 30 to 38 l i t r e s • m i n - 1 at maximal exercise i n e l i t e athletes (Shephard, 1984). Figure 7.1 summarizes the cardiovascular response to acute exercise. The cardiovascular adaptations which take place during prolonged exercise are due primarily to the requirements and demands of heat d i s s i p a t i o n , and thus varies according to the i n d i v i d u a l ' s f i t n e s s l e v e l , state of hydration, and the environmental conditions. As exercise duration i s extended, cardiac output remains e s s e n t i a l l y unchanged, but as more of the plasma volume i s directed to the skin for sweating, 160 stroke volume diminishes, and heart rate for the same amount of external work increases (Rowell, 1976). Cardiac Adaptations i n Normal Individuals a f t e r Habitual Exercise The questions concerning the l i m i t s and mechanisms surrounding central, or cardiac adaptations to chronic exercise t r a i n i n g have intriqued exercise s c i e n t i s t s for years. An additional argument of the r e l a t i v e importance of the roles of central vs. peripheral adaptation to exercise i s s t i l l hotly contested, but with the u t i l i z a t i o n of more advanced non-invasive technologies (echocardiography, doppler, nuclear medicine), the answers are changing. S a l t i n , who has studied the cardiovascular response to exercise extensively, has convincingly reasoned that the central component i s indeed (after the fast time-course i n which peripheral changes have occurred), the l i m i t i n g component to the adaptive response. It has been calculated that " the maximal l e v e l of perfusion of the muscle vascular bed, and thus the maximal oxygen uptake, may be c e n t r a l l y rather than per i p h e r a l l y l i m i t e d at the l e v e l of the contracting muscles, [and t h a t ] . . during exercise with 2 legs + 2 arms, an unreasonably high cardiac output of up to 70 l i t r e s • m i n - 1 would be required to sustain perfusion" (Savard, et a l . , 1987). The investigators also demonstrated 161 that VC^max d i d not increase when arm work was added to already hard two-legged work. Thus i n the healthy trained i n d i v i d u a l , i t would seem that peripheral adaptations are already maximal, and further increases i n maximum aerobic capacity must be accomplished by central cardiac changes. This i s further suggested by Holloszy and Coyle, (1983) who present data i n d i c a t i n g that over a wide range of VC^max values for recreational through to e l i t e athletes, past a VC^max of around 50 ml'kg - 1 •min--'-, mitochondrial c i t r a t e synthase lev e l s are the same. Cl e a r l y then, the periphery does not explain e n t i r e l y high l e v e l s of cardiorespiratory function. In an important paper, DeMaria (et a l . , 1978) demonstrated increases i n l e f t v e n t r i c u l a r chamber diameters, stroke volume, wall thicknesses, and rates of f i b r e shortening using echocardiography i n 24 subjects a f t e r 11 weeks of t r a i n i n g at 70% of maximal heart rate. These adaptations were observed despite an unchanged TPR which would also enhance cardiac performance, and as such, represented impressive data. Although Wolfe et a l . , (1982) did not show increased s y s t o l i c time i n t e r v a l s after a 6 month t r a i n i n g program i n males despite a 17% improvement i n VC^max, cardiac output, and stroke volume improved. Nevertheless, i t was the authors 162 conclusion that these changes were due to changes i n preload, rather than actual s t r u c t u r a l or c o n t r a c t i l e adaptations to the myocardium. This re s u l t agrees with a more recent study, comparing very well trained vs. moderately trained runners (Crawford et a l . , 1985). The authors found increases i n LVEDV at rest and at peak exercise, and ascribed these improvements to the f i t t e r subjects a b i l i t y to u t i l i z e the less-energy costing Frank- S t a r l i n g mechanism to increase cardiac function, which could be simply due to increased venous return. Improvements i n i n t r i n s i c cardiac function have been demonstrated i n healthy middle-aged indiv i d u a l s as well (Martin et a l . , 1987). After 12 weeks of intense swim and c i r c u i t weight t r a i n i n g , VC^max increased from 2 9 to 35 ml-kg-min - 1, stroke volume increased 18%, and l e f t v e n t r i c u l a r d i a s t o l i c dimension was enlarged. The conclusions to these data were that the improvements observed were a combination of increased capacity for peripheral vasodilation, with an accompanied improvement i n i n t r i n s i c cardiac c o n t r a c t i l i t y . Barnard (et a l . , 1977), also studying middle-aged men, found that t r a i n i n g resulted i n favourable improvements i n cardiac function, with post-training MVO2 requirements reduced by 18% vs. control subjects as measured by the tension-time index. The d i a s t o l i c pressure time index was s i g n i f i c a n t l y 163 greater during exercise a f t e r t r a i n i n g as well, i n f e r r i n g that myocardial O2 demand was reduced, e f f e c t i v e l y improving the supply/demand rela t i o n s h i p of myocardial perfusion. It would seem then, that for healthy i n d i v i d u a l s without p r i o r or present cardiac disease, the capacity for adaptations i n the pumping a b i l i t y of the l e f t v e n t r i c l e , as well as the capacity for simultaneous reductions i n the work of the heart (MVO2) at any submaximal exercise load, i s enhanced a f t e r endurance t r a i n i n g . For an more complete review and summary of cardiac chamber changes i n normals after exercise t r a i n i n g , the reader i s referred to Peronnet et a l . , (1981), and Dowell (1883) for d e t a i l s of proposed biochemical/cellular mechanisms. Cardiovascular Responses to Exercise i n Patients with Coronary Artery Disease or Myocardial I n f a r c t i o n Exercise superimposed on an already compromised myocardial function, either due to the presence of necrotic myocardium, or coronary occlusion without cardiac damage, presents a unique challenge to the body. Skeletal muscle perfusion must be maintained, even i n adverse environmental conditions. Since coronary oxygen extraction i s almost maximal at rest as discussed above, the patient with coronary obstruction reaches a point of s p e c i f i c exercise i n t e n s i t y (and 164 corresponding myocardial oxygen demand) where myocardial blood demand exceeds coronary supply. Energy for cardiac pumping must be transferred to the poorly adapted myocardial anaerobic pathways, and ischemic signs and symptoms ensue (Ellestad, 1975). Clearly, the exercise response i n CAD w i l l depend upon the extent of disease, the presence or absence of p r i o r MI, state of aerobic conditioning, i n addition to other more subtle factors. As i l l u s t r a t e d i n Figure 7.4, the CAD patient d i f f e r s from the normal subject during maximal exercise t e s t i n g i n the following respects. A true VC^max and RER > 1.15 i s rarely achieved due to premature termination of the t e s t , caused by anginal symptoms of coronary i n s u f f i c i e n c y , associated electrocardiographic abnormalities, and reductions i n muscle blood flow leading to anaerobiosis secondary to dete r i o r a t i n g cardiac function. (Dressendorfer et a l . , 1981, Taylor et a l . , 1963). A study by Roberts (et a l . , 1984) found that none of normal subjects, and only 8.6% of t h e i r CAD patients plateaued VO2 at the end of exercise t e s t s . 165 Figure 7 . 4 Summary of Acute Exercise Responses i n the Cardiac Patient Racing of Percieved Exertion or Absolute Workload 166 As a r e s u l t , the maximal VO2 observed d u r i n g e x e r c i s e t e s t i n g s h o u l d be r e f e r r e d t o as VC^peak as opposed t o VC^max, which would imply t h a t the p a t i e n t reached a t r u e p h y s i o l o g i c a l maximum. I t i s consequently not s u r p r i s i n g t h a t the changes i n c a r d i o v a s c u l a r f u n c t i o n accompaning i n c r e a s i n g e x e r c i s e loads d i f f e r s i n t h i s group compared wi t h h e a l t h y s u b j e c t s . A normal i n c r e a s e i n e j e c t i o n f r a c t i o n of 5% from r e s t t o e x e r c i s e as measured by r a d i o n u c l i d e angiography has been demonstrated i n h e a l t h y i n d i v i d u a l s . A f a i l u r e t o change, only s l i g h t i n c r e a s e s , or a f a l l i n LVEF can be demonstrated i n CAD p a t i e n t s (Borer et a l . , 1977). S l u t s k y et a l . , (1979) a t t r i b u t e s the f a l l i n EF t o i n c r e a s e s i n LVESV, i n d i c a t i n g impairment o f f o r c e g e n e r a t i o n and c o n t r a c t i l i t y . I s k a n d r i a n (et a l . , 1981) has observed however, t h a t EF alone does not e x p l a i n a l l the mechanisms of d i s t u r b a n c e s i n c a r d i a c f u n c t i o n i n the e x e r c i s i n g CAD p a t i e n t . They demonstrated a poor c o r r e l a t i o n between d u r a t i o n o f e x e r c i s e and r e s t i n g EF. Gibbons et a l . , (1987) r e p o r t s c o n v e r s l y t h a t peak e x e r c i s e EF i s more i n d i c a t i v e of o v e r a l l c a r d i a c f u n c t i o n than other measures of L.V f u n c t i o n such as s y s t o l i c p r e s s u r e / s y s t o l i c volume r a t i o s . There s t i l l remains the argument of which index o f c a r d i a c f u n c t i o n ( s ) a l t e r e d d u r i n g e x e r c i s e i n CAD p a t i e n t s i s 167 contributing to the abnormal exercise tolerances. Thompson et a l . , (1987), using echocardiography compared CAD patients with normals during exercise at 85% VC^max. Although SV was the same at rest between the two groups, the CAD patients could not increase SV with exercise. The same was the case for EDV, but for ESV however, both groups demonstrated no decrease i n t h i s parameter with exercise. As expected, submaximal cardiac output values were s i m i l a r at rest, but the CAD group had lower values at peak exercise. The normal group increased t h e i r EF from 66 to 77% (rest to exercise), but the CAD group increased from 62 to only 67%. This study was unique i n that i t measured subjects i n the supine position, where EDV i s maximal, thereby leaving only HR as a mechanism for increasing CO. Iskandrian et a l . , (1981) found that increasing CO was accomplished by tachycardia, since there were i n s i g n i f i c a n t changes i n the magnitude of EDV (257 to 259 ml) and ESV (189 to 187 ml) and SV (68 to 73 ml) with increasing exercise. It has been postulated that the i n a b i l i t y of CAD patients to increase EDV, which could u t i l i z e the Frank-Starling mechanism to augment CO, could be due to regional myocardial necrosis (prior MI) r e s t r i c t i n g myocardial compliance, reducing stretch from venous return (Thompson et a l . , 1987) . This i s further confirmed by recent increasing int e r e s t i n l e f t v e n t r i c u l a r d i a s t o l i c function as an equally important 168 variable i n cardiac performance during exercise (Gibson, 1987). Thus, i n summary, the CAD patient d i f f e r s from the normal subject i n terms of cardiac performance during exercise i n several respects. F i r s t l y , s y s t o l i c function i s impaired due to decrements i n myocardial perfusion past a s p e c i f i c MVO2 corresponding to a s p e c i f i c external work load and V O 2 . Secondly, due to cardiac scarring from p r i o r MI, or ischemia, d i a s t o l i c function (and hence compliance) i s compromised, minimizing the p o t e n t i a l contribution of CO from the Frank-Starling mechanism. The net r e s u l t i s a decreased SV and EDV, and an elevated ESV during exercise. Maximum CO w i l l be reduced. Other variables such as l e f t v e n t r i c u l a r stroke work and s y s t o l i c p r e s s u r e / s y s t o l i c volume r a t i o w i l l be reduced at any given l e v e l of exercise and at peak exercise. 169 Cardiac Rehabilitation-A Short H i s t o r i c a l Perspective From an h i s t o r i c a l perspective, exercise therapy for patients with heart disease i s a r e l a t i v e l y new concept i n medicine. The t r a d i t i o n a l l y accepted treatment for a MI has u n t i l only the l a s t few decades had been t o t a l bed rest. Typical treatment for the recovering cardiac patient is. best i l l u s t r a t e d from a quotation from Lewis (1933, p.49); "The patient i s to be guarded by day and night nursing and helped i n every way to avoid voluntary movement of e f f o r t " . After the myocardial scar had formed, the most a patient had to look forward to was a l i f e of i n a c t i v i t y , which would often prematurely end a career and provoke damaging subsequent psychological problems. However, as early as the nineteen f o r t i e s , the role of bed rest and chronic i n a c t i v i t y i n the treatment of CAD began to change. It was noted by Heberden (1941) as early as 1941 that although he had . . " l i t t l e to advance.."for the treatment of angina he knew of one patient "who set himself a task of sawing wood for a ha l f an hour every day and was nearly cured". Probably the f i r s t incentive for advocating a c t i v i t y during the recovery stage a f t e r MI was based upon the deleterious e f f e c t s of bed rest on p h y s i o l o g i c i c a l processes and 17 0 functional capacity. This had of course been elucidated by exercise physiologists, i n p a r t i c u l a r S a l t i n et a l . (1968) who studied the e f f e c t s of t o t a l bed rest on the waning of VC^max and the time course to gain i t back with resumption of t r a i n i n g . Additional research with CAD and post-MI patients demonstrated that prolonged immobilization reduced work capacity by 20-25%, and reduced blood volume by 700 to 800 ml with 7 to 10 days of bed rest (Dock, 1944, S a l t i n et a l . , 1968). The resultant orthostatic hypotension produces tacycardia, which places further O2 demand on an already deconditioned and ischemic heart. Blood v i s c o s i t y increases due to the decreased blood volume/RBC volume r a t i o , predisposing the patient to thromboembolism (Fareeduddin and Ableman, 1969). Additional changes also include decreased pulmonary v e n t i l a t i o n and v i t a l capacity, a l t e r a t i o n s i n nitrogen balance, a 10 to 15% decrease i n lean muscle mass aft e r as early as 7 days, with p a r a l l e l increases i n VO2 for any given l e v e l of work. This l a t t e r e f f e c t also dangerously increases the MVO2 i n the already compromised heart. Thus the beginnings of what i s now commonly known as "Phase I" cardiac r e h a b i l i t a t i o n was set i n motion. The more prophylactic applications of exercise, p a r t i c u l a r l y endurance or aerobic exercise well a f t e r the discharge period a f t e r an MI (Today's Phase II and III) would take a few more years to develop. 171 Leaders such as H e l l e r s t e i n i n the mid-nineteen s i x t i e s were developing the connection between the epidemiology of physical a c t i v i t y i n the prevention of CAD, and applying these concepts to secondary and t e r t i a r y prevention i n i n d i v i d u a l s wishing to return to f u l l and productive l i f e . More important c l i n i c a l l y , was the need to prevent further angina and recurrent MI (Hellerstein, et a l . , 1967). The London bus driver study by Morris et a l . , (1953, 1956) was also an important research landmark associating i n a c t i v i t y with increased r i s k of CAD. It was r e a l i z e d that the research pointing to some "protective e f f e c t " incurred by chronic exercise t r a i n i n g i n healthy i n d i v i d u a l s could be applied safely and e f f e c t i v e l y i n CAD patients. These exercise e f f e c t s could minimize work of the heart and reduce ischemic symptoms by increasing the aerobic capacity, diminishing body fat, and using exercise as a springboard to an o v e r a l l healthier l i f e s t y l e (ie., smoking cessation, stress management, dietary a l t e r a t i o n s ) . Many of these early p r i n c i p l e s are s t i l l routinely put to practice i n the 1980's. Although many cardiac r e h a b i l i t a t i o n programs were i n i t i a t e d around the world, the Toronto Reha b i l i t a t i o n Centre i s often recognized as one of the i n i t i a t o r s and innovators of the f i e l d i n North America. The use of walking, progressing to 172 jogging, and a s c i e n t i f i c methodology of prescribing and monitoring patients' exercise programs was formulated, and produced i n i t i a l l y impressive r e s u l t s . Kavanagh (et a l . , 1973) demonstrated increases i n estimated VC^max from 27 to 38 ml•kg - 1'min - 1 and decreases i n ST-segment depression with 2 years of exercise. A control group receiving only hypnotherapy did not demonstrate any of the b e n e f i c i a l adaptations. Kavanagh's Centre, and a selected group of exceptional patients amazed the world when they trained and successfully completed the Boston Marathon i n 1975. These patients demonstrated an improvement i n VC^max from 28 to 44 ml • kg-1-min--1-, 25% better than the healthy sedentary Toronto population norm for aerobic capacity (Kavanagh et a l . , 1977) . Ranges of values reported for peak oxygen uptake af t e r endurance t r a i n i n g i n CAD and Post/Ml patients i s summarized on Table 7.2. 173 Table 7.2 I n i t i a l Value and Change i n VC^max A f t e r Exercise Training i n Patients with CAD Source N, Hx VC^max Pre % change D u r a t i o n (ml-- -k q ~ X: '.min "-*-) (months) Detry et a l . , 6 MI 27 18 3 1971 6 angina 19 31 3 Redwood et a l . 7 angina 10 56 1.6 1972 Ferguson 14 MI, CAD 22 25 13 et a l . , 1978 Conner et a l . , 6 MI 20 19 8-12 1976 Clausen & Trap-Jensen 25 angina 100 3 1970 P a t t e r s o n et a l . , 37 MI (intense) 28 13 6 1979 42 MI (low i n t . ) 28 -2 .6 F r a n k l i n 16 MI 24 13 3 et a l . , 1978 Hagberg et a l . 11 MI, CAD 25 39 12 1983 F r o e l i c h e r et a l . , 69 CAD + c o n t r o l s 33 -3 12 1984 59 CAD + e x e r c i s e 33 18 12 Adapted from: Thompson, P.D. 1988, p. 1539 174 More recent developments i n cardiac r e h a b i l i t a t i o n include the greater va r i e t y i n modes of a c t i v i t i e s for the upper and lower body and more advanced methods of p r e s c r i p t i o n and patient education and motivation. However, the precise p h y s i o l o g i c a l mechanisms whereby the post-MI and CAD patient benefits from exercise are s t i l l hotly argued. The rationale for exercise for minimizing symptoms and reducing the psychological and pathological e f f e c t s of the disease are confirmed. What i s s t i l l not completely understood however, i s the rela t i o n s h i p between long-term p a r t i c i p a t i o n a f t e r MI, and the subsequent f a t a l and non- f a t a l r e - i n f a r c t i o n rate. Some research would suggest that exercise t r a i n i n g for CAD patients i s d i r e c t l y related to prevention of r e - i n f a r c t i o n however. Kanavagh, who has one of the largest ongoing patient data bases of any centre i n the world has suggested that compliance with the exercise regimen was the most important single determinant of long-term prognosis (Kavanagh et a l . , 1979). The r i s k r a t i o for f a t a l and non- f a t a l r e i n f a r c t i o n s was 23.6 times higher for those patients who complied poorly, and the authors suggested that exercise was responsible for maintaining a p o s i t i v e behaviour towards other important r i s k factors such as smoking. A more recent study has demonstrated that simply the a b i l i t y to 175 successfully complete a post-6 month exercise test with fewer ST-segment changes and normal blood pressure responses i s associated with a s i g n i f i c a n t l y lower f a t a l and non-fatal recurrance rates (Stone et a l . , 1988). This would seem to indicate that exercise, r e s u l t i n g i n the above e f f e c t s i n most cases, must have some favourable e f f e c t on mortality. F a i l u r e of some of the larger c l i n i c a l t r i a l s to s i g n i f i c a n t l y demonstrate t h i s e f f e c t was probably due to small sample sizes, s t a t i s t i c a l problems, and cross-over of the non-exercising control groups (Naughton, 1982). 176 P h y s i o l o g i c a l Aspects of Exercise Training i n CAD Patients; Generalized and Peripheral E f f e c t s . From the previous discussion on the t r a i n i n g e f f e c t s which occur af t e r a period of chronic endurance exercise i n healthy individuals, i t i s apparent that many of these p r i n c i p l e s apply to the CAD/post-MI patient as well. The early studies which examined the e f f e c t s of exercise t r a i n i n g i n t h i s population were revealing, but crude s t a t i s t i c a l l y and te c h n i c a l l y , but nevertheless, formed the basis for l a t e r investigations. Varnauskas (et a l . , 1966) investigated 9 patients a f t e r only 1 month of t r a i n i n g and measured A -VO2 differences and CO using the Direct Fick method before and af t e r t r a i n i n g . Although the exercise t e s t i n g was submaximal, the authors demonstrated an increase i n anginal threshold, A -VO2 difference, with decreased lactate production, no change i n CO and V O 2 . . The anginal threshold i s , and w i l l be defined i n the remainder of t h i s text as the HR, workload or VO2 at which ischemic/anginal symptoms appear during an exercise test (Figure 7.5). It should be noted that t h i s study, and many si m i l a r early studies are characterized by the short study periods and r e l a t i v e lack of pre c i s i o n i n c a l c u l a t i n g the exercise p r e s c r i p t i o n and exercise s t i m u l i s . 177 Figure 7.5 Exercise Training and Increased Functional Capacity i n Cardiac Patients The r a i s i n g of the ischemic threshold by increasing VC^peak v i a peripheral adaptations, (Lowered MVO2 [dashed l i n e ] , postponing angina. Postulated increases i n maximal MVO2 by i n t r i n s i c changes i n cardiac v a s c u l a r i t y ( c i r c l e d line) would further increase VC^peak to VC^max. 178 It has been previously mentioned that non-invasive i n d i c i e s of myocardial 0 2 demand (RPP, TTI) can be u t i l i z e d to predict actual MVO2 with surprising r e l i a b i l i t y . This has been u t i l i z e d extensively i n the c l a s s i c research, and was demonstrated i n the reductions of submaximal work RPP found by F r i c k et a l . (1968), Kasch et a l . (1969), Clausen et a l . , (1970), Detry et a l . , (1971), Redwood et a l . , (1972), and others (Table 7.3). F r i c k and co-workers found reductions i n TTI at the same absolute l e v e l of work from 5.17 to 4.38 x 10~ 3, and s i m i l a r changes for RPP i n 7 patients. Kasch et a l . , (1969) were' able to demonstrate resting as well as exercise reductions i n RPP i n 11 patients. In a well quoted and comprehensive study, Clausen et a l . , (1970) studied 9 CAD patients who trained for 5 d/week for up to 10 weeks and found that CO was reduced at submaximal work loads, but was increased at maximal work rates. Muscle blood flow rates followed a s i m i l a r pattern to CO (reductions of 15%), i n d i c a t i n g that the patients were able to more e f f e c t i v e l y r e d i s t r i b u t e the CO during exercise, thus reducing the work of the heart. Further studies by Clausen et a l . (1969), with very l i t t l e control over the exercise i n t e n s i t y ("adjusted i n d i v i d u a l l y according to the working capacity of each patient") were able to demonstrate lower s y s t o l i c blood pressure at the 179 same submaximal workloads, with a 34% improvement i n functional capacity as tested on cycle ergometers. 180 Table 7.3 Indirect Indicies of Myocardial Oxygen Demand Before and Af t e r Physical Conditioning by Male Coronary Heart Disease Patients Study Index Rest E x e r c i s e I n t e n s i t y pre post pre post Redwood et a l . TP 4300 3521 Submax WL 1972 4300 4885 Angina s t a r t F r i c k , K a t i l a TTI 2519 2941 5161 4382 Submax WL 1968 RPP 103 107 262 242 Submax WL Clausen et a l . TTI 2470 2380 3943 3393 Submax WL 1973 RPP — — 204 166 Submax WL H e l l e r s t e i n RPP 248 193 Submax WL et a l . , 1967 Detry, et a l . , RPP 81 64 116 94 45% of pre - 1971 V02max 166 137 75% of pr e - V02max Kasch & Boyer RPP 106 85 163 156 28 6 kpm pre, 1969 382 kpm post 247 296 Max WL Clausen & Trap-Jensen RPP 222 202 Submax WL 1976 222 220 at angina TP: T r i p l e Product (HR x SBP X E j e c t i o n Time) TTI: Tension-Time Index (area under s y s t o l i c p r e s s u r e curve x HR) RPP: Rate P r e s s u r e Product (HR x SBP X 10 z) Adapted From: H a s k e l l , W., 1977, p. 352 181 Sanne i n 1973, u t i l i z e d a large control and exercise group i n the experimental design, and found the c l a s s i c responses to exercise t r a i n i n g (reduced HR 10 to 24 bpm, reduced SBP at submaximal workloads, and increased work capacity). The i n t e r e s t i n g aspect of t h i s study i s not only the i n c l u s i o n of a control group, but that the exercise program consisted of low-intensity stimulus, and had patients exercise for only 2 sessions/week for 30 minutes. The applicatio n of varying l e v e l s of intensity, frequency and duration i n the exercise p r e s c r i p t i o n , as s h a l l be discussed i n further sections, might be the l i m i t i n g factor i n the p o t e n t i a l p h y s i o l o g i c a l adaptations which can occur i n t h i s popuation. Although the a b i l i t y for CAD and post-MI patients to show improvements i n functional capacity (and i n d i r e c t benefits to the myocardium) afte r exercise t r a i n i n g of varying lengths and i n t e n s i t i e s can be demonstrated, the exact cause of these adaptations has become an important research and c l i n i c a l issue. In most of the e a r l i e r l i t e r a t u r e , peripheral mechanisms have been primarily implicated, with some or questionable involvement of central or cardiac function. Detry et a l . , (1971) implied that peripheral adaptations were responsible for the 23% increases i n VC^max, reductions i n RPP and HR at given absolute workloads. However, the 182 bradycardia at rest and exercise was compensated for not by increases i n SV, as would be found i n normal populations, but increases oxygen extraction at the tissues (A-VO2 d i f f e r e n c e ) . The authors thus concluded that increased capacity for exercise a f t e r t r a i n i n g was a re s u l t of primarily increased a r t e r i a l 0 2 content (increased Hb and blood volume) and peripheral 0 2 extraction. Their patients trained 3 times per week for 3 months, 45 min/session. Sim and N e i l l (1974), u t i l i z i n g a s i m i l a r t r a i n i n g protocol with t h e i r 9 patients found increases i n maximal RPP, TTI, and anginal threshold, with p a r a l l e l decreases i n i n d i r e c t i n d i c i e s of myocardial 0 2 consumption during submaximal work. Although M V 0 2 was reduced at rest, t h i s change was non-significant, as were changes i n coronary A - V 0 2 difference and some cardiac volumes. When cardiac pacing was performed however, there was no change i n RPP, which the authors concluded, pointed to no i n t r i n s i c changes i n cardiac function or blood supply due to exercise t r a i n i n g . This was reinforced by Detry and Bruce (1971) i n a study with 11 patients who trained for 3 months, 3 days/week. Although V0 2max increased 21%, and complementary changes i n submaximal RPP and ST-segments, ST-segment depression s t i l l occurred at the same HR, (and presumably the same M V 0 2 ) a f t e r t r a i n i n g . This finding prompted the authors to conclude that submaximal changes are a function of 183 pe r i p h e r a l l y altered hemodynamics and increased O2 extraction, and the f a i l u r e to increase the threshold for ST-changes indicated that myocardial c i r c u l a t i o n or function does not change with exercise t r a i n i n g . This same conclusion was proposed by other investigators (Raffo et a l . , 1980, Myers et a l . , 1984), who found submaximal changes i n ST-segment depression, but no changes in maximal HR ST-segment depression which would have supported actual increases i n myocardial O2 consumption (and hence, cardiac c i r c u l a t i o n ) a f t e r t r a i n i n g . It i s worthy of mention however, that these two studies were characterized by low t r a i n i n g i n t e n s i t i e s (approximately 60% of HR reserve, using Karvonen's (1956) method). The evidence for the predominant nature of the peripheral t r a i n i n g e f f e c t was further supported by a study by Ogawa et a l . (1981). The investigators trained 11 patients with, treadmill exercise for 3 months at up to 75% of maximum, and using venous occlusion plythsmography, demonstrated impressive changes i n post-exercise hyperemia and limb blood flow during hand and ankle exercise. VC^max increased s i g n i f i c a n t l y (9.4 to 12.4 METs), and rest i n g and exercise c a l f blood flow decreased s i g n i f i c a n t l y i n the trained legs, but not i n the arms, as did other parameters ("flow debt", peak and t o t a l active hyperemic blood flow). This study demonstrated the importance of peripheral (biochemical and 184 c a p i l l a r i z a t i o n ) e f f e c t s of t r a i n i n g , i n addition to the s p e c i f i c i t y concept. Although these studies have implied peripheral changes i n the dominance of the t r a i n i n g e f f e c t s i n the CAD and post-MI patient, none had actually demonstrated h i s t o l o g i c a l and biochemical a l t e r a t i o n s i n the trained muscle. Only one study to date has v e r i f i e d the peripheral e f f e c t s with muscle biopsy techniques i n the CAD patient. Ferguson and Taylor (1982) studied 26 MI/CAD patients a f t e r 6 months of t r a i n i n g at an in t e n s i t y equivalent to t h e i r anginal threshold, one hour, 3 sessions/week. The patients increased VC^max by 41%, and demonstrated the expected changes i n submaximal HR, RPP and catecholamines. Muscle biopsy data revealed s i g n i f i c a n t increases i n succinate dehydrogenase a c t i v i t y (1.75 to 3.31 IU) and percentage of type I f i b r e s (43.6 to 54.3%). The authors also demonstrated small but suggestive changes i n cardiac i n d i c i e s . These included an 8% increase i n coronary sinus blood flow and MVO2 (11%). These adaptations were not correlated with the muscle biochemical changes, but curiously, were sim i l a r i n proportion to those observed i n highly trained endurance athletes. The res u l t s of t h i s study indicated s t i l l a preponderance of the periphery as the mediator of the t r a i n i n g e f f e c t , but with some in d i c a t i o n of central involvement. 185 Maximal Oxygen Consumption and Alternate Variables to Measure Functional Capacity i n CAD Patients It i s clear from the l i t e r a t u r e that the "gold standard" i n the measurement of maximal functional capacity has been the maximal oxygen consumption (V02n\ax) , either measured i n 1. min - 1, ml-kg - 1-min - 1 or METs (1 MET = 3.5 ml-kg - 1-min - 1) . Most patients cannot a t t a i n a true p h y s i o l o g i c a l l y defined V02max because of f a i l u r e to achieve the previously discussed p h y s i o l o g i c a l markers. One increasingly popular, as well as c l i n i c a l l y and ph y s i o l o g i c a l l y appealing alternative to r e l y i n g s o l e l y upon V02max when inte r p r e t i n g the magnitude of cardiorespiratory f i t n e s s i s the Ventilatory Threshold (VT), also referred to as the "anaerobic threshold" (Wasserman and Mcllroy, 1964, Wasserman et a l . , 1973, Sullivan et a l . , 1985, Skinner and McLellan, 1980). The VT i s controversial because of i t s name, detection patterns and the underlying p h y s i o l o g i c a l mechanisms. T r a d i t i o n a l l y , the abrupt increase i n minute v e n t i l a t i o n (V E) with increasing VO2 has been ascribed to the HCO-^ buffering of increased H + ion level s as the work rate exceeds that which can be accomplished e n t i r e l y a e r o b i c a l l y (Wasserman et a l . , 1973). The debate continues whether there i s a point where muscle O2 supply i s diminished, 186 l e a d i n g t o anaerobic metabolism and l a c t a t e output (Davis et a l . , 1976), versus the n o t i o n t h a t 0 2 d e l i v e r y i s maximal at maximal e x e r c i s e , l a c t a t e i s present even at r e s t , and t h a t l a c t a t e accumulation i s simply a f u n c t i o n o f v a r y i n g r a t e s of l a c t a t e disapparance versus l a c t a t e f ormation (Donovan and Brooks, 1983). In any case, the parameter i s a f a i r l y r e p r o d u c i b l e p h y s i o l o g i c a l event, r e g a r d l e s s of i t s mechanism, and can be used t o modify e x e r c i s e p r e s c r i p t i o n s based e n t i r e l y on the "percentage o f maximum" v a l u e s , which can not e n t i r e l y account f o r d i f f e r e n c e s i n e f f o r t (Katch et a l . , 1978). VT va l u e s are commonly r e p o r t e d as abrupt changes i n s e v e r a l v e n t i l a t o r y parameters o c c u r r i n g at e i t h e r percentages o f VC^max or at s p e c i f i c VC^/HR/Workload v a l u e s . E l i t e a t h l e t e s have VT's of up t o 85% of VC^max, i n d i c a t i n g v ery h i g h s u s t a i n a b l e s t e a d y - s t a t e e x e r c i s e c a p a c i t i e s (Kinderman et a l . , 1979). Symptomatic c a r d i a c p a t i e n t s , even w i t h low f i t n e s s l e v e l s have VT's at h i g h percentages (65 t o 80%) of VC^max, (Roberts et a l . , 1984) and h i g h percentages of HRmax. T h i s i s because c h r o n o t r o p i c medications can s h i f t the r e l a t i o n s h i p o f HR t o workload. In a d d i t i o n , due t o premature t e r m i n a t i o n o f the t e s t , the VT can occur at a "high" percentage of maximum. The VT has been shown t o s h i f t t o the r i g h t w i t h i n c r e a s e s i n t r a i n i n g i n a t h l e t e s and h e a l t h l y normals (Kinderman et a l . , 1979, Davis et a l . , 1979), even i f onl y s l i g h t changes i n VC^max have o c c u r r e d . 187 Only one study has compared the change i n the VT with t r a i n i n g i n CAD patients. As part of a much larger t r i a l , S u l l i v a n et a l . , (1985) followed a control and exercise group (1 year t r a i n i n g at 60 to 85% peak workload). Although there was no increase i n VT (using the V E / V 0 2 v e n t i l a t o r y equivalent for O2 parameter), there was as small c o r r e l a t i o n between the change i n V02max and change i n VT. This study however, included patients who demonstrated poor compliance and hence, a l i m i t e d t r a i n i n g e f f e c t . 188 Cardiac Adaptation and Exercise Training i n Cardiac Patients It has"been demonstrated i n previous chapters that cardiac morphologic and functional changes can be expected a f t e r a period of chronic endurance t r a i n i n g i n the healthy adult. Whether t h i s can be demonstrated i n cardiac patients i s s t i l l under debate. The most compelling evidence for cardiac adaptations with exercise superimposed upon cardiac disease seems to come from the animal l i t e r a t u r e , and some early anecdotal human observations, namely r e l a t i n g cardiac health to reduced rates of MI and CAD. In 1961, Currens and White studied Clarence DeMar, the famous four-time winner of the Boston Marathon i n the early part of the century, and examined his coronary anatomy af t e r his death from cancer. The diameter of his main coronary branches were more than twice that of a t y p i c a l non-trained male. Conclusions were put forth that i t was t h i s habitual t r a i n i n g that resulted i n the large coronary lumen, which must have provided greater coronary flow and resultant cardiac output. However, as we r e a l i z e now, his coronary size could have been simply inherited, and the sample size was i n e f f e c t i v e i n generalizing to the population. An equally a l l u r i n g study by Eckstein (1957) gave r i s e to 189 the concept of c o l l a t e r a l i z a t i o n r e s u l t i n g from chronic ischemia. His animals were s a c r i f i c e d a f t e r a r t i f i c i a l coronary l i g a t i o n , and casts of the coronary tree revealed increased coronary c o l l a t e r a l p r o l i f e r a t i o n . Unfortunately, there was no control group i n the study design, and the separation of c o l l a t e r a l i z a t i o n due to ischemia alone or ischemia plus exercise could not be evaluated. Caryle et a l . , (1981) found that there was an exercise- induced reduction of rat myocardial i n f a r c t i o n s i z e a f t e r a r t i f i c i a l l y occluding the coronary a r t e r i e s . The exercised rats had s i g n i f i c a n t l y increased c a p i l l a r y / f i b r e r a t i o s compared to the control animals, and the MI size a f t e r the t r a i n i n g period (60 minutes swimming, 5 days/week for 5 weeks) was 30% less than i n the control r a t s . One problem i n the study i s that the suddenly induced coronary occlusion i n these animals might i n fact d i f f e r from the slowly developing atherosclerotic process i n the human model. Nevertheless, i t provided a model for the protective e f f e c t s of exercise on the heart. A l a t e r study by Cohen et a l . , (1982) reproduced Eckstein's o r i g i n a l study, but t h i s time with more experimental controls, and , with the incl u s i o n of an exercise intervention. The re s u l t s demonstrated s i m i l a r trends towards improved i n t r i n s i c cardiac function and v a s c u l a r i t y a f t e r exercise t r a i n i n g . 190 In a 5 year study, the components of diet and exercise were separated i n an attempt to uncover the athe r o s c l e r o t i c process i n the coronary a r t e r i e s (Kramsch et a l . , 1981). Male monkeys were given either a control diet with no exercise, atherogenic diet with no exercise, or an atherogenic diet with exercise. The trained monkeys developed LV hypertrophy and enlarged coronary lumens, but the e f f e c t s of a subsequently high fat diet (experimentally inducing atherosclerosis) resulted i n coronary occlusion. The authors thus concluded that r e l y i n g upon dietary changes without exercise would be less e f f e c t i v e i n attempting to control the coronary occlusive process. The benefits of using primates i n the experimental design was that they more clo s e l y patterned the human b i o l o g i c a l and ph y s i o l o g i c a l model than rodents or canines. The work i n t h i s area of animal research i s extensive, and beyond the scope of t h i s short summary, and thus the reader i s referred to two excellent review a r t i c l e s which comprehensively cover t h i s aspect of exercise and the heart in animal research (Cohen, 1983, Dowell, 1983). Mention of some of the more outstanding papers i n t h i s area however, i s important i n understanding the related work i n the human model. In animal research, experimental conditions can be very well controlled. Cardiac biochemistry and 191 morphology pre and post-training can be assessed d i r e c t l y from autopsy, but only estimated i n humans. Furthermore, the exercise i n t e n s i t i e s administered to animals represents impossible equivalent work for humans to accomplish. This probably has enhanced the c o l l a t e r a l i z a t i o n e f f e c t found i n animals, and i s possibly responsible for the equivocal findings i n the human cardiac population, where the exercise stimulus i s much reduced. Furthermore, confounding factors such as environment, diet, and behaviour can be e f f e c t i v e l y eliminated i n animal research. Nevertheless, there i s a growing body of l i t e r a t u r e , which has attempted to demonstrate an i n t r i n s i c . cardiac adaptation r e s u l t i n g from exercise t r a i n i n g i n the MI and CAD patient, independant from the previously demonstrated peripheral e f f e c t s . Even before exercise t r a i n i n g i s i n i t i a t e d (approximately 6- 8 weeks afte r the uncomplicated recovery from MI) , the myocardium undergoes a spontaneous improvement i n function. Wohl (et a l . , 1977) indicated that l e f t v e n t r i c u l a r function improved gradually and then s t a b i l i z e d over the ensuing months as the myocardium heals. Obviously then, research attempting to document changes i n LV function as a r e s u l t of exercise t r a i n i n g should begin only aft e r t h i s process i s completed. Studies that f a i l to take t h i s spontaneous 192 recovery e f f e c t into account could erroneously suggest improvements i n LV function. The importance of improving the functional capacity by central, i n addition to peripheral mechanisms, i s not only important to determine for s c i e n t i f i c c u r i o s i t y purposes, but i t also holds important prognostic implications for CAD and post-MI patients. White et a l . , (1984) i n a study following 605 post-MI patients found that cardiac function i n d i c i e s (LVESV, LVEDV, LVEF) were r e l i a b l e and v a l i d prognostic indicators of prognosis for future cardiac events and mortality. The authors found that survivors had ESV's of 72 ml, non-cardiac death: 87 ml, and cardiac death: 122 ml. For LVEF, the pattern was 55%, 51% and 44%, respectively. Thus there seems to be some relat i o n s h i p between cardiac performance and o v e r a l l prognosis. The key question which needs to be addressed s c i e n t i f i c a l l y , i s , whether aft e r a MI the viable remaining human myocardium can demonstrate biochemical changes s i m i l a r to that found i n sk e l e t a l muscle when i t i s trained. Obviously, i n the human model these changes can be only demonstrated non-invasively (radionuclide angiograms), or implied from i n d i r e c t measures, such as symptomatology and ECG changes at peak or submaximal exercise loads. If i n fact the heart muscle can develop increased a c t i v i t y 193 of aerobic enzymes and/or increased v a s c u l a r i t y , t h i s would t h e o r e t i c a l l y reduce myocardial ischemia, probably not by recanalization of the e x i s t i n g a t h e r o s c l e r o t i c lesion, but by increasing the myocardial oxygen uptake i n the viable remaining myocardium, t h i s would e f f e c t i v e l y reduce the ef f e c t of the e x i s t i n g fixed narrowing. The "Bassler Hypothesis", f i r s t boldly put forth by pathologist Thomas Bassler i n the mid- 1970's (Bassler, 1977) implied that marathoning (ie., the t r a i n i n g neccessary to complete a marathon) would provide immunity to CAD. This hypothesis has been challenged now, even by pro-exercise c a r d i o l o g i s t s and physiologists, because of the many f i t marathoners who have gone on to develop CAD or die suddenly from MI. Nevertheless, the cardiac hypothesis, p a r t i c u l a r l y the c o l l a t e r a l i z a t i o n theory has many applications for the t r a i n i n g cardiac patient and the apparently healthy middle aged male. Figure 7.5 (above) summarizes the e f f e c t s of chronic endurance t r a i n i n g on the anginal threshold i n cardiac patients. Froelicher l i s t s some of the postulated cardiac mechanisms which could account for any benefit and reduced morbidity and mortality from CAD/MI i n Table 7.4. 194 Table 7.4 Factors A f f e c t i n g Cardiac Morbidity and M o r t a l i t y Postulated Cardiac Mechanisms 1. Myocardial hypertrophy 2. Myocardial H i s t o l o g i c changes 3. Increased Coronary Artery Size 4. Coronary C o l l a t e r a l C i r c u l a t o r y E f f e c t s 5. Ef f e c t s on Cardiac Performance (Peripherally Mediated) 6. Changes i n Mitochondrial Enzymes 7. E f f e c t s of F i b r i n o l y t i c A l t e r a t i o n s i n Cardiac Function (From Froelicher, 1977) 195 The l i t e r a t u r e documenting cardiac e f f e c t s of exercise t r a i n i n g i n CAD patients i s varied i n i t s methodologies, findings, and conclusions. Depending upon the sample size, t r a i n i n g i n t e n s i t i e s , duration of t r a i n i n g , and method of determining cardiac function, d i f f e r e n t conclusions can be made. In 1973, Rousseau et a l . , attempted to separate the contributions of central and peripheral adaptations i n 14 post-MI patients. Although the trained group of patients had higher A - V 0 2 differences (16.1 vs. 14.4 ml/100 ml), in d i c a t i n g a peripheral e f f e c t , SV decreased i n both groups af t e r 65% of VC^max. Stroke volume was not d i f f e r e n t at rest or exercise between the trained and untrained group, leading the investigators to determine that increased VC^max was a res u l t of a widening of the A -VO2 difference, and that t r a i n i n g e f f e c t s were a manifestation of greater O2 extraction by the working muscles, and a more e f f i c i e n t r e d i s t r i b u t i o n of the CO. Two studies i n 1976 were notable i n that they u t i l i z e d invasive catheterization to attempt to demonstrated changes i n c o l l a t e r a l i z a t i o n with exercise t r a i n i n g . Due to the nature of the methodology, the sample sizes were small, and both f a i l e d to detect any c o l l a t e r a l i z a t i o n e f f e c t or reduction i n the size and involvement of atherosclerosis, 196 thus c o n f l i c t i n g with the favorable reports i n the animal l i t e r a t u r e (Conner et a l . , 1976, Kennedy et a l . , 1976). The t r a i n i n g i n t e n s i t i e s u t i l i z e d i n the study were the standard 70% of VC^max, 3 days/week for 6 to 9 months. Although another d i r e c t catheterization study also yielded dissapointing r e s u l t s (increased workload by 17%, decreased RPP at submaximal work leve l s by 16%, but no change i n LVEF from 45% to 44%) , the authors conceeded that the t r a i n i n g stimulus might have been inadequate to induce cardiac adaptations (Letac et a l . , 1978). Ferguson et a l . , (1978) also discounted cardiac e f f e c t s by measuring coronary sinus blood flows (CSBF) afte r 6 months of t r a i n i n g i n 10 Post-MI patients. Despite expected peripheral changes, CSBF and M V 0 2 at rest were unchanged. At 400 kpm, HR was reduced from 163 to 103, RPP from 15 to 12.4, and CSBF from 163 to 135 ml/min., but these values at maximum exercise were unchanged. This led the authors to conclude that the lowered submaximal changes i n MVO2 and CSBF were due to the peripherally-mediated e f f e c t s . Nolewajka and Kostuk i n 197 9 using the f i r s t reported application of nuclear medicine techniques (albumen-labeled T c99ni) ^ n cardiac r e h a b i l i t a t i o n research demonstrated no evidence for c o l l a t e r a l development a f t e r i n j e c t i n g the tracer into the right and l e f t coronary a r t e r i e s . The advantages of t h i s r e l a t i v e l y non-invasive method of 197 inve s t i g a t i o n can be applied to the c i r c u l a t i o n , studies of generalized myocardial perfusion, or dynamic cardiac function. Consequently, i t i s not s u r p r i s i n g that the e a r l i e r studies u t i l i z i n g the small sample sizes appropriate to invasive studies, or the other non-invasive measures of CO and SV (CO2 re-breathing using the Fick Principle) did not y i e l d more p o s i t i v e findings. Paterson et a l . , (1979) used the CO2 re-breathing Fick p r i n c i p l e to determine cardiac changes a f t e r 6 and then 12 months of exercise t r a i n i n g as part of the Ontario Collaborative Heart Study. The study design u t i l i z e d a high and low i n t e n s i t y group (HIE and LIE, r e s p e c t i v e l y ) . Athough the HIE group improved V02max from 2 6 to 30.3 ml-kg - 1•min - 1, there was no change i n SV up to the 6 month period. A f t e r 6 months however, there was only a modest 10% increase i n SV, leading the investigators to side with the peripheral e f f e c t s and lowered sympathetic drive as the major determinants of the t r a i n i n g e f f e c t . A l a t e r report (Oldridge et a l . , 1985) followed the Collaborative Heart Study patients for 4 additional years and did demonstrate a 16% increase i n SV, but only at submaximal work loads. Two i n i t i a l l y well quoted studies appeared i n the same year using Thallium-201 and gated blood pool imaging techniques to uncover central t r a i n i n g e f f e c t s . The study by Froelicher (et a l . , 1980) u t i l i z e d an i n t e r v a l program and trained the 198 arms a n d l e g s f o r 6 m o n t h s . The t r a i n i n g i n t e n s i t y was "60 - 85% V C ^ m a x " . P e a k e j e c t i o n f r a c t i o n i m p r o v e d a m o d e s t 6%. J e n s e n e t a l . , (1980) i n a s i m i l a r s t u d y c o n v e r t e d t h e t r a i n i n g f r o m t h e i n t e r v a l scheme a b o v e t o c o n t i n u o u s w a l k i n g / j o g g i n g a t m o n t h 3. R e s t i n g L V E F i n c r e a s e d s i g n i f i c a n t l y f r o m 55 t o 59%, b u t t h e r e was no c h a n g e i n p e a k L V E F . T h e i r p a t i e n t s were a b l e t o i n c r e a s e p e a k R P P , b u t w i t h o u t c h a n g e s i n s u b m a x i m a l R P P . The a u t h o r s f o u n d some s u b t l e c h a n g e s i n T h a l l i u m s c o r e s , b u t t h e d a t a i s p r o b a b l y t o o s u b j e c t i v e i n n a t u r e t o d e t e r m i n e i f i n c r e a s e d v a s c u l a r i t y h a d o c c u r r e d . I n c o n t r a s t t o t h e s e e a r l y s u g g e s t i v e r e s u l t s , V e r a n i ( e t a l., 1981) f o u n d no c h a n g e s i n L V f u n c t i o n a t s u b m a x i m a l l o a d s d e s p i t e an i n c r e a s e d r e s t i n g E F a f t e r 3 m o n t h s o f t r a i n i n g a n d a 17% i n c r e a s e i n V C ^ m a x . E j e c t i o n f r a c t i o n s w e r e d e t e r m i n e d b y t h e s o m e t i m e s v a r i a b l e f i r s t - p a s s m e t h o d . S i m i l a r l y , C o b b (et a l., 1982) f o u n d no c h a n g e s i n L V E F a t r e s t , s u b m a x i m a l o r m a x i m a l work r a t e s a f t e r a 3 d a y / w e e k , 6 m o n t h p r o g r a m . T h e s e p a t i e n t s t r a i n e d a t a n i n t e n s i t y o f 75 t o 85% o f s y m p t o m - l i m i t e d V C ^ m a x . Hung e t a l., (1984) i n c l u d e d a c o n t r o l g r o u p i n t h e d e s i g n , a n d t h e t r a i n i n g g r o u p c o n d u c t e d t h e e x e r c i s e p r o g r a m a t home, w h i c h was m o n i t o r e d b y t e l e p h o n e c a l l s . A l t h o u g h t h e t r a i n e d g r o u p i n c r e a s e d M E T ' s , a n d d e m o n s t r a t e d t h e u s u a l s u b m a x i m a l t r a i n i n g a d a p t a t i o n s , L V E F a n d T h a l l i u m s c o r e s w e r e u n c h a n g e d . The c o n t r o l g r o u p a c t u a l l y d e m o n s t r a t e d t h e 199 greatest absolute changes i n cardiac parameters, causing the investigators to conclude that home programs e f f e c t i v e l y improve functional capacity, but that t h i s i s due to mainly peripheral e f f e c t s . Foster et a l . , (1984) randomized 28 post-MI males to either an exercise (30 minutes of cycle and treadmill training) or progressive relaxation and no exercise group. Gated blood pool angiograms were conducted at rest, submaximal (75%) and peak l e v e l s . Both the control and exercise groups increased t h e i r functional capacities. There were also no changes i n LVEF with the t r a i n i n g program for any l e v e l of metabolic stress. Other methods of determining cardiac a l t e r a t i o n s i n function and structure from exercise have been applied to the cardiac patient with generally less conclusive r e s u l t s . Ditchey et a l . , (1981) using echocardiography, found no improvements i n LV wall thickness or chamber dimensions, but the authors reported only a 21% gain i n aerobic capacity. Vanhees et a l . , (1984) however used 2-d echocardiography also to assess cardiac changes i n 20 combined CAD/Post-MI patients. They trained for only 3 months, 75 min/session 3 days/week, and u t i l i z e d the upper and lower extremities. The authors state that the t r a i n i n g i n t e n s i t y range was between 70 - 90% of functional capacity. Peak VO2 increased from 1.67 to 2.30 l - m i n - 1 , an increase of 38%. LV wall thicknesses were 200 increased for End-systole and diastole, as was the LV cross- sectional area. Pre ejection period decreased from 107 to 100 msec, suggesting increased c o n t r a c t i l i t y . There was however no s i g n i f i c a n t increase i n LV i n t e r n a l diameter i n systole, i n d i c a t i n g no changes i n preload. There was a s i g n i f i c a n t c o r r e l a t i o n between the change i n LV wall thickness and VC^max, which led to the conclusion that myocardial hypertrophy did occur, and was re l a t e d to afterload. Unfortunately, other i n d i c i e s of a f t e r l o a d were not accounted for i n t h i s study. A study by Williams et a l . , (1984) included a larger sample of 53 patients who had trained for 6 months at 65 to 85% of HRmax. Radionuclide angiograms demonstrated some improvement i n submaximal LVEF at workloads equal to the p r e t r a i n i n g maximal workload (50 to 54%) , but there were no changes i n r e s t i n g or maximal LVEF. One s i g n i f i c a n t f inding however was an inverse r e l a t i o n s h i p between submaximal HR and LVEF; as the HR i s reduced at any given l e v e l of work post-training, LVEF i s increased. In the case of other volumes, there were no s i g n i f i c a n t changes• i n both LVEDV and LVESV, although these variables displayed indications of change. Hindman and Wallace (1981) presented some impressive data which would indicate a d e f i n i t e cardiac e f f e c t of endurance t r a i n i n g i n CAD patients. A l l parameters were s i g n i f i c a n t l y increased; LVEDV: 177 to 194 ml, SV: 93 to 100 ml at 201 submaximal le v e l s exercise. The data should be viewed with caution however, due - to the small sample size, and the f a i l u r e to compare these variables to those which could a r t i f i c i a l l y change them, namely changes i n peripheral resistance which would augment SV, LVESV, and possibly LVEDV as well. One study which was designed to avoid these problems, especially, the problems of achieving true randomization, small sample sizes, wide variance of the samples, and many confounding physiological variables was undertaken .by Froelicher et a l . (1984). One-hundred and f o r t y - s i x males were randomized to two level s of t r a i n i n g i n t e n s i t y . The higher i n t e n s i t y group started at 60% of heart rate reserve, and progressed to 85% by week 8. The sessions consisted of 45 minutes of combined arm and leg exercise using rowers, arm ergometers, walking and jogging. The investigators con t r o l l e d the s t a t i s t i c a l aspects of the study by u t i l i z i n g analysis of covariance, and retaining drop-outs from the exercise group for analysis. Results indicated that i n d i c i e s of aerobic f i t n e s s had improved; increases i n V02max of 18% versus -3% for control patients, decreases i n submaximal RPP and increased maximal RPP. Thallium scores improved only i n patients with angina, but not i n the other subsets of patients. Radionulide angiographic data demonstrated only modest changes, with the only improvement aspect surfacing being a tendency for the trained group to r e l y less on the 202 Frank-Starling mechanism. This was suggested by less change (tendency to increase) i n LVEDV. This study was i n t e r e s t i n g i n that the study design and s t a t i s i c a l controls should not have biased the r e s u l t s . However, there were a few weaknesses which could have l i m i t e d the poten t i a l change for cardiac a l t e r a t i o n s . F i r s t l y , a l l RNA measurements were made i n the supine position, which would have attenuated increases i n SV and possibly LVEF more than i f they were measured i n the erect p o s i t i o n . Secondly, the t r a i n i n g i n t e n s i t y might have been too low for cardiac changes, despite the study period consisting of one year. Thirdly, although t h i s i s overtly stated i n . the resu l t s , i n c l u s i o n of drop-outs from the trained group would have seriously contributed to type II errors. It i s clear from the preceeding l i t e r a t u r e that although attempts to demonstrate a. clear cardiac e f f e c t from endurance t r a i n i n g have been undertaken u t i l i z i n g various interventions, the physical p o s i t i o n of the patient during tes t i n g , the appropriate controls for systemic resistance, and the actual i n t e n s i t y stimulis of exercise (normally attenuated t r a d i t i o n a l l y for the sake of safety) have not been addressed s u f f i c i e n t l y to make conclusive statements regarding the presence or absence of adaptations. Table 7.5 203 l i s t s some of the reasons investigators might have f a i l e d to uncover these changes afte r exercise t r a i n i n g . 204 Table 7 . 5 Reasons f o r F a i l u r e to Identify I n t r i n i c Cardiac Adaptations a f t e r Exercise Training 1. I n s e n s i t i v i t y of standard radiopaque dye techniques to i d e n t i f y c o l l a t e r a l p r o l i f e r a t i o n i n humans 2. F a i l u r e to i d e n t i f y s p e c i f i c changes i n c o l l a t e r i z a t i o n using radionuclide imaging techniques i n humans 3. I n s u f f i c i e n t exercise t r a i n i n g frequency 4. I n s u f f i c i e n t exercise t r a i n i n g i n t e n s i t y (or exercise t r a i n i n g occurring at low percent of true maximum due to symptom-limited maximum) 5. I n s u f f i c i e n t exercise t r a i n i n g duration 6. F a i l u r e to d i f f e r e n t i a t e between vascular and biochemical myocardial c e l l u l a r adaptations 7. The rate and extent of peripheral adaptations ou t s t r i p or mitigate possible central changes 8. Technical and s t a t i s t i c a l problems associated with human experimentation 9. The confounding e f f e c t s of simultaneous pharmacological interventions a f f e c t i n g t r a i n i n g capacities/measures 10. Heterogeneity of the study population (infarct size, medications, psycological factors, medical problems) J 205 There have recently been a group of studies which have con t r o l l e d for these d e f i c i e n c i e s , a l t e r i n g the assumptions of t r a i n i n g s t i m u l i which Post-MI patients can tole r a t e , with impressive r e s u l t s . S i c o n o l f i et a l . , (1984) found a large increase i n VC^max afte r t r a i n i n g i n 14 patients, but the expected drop i n t o t a l peripheral resistance was not correlated to improvements i n VC^max (r = -.23), which indicated that peripheral e f f e c t s are not always the important variable the other studies have shown, and that some proportion of cardiac involvement must take place i n the average medically stable patient. In a landmark study, which was followed by a series of progressive studies, Ehsani et a l . , (1981) i n s t i t u t e d a departure from the t r a d i t i o n a l l y conservative t r a i n i n g programs of other workers (excepting work by Blessey et a l . , 1981, and Kavanagh et a l . , 1974), who trained post-MI marathoners, with impressive r e s u l t s ) . The authors exercised the patients at the usually recommended i n t e n s i t i e s of 60 to 75% of maximal VO2 or 75 to 85% of HRmax for the f i r s t three months (Fardy, 1977, Fox et a l . , 1972, Pollock, 1973, and Zohman, 1970). From the 4th to the 12th month however, the t r a i n i n g stimulus was increased to upwards of 90% of VC^max, for sessions of up to 60 206 minutes, 4 to 5 days/week, of walking and progressing to continuous jogging. This was equivalent to 25 to 30 miles/week of jogging for some patients, equal to that normally prescribed to healthy adults. The e f f e c t of t h i s t r a i n i n g was to increase RPPmax from 24.9 to 29.8 and VC^max 38%. The patients increased t h e i r ischemic threshold from 119 to 138 bpm, and s y s t o l i c blood pressure from 164 to 173 mmHg. The l e v e l of ST-segment depression was s i g n i f i c a n t l y altered both at maximal exercise and at submaximal leve l s , i n d i c a t i n g that the myocardial 0 2 comsumption had increased. Obviously, the departure from the other studies which did not display such clear adaptation was that both prolonged and intense r t r a i n i n g was employed. The authors also demonstrated concommitant changes i n echocardiographic LV mass and LVEDV index. Although L a s l e t t et a l . , (1985) also demonstrated s i m i l a r changes i n the ST-segment and ischemic threshold (increasing from 107 bpm to 119 bpm) , they did not study cardiac function. Ehsani and co-workers (1982) attempted to determine i f the above i n i t i a l changes i n echocardiographic i n d i c i e s of 'myocardial adaptation were i n c o r r e c t l y implied by changes i n systemic resistance. They compared the v e l o c i t y of circumferential f i b r e shortening against various arm 207 isometric voluntary contractions at graded percentages of maximum (MVC). In t h i s group of patients, the increase i n VC^max was 42%, and the patients trained s i m i l a r l y to the previous study. In the trained group, the slowing of f i b r e shortening was not attenuated af t e r t r a i n i n g even at high percentages of MVC, with the control group demonstrating a progressive erosion of f i b r e shortening v e l o c i t y as systemic resistance from the isometric contractions increased. A subsequent study from the same centre (Hagberg et a l . , 1983) measured CO and SV with CO2 re-breathing methods i n a group of selected post-MI patients a f t e r the same intense t r a i n i n g program. V02max increased 39% and re s t i n g SV increased from 66 to 81 ml. Although CO at an absolute workload remained unchanged, heart rate was reduced by 10 to 15 bpm, meaning a change i n stroke volume had occurred (16% increase). In addition, mean a r t e r i a l pressure remained unchanged, leading to the conclusion that increases i n SV were actually a resu l t of improved cardiac c o n t r a c t i l i t y , and not simply a result of decreased afterloading conditions, unlike other studies which demonstrated increased SV, but with no measurement of blood pressure (Paterson et a l . , 1979). Additional research from t h i s team, u t i l i z i n g again the same intense exercise protocol has also demonstrated s i g n i f i c a n t l y increased s y s t o l i c time i n t e r v a l s (Martin et 208 a l . , 1984), and g r e a t l y a t t e n u a t e d catecholamine response at submaxinal e x e r c i s e (epinepherine from 209 t o 132 pg/ml), and augmented l e v e l s at peak e x e r c i s e (norepinepherine from 2049 t o 3408 pg/ml) p o s t - t r a i n i n g . T h i s e f f e c t a c t s , as the authors concluded, t o lower the myocardial 0 2 requirements, and might even reduce the myocardium's i r r i t a b i l i t y and hence tendency towards arrhythmias at h i g h e x e r t i o n l e v e l s . The most re c e n t and perhaps most e x c i t i n g r e s e a r c h from t h i s group i s t h a t which has u t i l i z e d the combination o f t h i s i n t e n s e e x e r c i s e s t i m u l i s with r a d i o n u c l i d e techniques (Ehsani et a l . , 1986). The same study d e s i g n as b e f o r e was a p p l i e d t o 25 post-MI p a t i e n t s f o r one year, y i e l d i n g a 37% improvement i n VC^max. Although no changes i n r e s t i n g EF were found, at e x e r c i s e , t h e r e was an upward and l e f t s h i f t i n the r e l a t i o n s h i p between s y s t o l i c b l o o d p r e s s u r e - and ESV and LVEF v s . RPP, i n d i c a t i n g evidence f o r i n t r i n s i c c a r d i a c c o n t r a c t i l e f u n c t i o n . The authors were a l s o able t o demonstrate however, an a d d i t i o n a l but smal l c o n t r i b u t i o n o f the Frank S t a r l i n g mechanism t o the o v e r a l l a d a p t a t i o n by the upward and r i g h t s h i f t o f the r e l a t i o n s h i p o f LV s t r o k e work versus LVEDV d u r i n g the t r a n s i t i o n from r e s t t o e x e r c i s e . These f i n d i n g s were i n a d d i t i o n t o expected i n c r e a s e s i n the parameters which would i n d i c a t e t h a t p e r i p h e r a l changes had r e s u l t e d 209 (reduced HR and RPP at equivalent submaximal workloads aft e r t r a i n i n g ) . This confirmation of the i n t r i n s i c and independent adaptation of pump function was recently reinforced by a recent study by the same authors who studied a subset of Post-MI patients with exertional hypertension during exercise (Martin et a l . , 1987). The intense t r a i n i n g program i n t h i s study resulted i n a 41% increase i n VC^max, with associated peripheral adaptations. These patients were able to increase t h e i r peak SBP from 162 to 174 mmHg af t e r t r a i n i n g at a higher HR (132 to 157 bpm). Peak EF increased from 52.4 to 56.2% despite t h i s increase systemic pressure development. Stroke volume increased from 81 to 90 ml at peak exercise. The ST-segment at peak exercise reduced from 1.3 mv to 1.0 mv despite achievement of a higher SBP and thus MVO2• There was however a modest 11% decrease i n TPR at peak exercise, but the authors conclude that t h i s i n e v i t a b l e decrease i n systemic resistance was minimal compared to the increase i n the ov e r a l l increases i n afterload. This l a s t series of studies can be summarized appropriately by s t a t i n g that i n addition to the uncontested peripheral adaptations which probably s t i l l account for the predominance of the t r a i n i n g e f f e c t i n t h i s population, under conditions of high exercise volumes and i n t e n s i t i e s , 210 s i g n i f i c a n t a l t e r a t i o n s i n cardiac c o n t r a c t i l i t y and function can be demonstrated i n selected patients. The application of extreme exercise i n t e n s i t i e s however i s c o n t r o v e r s i a l . Data from Hossack and Hartwig (1982) t e n t a t i v e l y indicates that patients who exceed the 85% i n t e n s i t y l e v e l experience a greater rate of cardiac events during exercise than those who maintain themselves within the " t r a i n i n g range". We have however, already discussed the possible myth of the r e l a t i v e percent concept and the u t i l i z a t i o n of the v e n t i l a t o r y threshold to i n d i v i d u a l l y prescribe exercise i n t e n s i t y . Obviously, t h i s question has to yet be adequately answered. The additional argument which can be advanced with regard to the intense t r a i n i n g and the impressive r e s u l t s i s that the g e n e r a l i z a b i l i t y to the average cardiac patient i s l i m i t e d . It has been argued that Ehsani's patients were unusually free of complications, were highly motivated and select. Unfortunately, determination of the exact biochemical and h i s t o l o g i c a l mechanisms responsible for these e f f e c t s has not been uncovered, and probably w i l l not be u n t i l better technologies are available to non-invasively determine cardiac biochemistry and v a s c u l a r i t y . Promising areas include d i g i t a l subtraction coronary angiography and nuclear magnetic resonance cardiac spectra analysis. 211 Upper Extremity Exercise Training i n Cardiac R e h a b i l i t a t i o n T r a d i t i o n a l l y , the mode of t r a i n i n g for the post-MI patient has been dynamic large muscle exercise, confined to the lower extremities. Walking or jogging has been the preferred mode due to i t s af f o r d a b i l i t y , ease of learning, convenience, and favorable acute and chronic p h y s i o l o g i c a l e f f e c t s (Kavanagh et a l . , 1973). It was generally accepted at the time that upper extremity exercise would raise systemic resistance and increase myocardial O2 demand, es p e c i a l l y i n tasks with large isometric components. However as early as the mid-nineteen seventies, investigators were already questioning the avoidance of arm exercise i n the complete r e h a b i l i t a t i o n of the CAD patient. H e l l e r s t e i n (1977) pointed out that although walking/jogging provides a b e n e f i c i a l generalized t r a i n i n g e f f e c t , accomplishing the sought aft e r physiological and metabolic adaptations, i t has li m i t e d value i n the r e h a b i l i t a t i o n of patients for a majority of occupations which r e l y on upper extremity f i t n e s s ; because of the high degree of the s p e c i f i c i t y of fi t n e s s , the t r a i n i n g e f f e c t of lowering MVO2 for a given amount of leg work would not be transfered to the arms, provoking ischemia during arm e f f o r t s i n a "trained" patient (Fardy et a l . , 1977). Studies undertaken to actually measure the isometric 212 component of upper extremity exercise have found less isometric and cardiac 0 2 costs associated with these a c t i v i t i e s than previously thought (DeBusk et a l . , 1978). Magder et a l . , (1981) tested 8 post-MI patients with both cycle and swim-tethered maximal graded t e s t s without s i g n i f i c a n t differences i n ischemic responses. Maximal HR for the swim te s t reached 87 to 89% of the cycle t e s t . Kelemen et a l . , (1986) compared the p h y s i o l o g i c a l responses of 10 weeks of c i r c u i t weight t r a i n i n g i n an exercise group to a control group of patients receiving only v o l l e y b a l l and l i g h t walking and jogging. Both maximal single r e p e t i t i o n strength as well as treadmill time was improved i n the c i r c u i t group, which indicated not only a strength gain, but an unexpected gain i n aerobic capacity due to c i r c u i t weight t r a i n i n g . The authors concluded that t h i s form of exercise r e h a b i l i t a t i o n i s not only safer than previously thought, but might be more s p e c i f i c to c e r t a i n patients than endurance t r a i n i n g alone. The e f f i c a c y of the aerobic c i r c u i t t r a i n i n g method, which u t i l i z e s several linked "stations" of endurance a c t i v i t i e s (rowing, cycle and arm ergometry, b a l l throwing, walking/jogging, and arm pulleys) was assessed by LaFontaine et a l . , (1987). Maximal 0 2 uptake was estimated by the Bruce tes t i n 31 CABG patients a f t e r 12 weeks of t r a i n i n g which consisted of various a c t i v i t i e s for 25 to 60 minutes per 213 session, 3 days/week. The authors found improvements i n aerobic capacity equal to more t r a d i t i o n a l single mode programs; res t i n g HR was reduced from 67 to 61.5 bpm, and aerobic capacity increased from 7.3 to 12.2 MET's. Wrisley et a l . , (1983) followed 13 patients for 6 weeks, with t r a i n i n g consisting of 5 sessions/week of 30 minutes at 60 to 80% of VC^max. Both upper and lower extremity t r a i n i n g modes were incorporated i n the t r a i n i n g program. Patients were able to increase cycle VC^max by 11%, and arm crank VC^max 13%, leading the authors to conclude that t h i s form of multi-mode c i r c u i t t r a i n i n g was as e f f e c t i v e i n producing favourable ph y s i o l o g i c a l t r a i n i n g e f f e c t s as leg t r a i n i n g alone. Thus the programs which balance the exercise t r a i n i n g over the whole musculature have been t e n t a t i v e l y found to r e s u l t i n favourable phy s i o l o g i c a l adaptations s i m i l a r to that found with other single modes of endurance t r a i n i n g . In addition, other advantages of reducing the emphasis of lower extremity exercise t r a i n i n g not usually mentioned, re l a t e to the patient with lower extremity musculoskeletal problems which would normally contraindicate t r a i n i n g (diabetic ulcerations, a r t h r i t i s , severe obesity, biomechanical l i m i t a t i o n s , and overuse i n j u r i e s incurred from weight- bearing training) (American College of Sports Medicine, 1986). The l a t t e r example i s well i l l u s t r a t e d by e l i t e 214 a t h l e t e s who use a l t e r n a t e t r a i n i n g modes t o m a i n t a i n endurance f i t n e s s d u r i n g the recovery from lower e x t r e m i t y i n j u r i e s , and the p o p u l a r i t y r e c e n t l y of " c r o s s - t r a i n i n g " and t r i a t h l o n p a r t i c i p a t i o n . The Acute Ph y s i o l o g i c a l E f f e c t s of Upper Extremity Exercise Although the p r e v i o u s s e c t i o n has demonstrated the e f f i c a c y and s a f e t y of upper e x t r e m i t y e x e r c i s e t r a i n i n g f o r the CAD and post-MI p a t i e n t , the p h y s i o l o g y of upper e x t r e m i t y e x e r c i s e does d i f f e r from l a r g e r muscle groups of the lower e x t r e m i t i e s , and should be reviewed. S t u d i e s i n h e a l t h y i n d i v i d u a l s have demonstrated t h a t arm e x e r c i s e r e s u l t s i n g r e a t e r i n c r e a s e s i n s y s t o l i c b l o o d p r e s s u r e , HR, RPP, V E, V O 2 , RER, and l a c t a t e at any g i v e n a b s o l u t e work r a t e compared t o l e g e x e r c i s e (Astrand et a l . , 1965). However, SV and anaerobic t h r e s h o l d s were lower at the same workloads than f o r l e g work. The authors a l s o found t h a t the a b s o l u t e l e v e l s of VC^max were lower f o r arm work (reaching 64 t o 80% of l e g VC^max) . Maximal HR was comparable or j u s t s l i g h t l y lower than f o r the l e g , as was RPP and s y s t o l i c BP. F r a n k l i n (1985) has demonstrated t h a t arm f i t n e s s c o r r e l a t e s p o o r l y w i t h l e g f i t n e s s (r = .42 f o r arm max workload versus l e g max workload and r = .32 f o r arm VC^max versus l e g VC^max), i l l u s t r a t i n g the s p e c i f i c i t y concept. However, the 215 regression of HRmax to r e l a t i v e VC^max i s the same for arm and leg exercise (ie., 57 - 78% VC^max i s equivalent to 70 - 85% HRmax for both arm and leg exercise). This i s fortunate in that the same pr e s c r i p t i o n methods can be u t i l i z e d for' both arm and leg t r a i n i n g , provided both sets of limbs are assessed separately. Nevertheless, Franklin has estimated that a workload e q u i v i l l e n t to 50% of the leg workload can be applied to arm t r a i n i n g , i f arm t e s t i n g has not been performed. Baldy et a l . , (1985) sought to examine the value of arm exercise t e s t i n g i n the detection of CAD. Thirty patients were assessed by either arm ergometery or Bruce treadmill t e s t s . The arm test consisted of the a p p l i c a t i o n of 25 W every 3 minutes, s t a r t i n g at 35 W. VC^max was 13 METs for arm t e s t i n g and 18 MET's for treadmill t e s t s . Maximal HR for arm ergometry was s i g n i f i c a n t l y lower than for treadmill (109 vs. 101 bpm.) but ST-segment depression occurred at a higher percentage of maximum (62%) than treadmill t e s t i n g (35%) . Coplan et a l . , (1987) also compared the responses of arm and leg exercise at 85% predicted maximal HR i n middle-aged subjects to determine the appropriateness of arm t e s t i n g to screen for CAD. They found that BP and HR increased at d i f f e r e n t rates for arm vs. leg tests, and that BP was higher i n arm exercise at low work rates. However, the 216 s i t u a t i o n reversed i t s e l f as maximal work rates were approached; at 85% HRmax, arm RPP, VO2 and HRmax values were 28 mmHg/bpm x 10 - 3, 2.1 l - m i n - 1 , and 187 bpm, respectively, and treadmill values were 30 mmHg/HR x 10 - 3, 2.7 l - m i n - 1 , and 174 bpm, respectively. The authors concluded that because of the v a r i a b i l i t y i n responses, t e s t i n g with arms only would lead to an increase i n false-negative t e s t r e s u l t s , because the maximal physiological stress i s less at maximal arm work rates compared to standard treadmill t e s t s . The d i f f i c u l t y i n assessing s y s t o l i c blood pressure during arm exercise was overcome by Schwade et a l . , (1977) by the use of automated blood pressure units. Upon t e s t i n g 33 male CAD patients, peak workload was found to be only 41% of the legs, but at the same absolute work rates, arm HR, s y s t o l i c BP, and RPP were twice that of the legs. As suggested i n the Coplan et a l . study however, physiological measures became i d e n t i c a l at maximal loads for both modes. Exercise S p e c i f i c i t y and Transfer E f f e c t s i n Arm and Leg Exercise. The p o s s i b i l i t y that t r a i n i n g s p e c i f i c i t y i s not 100% operative, and that there i s perhaps some degree of g e n e r a l i z a b i l i t y which would allow a "transfer" of fi t n e s s to a group of untrained limbs, has been an a l l u r i n g t o p i c of inte r e s t for some time. Clausen et a l . , (1970, 1973) f i r s t demonstrated that a f t e r t r a i n i n g of the legs, there was a 217 s l i g h t reduction i n post-training submaximal heart rate for the untrained limbs. Arm VC>2max increased 10% (non-significantly) a f t e r t r a i n i n g the legs v i a cycle ergometery, and the authors concluded that although the predominance of the t r a i n i n g e f f e c t was therefore central, some transfer of f i t n e s s due to increased limb blood flow (due to increased cardiac performance) was responsible for the e f f e c t (Figure 7.6). 218 Figure 7.6 Exercise S p e c i f i c i t y and Transfer E f f e c t of Training _ 1 8 0 r c 'E 1160 XD A r m training (arm) / (\eqyy' ro 1 1 2 0 / -* a 1 0 0 * ' i i • • i i _ 1 8 0 c jE 1" 160 ca £ ^ w ro I 120 L e g training f: • / ( a r m ) / ('^X X * * - b 10C 2 0 0 4 0 0 600 8 0 0 1000 1 2 0 0 W o r k l o a d (kpm/min) Group mean heart rate and workload response to arm and leg exercise before ( ) and afte r (----.) t r a i n i n g , (a) Arm t r a i n i n g markedly reduced the heart rate response to arm exercise; however, the heart rate response to leg exercise decreased only s l i g h t l y a f t e r arm t r a i n i n g , (b) Leg t r a i n i n g markedly reduced the heart rate response to leg exercise; however, the heart' rate response to arm exercise decreased only s l i g h t l y after leg t r a i n i n g . From Franklin, B. 1985, p. 108. Adapted from Clausen, et a l . , 1970. 219 S a l t i n et a l . , (1976) noted the same e f f e c t for the untrained limb af t e r one-legged cycle t r a i n i n g , and demonstrated unchanged mitochondrial enzyme adaptations i n that limb. The authors speculated that i n the absence of central cardiac factors being responsible for t h i s e f f e c t , improved f i t n e s s i n the untrained limb could have resulted from a greater e f f i c i e n c y of the heart, l i v e r , kidney and the a b i l i t y of slow-twich muscles to oxidize l a c t a t e . One aspect of the transfer e f f e c t was highlighted by McKenzie et a l . , (1976), and relates to the magnitude of the cross-over e f f e c t according to the size of muscle groups trained. There was a larger e f f e c t of t r a n s f e r r i n g f i t n e s s (as measured by HR response only) to the untrained arms when the legs were trained than the reverse s i t u a t i o n . This agreed with the Clausen et a l . , (1973) observations. The i n i t i a l l e v e l of fit n e s s i s another factor which determines the po t e n t i a l transfer e f f e c t . Magel et a l . , (1978) found that subjects with i n i t i a l l y high l e v e l s of aerobic f i t n e s s had no improvement i n treadmill VT^max af t e r arm t r a i n i n g . A study by Lewis et a l . , (1980) reproduced these r e s u l t s ; b i c y c l e t r a i n i n g resulted i n a 15% increase i n leg VC^max and a 9% increase i n arm VT^max, but the subjects with an i n i t i a l l y low VC^max benefited more from any p o t e n t i a l transfer e f f e c t s that the subjects with higher endurance f i t n e s s l e v e l s . 220 Rosier and co-workers (1985) hypothesized that the untrained muscles actually undergo u l t r a s t r u c t u r a l adaptations due to an independent central cardiovascular t r a i n i n g e f f e c t . This was tested i n 10 subjects who trained on cycle ergometers for 8 weeks, 5 days/week. They trained at a high i n t e n s i t y equivalent to 90 to 95% of VC^max. Muscle biopsies were obtained from the d e l t o i d and vastus l a t e r a l i s for analysis before and af t e r t r a i n i n g . Leg VC^max increased 13% from 3.7 to 4.1 l.min-1 and arm VC^max increased 9% from 2.7 to 2.9 l.min-1. The power output capacity at a HLa l e v e l equal to 4 mM*l - 1 increased 27% for the legs, but not for the arms, however. H i s t o l o g i c a l examination revealed increased leg muscle mitochondrial densities, and c a p i l l a r y / f i b r e r a t i o s , where as these changes were absent i n the arm. Clearly, increased c a p i l l a r i z a t i o n due to increased cardiac output and muscle blood flows d i d not occur, and led the authors to conclude that t h i s was not the reason for the increased capacity for arm work af t e r leg t r a i n i n g . They speculated rather, that because the post-training arm VC^max was lower than pre- t e s t i n g leg VC^max, even before t r a i n i n g , the cardiovascular capacity was already s u f f i c i e n t to support the increased arm V02max. Consequently, they concluded that during arm exercise, the trained but now inactive leg muscles, i n addition to the l i v e r , metabolized lactate, r e s u l t i n g i n a 221 greater capacity for arm oxidative processes, and hence higher external work output. Thompson et a l . , (1981a) subjected healthly young adults to 11 weeks of either leg or arm t r a i n i n g , and compared the cardiac responses during t e s t i n g of the untrained and trained limbs. In contrast with the study by Rosier et a l . (1985), cardiac changes were observed during t e s t i n g of the untrained arms, and characterized by increases i n LV ejection time (presumably c o n t r a c t i l i t y ) using echocardiography. Transfer E f f e c t From Training i n Cardiac R e h a b i l i t a t i o n Surprisingly few studies have been conducted by applying the exercise s p e c i f i c i t y model u t i l i z e d i n healthy populations to uncover the role of central vs. peripheral t r a i n i n g adaptations i n CAD/ post-MI patients. Thompson et a l . (1981b) randomly assigned patients to either arm, leg or control exercise t r a i n i n g settings for 8 weeks. The t r a i n i n g groups exercised at or near t h e i r anginal thresholds for 40 minutes, 3 days/week. After t r a i n i n g , the workload at the onset of angina and VC^peak increased by 19% for the trained and 10% for the untrained (arm) limbs. However, there were no changes i n the HR at which angina occurred for the trained and untrained limbs, and t h i s was also the case for RPP. 222 The authors concluded that the apparent increased exercise capacity for untrained limbs did not necessarily imply that an i n t r i n s i c cardiac t r a i n i n g e f f e c t had occurred, because decreases i n sympathetic tone and c i r c u l a t i n g catecholamines and reductions i n TPR could cause these e f f e c t s . It was. thus speculated that approximately h a l f the t r a i n i n g e f f e c t s were peripheral and the other h a l f c e n t r a l . Unfortunately, the sample size i n t h i s study was small, the t r a i n i n g stimulis mild, and no d i r e c t measurements of cardiac function were performed to v e r i f y the above speculation. A more recent study also designed to detect a central t r a i n i n g component by t e s t i n g a set of untrained limbs was undertaken recently by Ben-Ari et a l . , (1987). Two groups, d i f f e r i n g only by the t r a i n i n g i n t e n s i t y (at the anginal threshold and at 70 to 85% of symptom-limited HR) were followed for 6 months. Both groups trained continuously on cycle ergometers for 30 minutes 2 days/week. The r e s u l t s demonstrated that although the magnitude of the t r a i n i n g adaptations did not d i f f e r across t r a i n i n g i n t e n s i t i e s , there was some ind i c a t i o n of transfer e f f e c t from the legs to the arms as quantified by reductions i n submaximal HR and RPP, and increases i n the anginal threshold HR. Again, the authors concluded that a component of i n t r i n s i c myocardial adaptations could have occurred, but these were not d i r e c t l y measured i n the study. 223 Appendix II Nuclear Medicine Calculations and Processing Samples 1. F i r s t Pass Cardiac Output Processing em o v ; W; /v *r'W^~-: ŝ-vsestjv...... Forward C O . = B V X A E 224 Gated Blood Pool Angiography Processing 225 Appendix III Ven t i l a t o r y Threshold Sample Plots 1. End-Tidal PC0 2 vs. End-Tidal P0 2 2. Minute V e n t i l a t i o n (V E) vs. V0 2 226 Appendix IV Sample of Consent Form C a r d i a c R e h a b i l i t a t i o n and E x e r c i s e s p e c i f i c i t y s t u d y INFORMED CONSENT FORM I n v e s t i g a t o r s : L.S. Goodman, D.C. M c K e n z i e , W. Schamberger, M.B W a l t e r s , W. Aaman, J . F l e e t h a m . The purpose of t h i s s t u d y i s to 1., e v a l u a t e and compare the e x t e n t of the a d a p t a t i o n s of t h e h e a r t t o endurance t r a i n i n g f o r whole-body v s . l e g s - o n l y t r a i n i n g g r o u p s of p o s t - m y o c a r d i a l I n f a r c t i o n p a t i e n t s , and 2., t o d e t e r m i n e i f c e n t r a l ( h e a r t ) or p e r i p h e r a l ( m u s c l e s of the l i m b s t h a t were t r a i n e d ) a r e the main f a c t o r s i n b r i n g i n g about the p h y s i o l o g i c a l a d a p t a t i o n s i n t r a i n i n g c a r d i a c p a t i e n t s . You w i l l be a s k e d t o undergo two two-day s e r i e s of e x e r c i s e t e s t s ; one s e s s i o n b e f o r e you s t a r t e x e r c i s i n g , and the second a f t e r 6 months on the e x e r c i s e program. These w i l l c o n s i s t o f : Day 1. A maximal t e s t w i t h the arras on an arm-crank machine, 2 h o u r s r e s t , and t h e n a maximum t e s t w i t h the l e g s on a b i c y c l e e r g o m e t e r . Both t e s t s w i l l s t a r t out a t e a s y l o a d s , and t h e n p r o g r e s s i n d i f f i c u l t y as the p e d a l l i n g t e n s i o n i s i n c r e a s e d . You w i l l be b r e a t h i n g i n t o a m outhpiece so t h a t y o u r e x p i r e d a i r can be a n a l y z e d f o r c o n t e n t o f oxygen and c a r b o n d i o x i d e . These t e s t s w i l l be' m e d i c a l l y s u p e r v i s e d , and a c t as a t e s t t h a t y o u r c a r d i o l o g i s t would r o u t i n e l y p e r f o r m i n y o u r c l i n i c a l work- up. Day 2. The n e x t day, or w i t h i n one week, you w i l l undergo a n o t h e r s e r i e s of arm and l e g e r g o m e t e r y t e s t s i n the Department o f N u c l e a r M e d i c i n e t o e v a l u a t e c a r d i a c f u n c t i o n w h i l e you a r e e x e r c i s i n g . A s m a l l amount of l o w - l e v e l r a d i o c a t i v e t r a c e r w i l l be i n j e c t e d i n t o a f o r e a r m v e i n , and a s c a n n e r w i l l be p l a c e d over the c h e s t t o t a k e p i c t u r e s o f - the l e f t v e n t r i c l e c o n t r a c t i n g w h i l e e x e r c i s i n g , f i r s t w i t h the arms, f o l l o w e d by a 2 hour r e s t , t h e n w i t h the l e g s a t 3 two-minute w o r k l o a d s , and t h e n a t maximum e x e r c i s e . The amount of r a d i o a c t i v i t y i s m i n i m a l and does not r e p r e s e n t a h e a l t h h a z a r d . Your h e a r t r a t e and ECG w i l l be c o n t i n u a l l y m o n i t o r e d t h r o u g h o u t t h e t e s t s . . The r i s k s of the arm and l e g e r g o m e t r y t e s t s a r e m i n i m a l , bu t i f any problems do a r i s e , the l a b o r a t o r y does have a l l t h e n e c e s s a r y m e d i c a l equipment f o r t r e a t m e n t of e m e r g e n c i e s . Based on the r e s u l t s o f the maximum t e s t s , you w i l l t r a i n l n e i t h e r the YMCA or Shaughnessey H o s p i t a l c a r d i a c r e h a b i l i t a t i o n programs, as p r e v i o u s l y d e c i d e d f o r 6 months. The f i n a l 3 months t r a i n i n g w i l l be more i n t e n s i v e t h a n your n o n - p a r t i c i p a t i n g p e e r s , and you w i l l be m o n t i o r e d c l o s e l y to m a i n t a i n a s a f e l e v e l of e x e r c i s e . You w i l l be r e q u i r e d t o f o l l o w the e x e r c i s e p r e s c r i p t i o n s e x p l i c i t l y , e s p e c i a l l y w i t h r e g a r d t o the s p e c i a l i n s t r u c t i o n s f o r YMCA p a r t i c i p a n t s r e g a r d i n g the a v o i d a n c e of arm e x e r c i s e . A l l d a t a w i l l be t r e a t e d i n c o n f i d e n c e . In r e p o r t i n g the r e s u l t s , names of the s u b j e c t s w i l l not be used. We w i l l be happy to answer any i n q u i r i e s c o n c e r n i n g the p r o c e d u r e s f o r the s t u d y i n g e n e r a l . I c o n s e n t t o p a r t i c i p a t e i n t h i s r e s e a r c h p r o j e c t , and I u n d e r s t a n d t h a t I may w i t h d r a w f r o m the s t u d y a t any time w i t h o u t p r e d u d i c e to f u r t h e r c a r e . ( S i g n a t u r e ) ( W i t n e s s ) (Date) 227 Appendix V Subjects' Raw Group Mean Data Description of Variables on SAS Output Variable Description S u f f i x : PRE = pre-testing PST = post-testing ID i d e n t i f i c a t i o n (not applicable) HT subject's height i n meters WT body weight i n kg BMI body mass index SOS sum of 5 skinfolds i n mm WHR Waist-Hip r a t i o SOTS Sum of trunk skinfolds i n mm FPCO First-pass cardiac output i n 1/min. FPCI First-pass cardiac index i n ml/kg PFSV First-pass stroke volume i n ml AVO Arm maximum oxygen uptake i n 1/min ARER Arm respiratory exchange r a t i o AWL Arm maximal workload i n Watts AVTRHR Arm ven t i l a t o r y threshold as % of maximal heart rate- pre-testing s u f f i x : PR, post-testing s u f f i x : PT. AVTVOR Arm ven t i l a t o r y threshold as % of maximal oxygen uptake- pre-testing s u f f i x : PR, post-testing s u f f i x : PT. LVO Leg (cycle) maximum oxygen uptake i n 1/min. LRER Leg respiratory exhange r a t i o LWL Leg maximal workload i n Watts LVTHRR Leg ve n t i l a t o r y threshold as % of maximal heart rate- pre-testing LVTVOR Leg ve n t i l a t o r y threshold as % of maximal oxygen uptake AHRM Arm maximal heart rate, bpm APHRM Arm % age-predicted maximal heart rate AST Arm ST segment depression at maximal exercise i n mm LHRM Leg maximal heart rate, bpm LPHRM Leg % age-predicted maximal heart rate LSB Leg maximum s y s t o l i c blood pressure, mmHg LST Leg ST segment depression at maximal exercise i n mm HDL High density l i p o p r o t e i n cholesterol, mg/lOOml LDL Low density l i p o p r o t e i n cholesterol, mg/lOOml CHOL Total serum Cholesterol, mg/lOOml TG Tr i g l y c e r i d e , mg/lOOml SBP S y s t o l i c Blood Pressure, mmHg 228 DBP HR EDV EF D i a s t o l i c Blood Pressure, mmHg Heart r a t e , bpm E n d - d i a s t o l i c volume, ml L e f t v e n t r i c u l a r e j e c t i o n f r a c t i o n , % Pre-T e s t i n g Workload S u f f i x e s : R = Resting, 1 = WL-30, 2 = WL-50, 3 = WL-70, 4 = WL-90. P o s t - T e s t i n g Workload S u f f i x e s : R = Resting, 1 = WL-30pre, 2 = WL-50pre, 3 = WL-70pre, 4 = WL-70post, 5 = WL-90pre, 6 = WL-90post. 229 STANDARD MINIMUM MAXIULIU STD ERROR DEVIATION VALUE VALUE OF MEAN ID 13 7 . 00000000 3. 89444048 1 . 00000000 HT U 17Z. 37692308 7 . 23739153 159. 90000000 AGE 13 4 9 . 92307592 7 . 55492707 34. 00000000 WTPRE 13 75. 05394515 15. 59249902 S4 . 20000000 BWIPRE 13 24 . 9 1539452 3. 75 123343 18. 32  S05PPE 13 53 . 69230759 17 . S5535621 33. 50000000 WHRPRE 13 0. 90746 154 0 . 05761310 0 . 81700000 SOTSPRE 13 33. 8 6923 I 9. 6 U 5 2 5 6 0 17 . 50000000 FPCOPRE 12 5 . 12533333 0. 89325206 3. 90000000 FPCIPHE 1 1 2. s o i a i e i e 0 . 39239822 2. 05000000 PFSVPRE 12 97. 95633333 18. 7B92E410 5 . 40000000 IVOPRE 13 1. 34546 154 0 . 32370501 0. 59200000 ARERPRE 13 1. 03759231 0. 05 173993 0 . 91000000 AWLPRE 13 4 1 . 703S4615 Id . 19B39283 IB. SOOOOOOO AVTRHP.PR 13 76. d769230B 10. 97347544 56. 50000000 AVTVORPR 13 62 . 43076923 12. 18895570 42 . 50000000 IVOPRE 13 t . 99236d62 0 . 53032043 0 . 96200000 LRERPRE 13 1 . 01845 15d 0 . 05459542 0. 90000D00 LWLPRE 13 131 . 9539415 15 33. 54253647 65. 40000000 LVTHRRPR 13 79. 36 153B46 5. 95360375 66. 00000000 LVTVORPR 13 70. 18461538 8. 13929216 55 . 5 AHRMPRE 13 115. 23076923 20 . 43344418 85. COOOODOO APHRMPRE 13 95 . 0846 1530 12. 21 145952 47 . 00000000 ASTPRE 13 0. 15334615 0. 31521259 0 . 00000000 LHRMPRE 13 129. 23076923 22. 55 1 10414 93.  LPHRMPRE 13 7 1 . 4 1539452 1 1 . 00950536 52. 00000000 LS5PPRE 13 17 1. 645 15325 20 . 31355753 135. OOCOOODO LSTPRE 13 0. 53946154 0. 51897452 0. 00000000 HDLPRE 13 36. 92307592- 5 . 42211723 29. DOOOOOOO LDLPRE 12 15 1 . 4 1666567 36. 54231345 91 . 00000000 CHOLPHE 13 2 2 ? . 76923077 32. 32922425 161 . 00000000 TGPRE 13 t7 1 . 07692308 92 . 5S9B5059 86. 00000000 SBPPREfl 13 117. 53846154 13. 0742455B 94 , 00000000 DBPPRER 13 75. .92307592 9 . 04121517 65. .00000000 HRPRER 13 57 . 16923077 9 . 34333202 4 1 . . 30000000 EOVPREft 12 138. 244 i 6 e 5 7 33. 00200530 91 . 73000000 EFPRER 12 0. 464 16567 0 . 08207074 0. .35000000 SBPPRE1 13 129. . 153846 15 11 . 74624872 1 10. .00000000 DBPPRE1 13 78 . 23076923 6. 80B74249 70. .00000000 HRPRE1 13 75. .36923077 11. 93240578 57 . 50000000 EDVPRE1 12 173. . 85 166657 3B. 14875000 114. .60000000 EFPRE1 12 0. . 52916667 0. 09009675 0. , 40000000 SBPPRE2 13 141 . 3B46 1538 14 . 1570B575 120. .00000000 DBPPREE 13 81. . 30789231 6. 82595241 70 .00000000 HRPRE2 13 89. . 32307692 13. 8612e525 68. 70000000 EDVPRE2 12 180 .60583333 47. 63063B62 126. . 50000000 EFPRE2 12 0. .55500000 0. 09571690 0. .42000000 S8PPRE3 13 155 . 15384615 17. 48259207 125 .00000000 DePPPE2 13 84 .00000000 9. 79795597 68. . 00000000 HRPRE3 13 103. . 96 1 53?4fi 16 . 3472=150 80. . 50000000 EDVPRE3 12 190 .88583333 48. .91924244 107 . .56000000 EFPRE3 12 0. .55333333 0. 03752483 0 .36000000 SBPPREd 13 155 .61538462 IB. .23247314 130 . 00000000 08PPRE4 13 86 .69230769 9 . 186B077 1 71 .00000000 HRPRE4 13 121 .51538462 22 .05141137 89 .60000000 EOVPRE4 12 195 .20333333 51 .50843956 120 .34000000 EFPRE4 12 0 .53333333 0 . 10815253 0 . 34000000 ERP ER 12 1 . 7 1833333 0 -43299B71 1 .05000000 ERFREd 12 2 .90566667 0 .67231396 1 .98000000 FRPRER 12 1 -08333333 0 . 22106717 0 .60000000 FRPRE4 12 3 . 15000000 0 . 99 127099 1 .38000000 WT ST 13 75 .43845|54 15 . 50293190 57 . 3000C000 BMIPST 13 2d .94384615 3 . 42 1229 16 19 . 57COOOOO SOSPST 13 61 .03346154 20 .43736523 40 . 5QO 00OO hHRPST 13 0 .90884615 0 .06131048 0 .32000000 SOTSPST 13 34 . 11539*62 1 1 .5)937996 14 .oooooooo FPCQPST 9 5 .54665667 0 .90522 45 4 . 17000000 FPCIPST g 2 .95566657 0 .43550303 2 .21000000 PFSVPST g 99 .22222222 21 . 1 7527079 61 .20000000 AVOPST 12 1 .45350000 0 .33B 1C536 0 . 6 0000 AfiERPST 12 1 .03916657 0 .06656B55 0 .91000000 AWLPST 12 45 .85666567 12 .87 1 76350 IB .90000000 AVTHRRPT 12 83 .3750C0OO- 7 .535^3379 67 . 50000000 AVTVOflPT 12 7d .65833333 10 . 45813152 53 .80000000 LVOPS7 12 2 .22056557 0 .53776986 1 .01000000 LRERPST 12 1 .04250000 0 .05690902 0 .92000000 LWLPST 12 144 .30000000 36 . 73432976 65 . dOOOOOOO LVTHRRPT 12 85 .07500000 5 .41515130 76 . 9000D00O LVTVORPT 12 80 - 15000000 5 . 30771308 72 . 10000000 AHRMPST 12 118 .33333333 Id .92303487 97 .00  APHRMPST 12 SB . 83333333 9 . 333 1 J921 54 . coccoooo ASTPST 12 0 .0418565 7 0 . U433757 0 .00000000 LHRMPST 12 135 .911:56567 18 .5641?024 112 .00000000 LPHRMPST 12 77 .OS333333 10 . 0552259 6  .00000000 LSBPPST 12 17B .50000000 20 . 78242294 150 .00000 LSTPST 12 0 .56666657 0 .38473193 0 .00000000 HDLPST !3 36 . 79230769 5 .89 172505 26 .00000000 IDLPST '3 175 .36923077 49 .88893305 99 . 4C000000 CHOLPST 13 221 .584? 1538 44 . 734̂ 7203 140 . 40000000 TGPST 13 1 15 .99230759 109 . 19794335 55 . 30000000 SBPPSTR 13 113 . 38*5 1538 10 .51282473 95 .00000000 08PP57S 13 75 .23D76923 7 .68231455 60 .00000000 HRPSTB 13 58 .55153345 10 . 57T31972 47 .500C0000 EDVPSTp 13 154 .7000CC"0 33 .4 1 352-121 87 . 7 1000000 EFP3TR 13 • . 525 = 230S 0 .C9277C7-: 0 . JGCOOOOO SBPPST l 13 12/ . 394= 1535 12 . '4 '79052 110 .OCOODOOO DBPPSTl 13 78 .oooocooo 7 . 7 1 3624 3 1 6  .00000000 HPPST 1 13 74 . -12307592 1 1 . 19025019 63 .20000000 EDVPST1 13 190 . 710/6923 48 .'91035106 105 .60000000 EFPST1 13 0 .559a6154 0 . 10245700 0 . 4 2000000 SSPPST2 13 n g . 765230~7 13 .35 1 3437/ 112 .oooooooo DBPPSTZ 13 79 .46 153346 5 .2050 (2 30 70 .00000000 HRPST2 t3 95 .97592303 12 .99371789 71 . 100QOOOO EDVPST2 13 2C0 .58515395 52 .53939123 97 . 39 00000 EFPST2 13 0 .594fj 1538 0 ,09377414 0 .4 5000000 SBPPST 3 13 157 .32307692 20 . 43469S00 130 .oooooooo 13. OOOOOOOO X . 08012345 91 . ooooooo 15. 166667 55. 635 183. 50000000 2. 02393225 2247. 4000000 53 . 251923 4 . 221 64 . OOOOOOOO 2. 09535976 64g. ooooooo 57 . 076923 15. 133 100. OOOOOOOO 4 . 3245B113 975. 7000000 243. 126025 20. 775 31 . 90000000 1. 04317846 323 9000000 14 . 146B77 15. 095 104 . 500000CO 4 . 95218757 776 . ooooooo 316. 8 U 103 29. 6 . 3 12 1. 02O0000D 0. 01597900 1 1 . 7970000 0. 003319 349 57 . OOOOOOOO 2. 66658962 439. 5000000 9 2 . 439103 28. 4 39 6. 79000000 0. 25785966 61 . 5100000 0. 797B99 17 . 25 3. 58000000 0. 11831252 30. 3200000 0. 153976 14. 005 181 120. 20000000 5. 42399912 1175. 5000000 353. 037197 19 . 2. 02000000 0. 08977962 17 . 49 10000 0. 104785 24 . 059 1. 13000000 0. 01714022 13. 4900000 0 . 003B19 5. .956 6 5 . 300DD000 3. 93792564 542. 1500DD0 201 . 594359 34 . 045 93 . 600Q0000 3. 04488124 994 . 2000000 120. 526923 14 . 355 81 . 60000000 3. 38060306 811 . 8000000 148. 570641 19 , 524 2. 870DOOOO 0. 14708442 25. 9010000 0. 2812 0 26 . 617 1. 07000000 0. 01514232 13. 2400000 0. 002981 5. 36 1 179. 700COOGO 9 . 330805(7 17 15. 40OC000 1131. 931C26 2 . 43G SB. tooooooo 1 . 65539284 1038. 2000000 35. G24231 7 . J 74 85. 20000000 2. 25743348 912. 4000000 66 . 248077 1 1 . .597 154 . OOOOOOOO 5. 66721775 149B . . OOOOOOO 417 , 525641 7. 733 ae . OOOOOOOO 3. 38684950 846 . 1000000 149. I 19744 18. 762 888 i . OOOOOOOO 0. 087424?* 2. OOOOOOO 0. 099359 204 . 170. OOOOOOOO 6. 2B505946 1680, ooooooo 513. 525641 17 . 535 4 16 93 . 700000CO 3. 05351513 923 . 4000000 12 1 . 211410 15, 1 1 . 200. oooooooo 5. 53395995 2234 . .ooooooo 412. 541025 22 J 1 . 50000C03 0. . 14390990 7 . . ooooooo 0. 259231 96. 362 50 . oooooooo 1. 78 1 1 7484 480, ooooooo 4 1 . . 243590 17. 39 3 221 . oooooooo 10. .63545979 1817 .ooooooo 1357 . 356061 24 332 288 . oooooooo 9.  1049 l 122 2935. .ooooooo 10'7 , ,69230e 14 , St l 385 . oooooooo 25. 70754 193 2224 . .ooooooo 8591 . 410255 54 . ISO 140. oooooooo 3. 626 14329 1528 .ooooooo 170. .935897 1 1 . . 123 90 . oooooooo 2. . 50758219 987 . ooooooo 81 . . 743590 1 1 90S76. oooooooo 2. 59139059 743 . 20000D0 87 . 298974 6 . . 343 212. 79000000 9. .52685632 1658 .9300000 toeg 132354 23. 372 0. .59000000 0. 02369178 5. .5700000 a . .006736 17 . .58 1 150. oooooooo 3. .25782323 1679 . ooooooo 137 . 97435S 9. 095 90. oooooooo l . 8BB40540 1017 , . ooooooo 46. . 358974 3 . . 703 102. oooooooo 3. . 30945391 999 .3000000 142, .3823D8 15, 523 221 . oooooooo 1 1 .01260709 2086 .2200000 1455. . 330179 21 . .343 0. . 70000000 0. .02600869 6 . 350000D 0. 008117 17 . 025 170, .oooooooo 3 .92646912 1838 .ooooooo 20 . . 423077 10. .013 100 000DD000 2 . 44787877 1096 .ooooooo 77 . B97435 10. . 469 110. 60000000 3 . 844423io 1161 .2000000 192 . 135256 5 .5 18 282. , 18000000 13 . 74978102 2167 .2700000 2268. .677736 25 . 373 0. . 70000000 0 .02792034 6 .6600000 0 .009355 17 . 427 194 . oooooooo 4 .84879853 2D30 -OOOODOO 305 . 541026 11 . 196 100 . oooooooo I .71746483 1092 .OOOOOOO 96 .000000 11 .564 133. . 50000COO 4 .57259521 1351 .5000CQ0 283 . 23029 ' 5 . 205 291 . 93000COO 14 . 12 1 76890 2290 .6 300000 2393 .092231 25 . 527 0. .55000000 0 .02526626 6 .6 400000 0 .007681 IS .818 202. oooooooo 5 .05577822 2166 .OOOOOOO 332 .423077 10. .943 100. .oooooooo 2 .54796202 1127 .OOOOOOO 84 . 397436 10 . . 537 158 .70000000 6 .11596 1 1 1 1579 .7000000 486 .264 744 8. . 147 291 . 18000000 14 .86920543 2342 .4400000 2653 .119242 25. . 287 0 . 72000000 0 .03122095 6 .4000000 0 .01 1597 20 .275 2 .39000000 0 . 12499596 20 .62000GO 0 . 1874B3 25 . 199 4 . 130000GO 0 . 19403032 33 .5800000 a .452006 23. .954 1 .52000000 0 .09268968 13 .OOOOOOO 0 .103097 29 .5 39 5 . 15000000 0 .286 15529 37 .8000000 .9825 18 31  46  104 .50000000 t .29373969 980 .70000Q0 240 , 340997 20. .550 32 .30OOOC00 0 .94887B24 324 .2700000 1 1 . 704809 13 . 7 16 115 . 50000000 5 .66830525 793 .5000000 417 .585397 33 .483 1 .02000000 0 .01700447 11 .8150000 0 .003759 5 . 746 59 -OOOOOOOD 3 . 19462381 443 .5000000 132 . 573077 33 . 753 6 .55000000 0 . 30207615 49 .9200000 a .321250 16 .339 3 . 40000000 0 . 14520101 26 .6 100000 0. . 189 7 50 14 . . 733 123 .20000000 7 .05875693 89 3 .OOOOOOO 448 .4 34444 21 . 342 1 . 76 70000C 0 .09760250 17 .4420000 0 . 1 14315 3 . 262 1 . 16000000 0 .01924555 12 . 4 70CCQO 0. .004445 6. 4 16 66 . 80000000 3 . 7 1575950 550 .4000000 165 . 682424 28 .05 3 93 .ooooocco 2 . 175G955 1 1000 .5000000 56. .803264 9 .040 90 .ooooccco 3 .01901695 895 .9000000 109 .373551 14 . .003 3 . 12000000 0 . 15524079 26 .5480000 0, .289 (96 24 .217 1 . 12000000 a .01642822 12 .5100000 0 . .003239 5. 459 196 . tooooooo 10 .50428730 1731 .6000000 1349, .410909 25 . 457 95 .80000000 i .56321953 1020 .9000000 29. . 323864 6 .365 88 .20000D0O i .53220479 96 1 . 8000000 28 .17 1819 8 . 522 142 .COOOOCOO 4 .30790910 1426 .OOOOOOO 222 696970 12. . 553 81 .OGOOCCCG 2 . 5932 1 15 1 802 .ooooooo 80. .598970 3 J J 1 0 .5000Q0CO 0 .04 156667 0 .5000000 0 .020333 346 .4 10 187 .oooooooo 5 . 35901 723 1643 .ooooooo 34d .528798 13 . £59 96 -OCOOOCOO 3 .03271202 924 . 7000000 1 10 .358 105 13 . 633 220 .OOOOOOOO 5 .99935865 2142 .ooooooo 431 .90909 1 11 .543 3 .OOOOOOOO 0 . 28426762 3 .ooooooo 0 .969597 147 .710 46 .OOOOCOOC l .53407080 4 7B .3000000 34 . 7 12*35 16 ,013 26 1 .OOOOCSGC 13 .33570048 22 7 9 .8000000 2489 . 90554! 28. . 448 301 .OOOOOOOO 12 .407 11048 2920 . 9000000 2001 , 1 7307 7 19 .9 10 468 .OOOOOOOO 30 . 28603271 1507 .9000000 11924 . 169 103 94 . 142 132 . OOOOOOOO 3 .02667301 1474 .ooooooo 119 .099744 9 .525 90 .OOOOOOOO 2 . 13082940 978 .ocooocc 59 .025641 10 .l\Z 85 .60000000 2 .9343 1375 762 .6000CC0 11 l .93255J 10 .035 199 .54000CCO 3 . 2572J422 20 1 1 . 1000CG0 1 6 .463500 21 . . 595 0 .eeaorccr, 0 . C2572597 6 .5500000 0 .009505 17 . 505 140 .OCCDCGOO 3 .36752679 1551) .coocooo 147 . 423C77 9 = 32 90 .ooooocoo 2 . 13937446 10 [4 .ooooooo 59 ,5C0G00 9 . £99 98 .20000000 3 . 10361976 967 . 5000Q00 125 .22 1923 15 .036 273 .97000000 13 .56529067 247g .2400000 2392 . 222*41 25 .546 0 . 740000C0 0 .02341646 7 . 25O0C0O 0 .010497 18 . 345 158 .oocoo^ca j .70577139 18 17 ,OCOCOOO 178 .525541 9 . 550 90 .ooaocsoo I . 44388902 1033 .0000020 27 . '.02554 5 .552 109 .40000000 3 .577*5087 1117 . 7000000 166 . 376923 15.003 272 .60000000 14 59954032 2608 .92O0D0O 2770 .905509 26 .230 0 .7BOO0C02 0 .025D0927 7 .7 3OOCC0 0 .008734 15 . 77 1 192 .oooooooo 5 .65755577 2053 .OOOOOOO 4 1 7 .576923 12 .940 230 STANDARD O E V U T I O H UIM1MUU V A L U E MAXIMUU VALUE STD ERROR OP U£AN 0HPPST3 H P P S T 3 EDVPST3 EFPST3 SBPPST4 oep°STd H R P S T J EDVPST4 EFPST4 SBPPST5 DBPPST5 H R P S T 5 EDVPSTS EFPST5 S B P P S T 6 DBPPSTS H R P 5 T 5 EDVPST6 EFPST5 SBPPSTP D E P P S T P HRPSTP EDVPSTP EFPS7P ERPSTP ERPST4 E P . P S T P FRPS7F FRPST4 FHPSTP LRPPMPPE tRPP'JPST RATIOFPE R A T I O r S T RPPPPc.P R p p p O C i RPPPDC2 H P P P p c T RPPPRE4 SVPPER SVPR=i SVPRE2 S V P P E : SVPRE4 C O P P E R COPPE1 CCPPE2 COPPE3 COPSE* ESVPOE 1 ESVPPE2 E S V P R E i ESVP°Ed UAPPR£ 3 MAPPRE I MAFPREc Ui P P P E 3 HflPDRc-1 TPRPRHP TP R o n c i TPRPRE2 TPRPBEi p v p r p c p p v c p o c l P V R P o c j PVRPRE3 PVPOcc^ LVSWPse I L V S f c P " L V S W P S LVSVIPe AVCFP E - LVOPPE30 LVCPRESO L V O P ° E 7 0 LVOPRE50 AVOPPE1 AVDPFE2 A V D P = E 3 AVOPCE-l RPPFSTB RPPPST1 RPPPST2 RPPPS'3 RPPPST a RPPPST 5 R P D P S I 5 RPPPSTP SVPSTR SVPST 1 SVPS72 SVPST3 SVPST4 SVPST 5 S V P S T S SVPSTP CCPSTP CCPST . CCP S T £ COPST3 CCPST4 CCPST5 COPST5 •"E3 1 3 1 3 1 3 13 ' 13 1 3 13 1 2 12 12 12 12 12 13 13 12 12 12 12 12 12 13 1 3 13 6 2 100 2 C 5 . 123 169 0 1 8 9 B 5 . 1 2 0 . 173 0 ia< 95 .9. 12 16 20 62 10^ 10 I 3 . B. 107 113 IE 1 154 3 13 13 13 30769231 73fl<8154 33307692 61538462 53346154 07552303 345 15385 97923077 65846154 383B3636 00000000 B5454545 5318 1819 57636364 33333333 cooooooo 700OOD0O 37COCOOO .57666587 5 1538*62 .07592208 45384515 .09384615 ,64846154 .88078923 .05334615 .3307592: . 166 1 5235 . 44923077 .72207592 . 4 1953846 .33983333 . 297467 15 . 14782203 . 778546 15 96685355 7J253462 39530000 5105461= 80015833 36705633 46677500 16 14Q000 22621667 44783554 88974528 56472424 . 75 192489 1964 1874 444QQS33 .36450S32 . 13505533 . 72*43333 . 977 1 1567 .655 15355 .035384(52 . M307S92 .31076923 .05692308 . 489672CO . 54532555 .71462297 .5 1424520 . 55850005 .73034437 . 72077032 .0 1465432 .05326552 . 18769755 . 1 1 753547 .74887014 .0*977 M7 . 75923417 44585540 . 477B0274 .59771538 .996 1923 1 . 39466923 . 793 U 6 1 5 . 79 1S9624 .33154335 .05634550 . 38738907 .5542S4R2 .50555355 .OS577632 .03235523 . 14 196 154 .22033536 .04525557 . 43* 43346 52135335 .39762306 . 46442302 35346323 . 55=035*5 27473535 . 7 3340000 . 70/7 1533 .58543334 .50483545 .01304216 . 52303366 35127753 . 44693P31 .3ES07693 * . 9730O4O4 16.04875564 60.23359318 0.03079422 2* .362022J4 -.S3 101757 16.39673 I 10 68.0544 t 7 36 0. 10884593 23.59352752 7.05591151 24.2958B3B5 81.64153513 0.10307S8S 31 .00537588 5.Z91S0252 15. 15948548 86 . 70847075 0. 12502333 2*.35001 135 6.34378355 22.95738223 59 .03064486 0. 10 114727 0.39604 127 0.59807333 O.SC307310 0.297 ; 12 17 1 .03165239 '.330209 16 5. 57 1 746 10 3.6759e310 1-48109395 1- 03354502 1.70237 172 1 .3793992? 2.32411571 * .020663 18 5.53523343 1 1 -39073B75 25 .e5125754 17..00141562 26.35160887 22.501691 4 0 0.57561130 2.05282723 2- 32035565 3.35093054 3.26339)48 25.31764151 . .24 . 22553257 37 . 44064922 33.35090434 40.55355669 9.23313249 7 .21083169 8.92927431 10.07523735 9.55733713 0. 306855 12 0.25334153 0. .6545744 0. 17553076 0. 128284^9 O.695500S1 0.62351593 0. 977J 7302 0.£447039 1 0. eeos7so5 14 .020317 19 40.52316350 28.40407521 41 14935013 34 75535300 1.53ZC2324 0. 155035 13 0-26516021 0. 37122430 0-47728939 3. 1554 7202 2.515C005 I 2.55500492 2. 43025635 I.4i161739 I.85551522 2.53321335 3 . 8720474 t S.48371954 6.25222190 5.68981680 5.25583953 19.91873533 33 . 75050356 31 . J9423306 34 553J5171 42.38592759 40 18351103 45.46 182332 3*.43422t36 1. 26443104 2.39002215 2.55937561 3. 73905210 4.54222181 5. I 3976SB7 5.62297837 75. 00000000 90. 00000000 1. ,37526316 7e. 20000000 127 . 50000000 4 . .45 1 1240 1 113. 32000000 309 . 43000000 16  70717834 0. jsoaooco a . 8 1000000 0, 02519178 140. G0O0DO0O 212. OCOOOOOO 6. .3 221937 72. cooooooo 30. COOOOOOO 1. .33425521 87. 500000CO 145 . aoocooao 5. 268753 10 96. 3500QOOO 302. 78000000 18. 32297254 0. 4 7000000 0 . 37000000 0. .03013643 118. aaooDooo 220. 00000000 7. .1 137 1524 76. 00000000 100. 00000000 2. . 127 2889 85. 50000000 153. 00000000 7. 32277101 95 . 02000000 294 . 53000000 18 . ,5e5S2244 0. 53000000 a. 8 7000000 0 , .03107974 153. 00000000 220. 00000000 17 , . 90095211 80. 00000000 90 . cooooooo 3. 0550 046' 104 . 50000000 134 . 70000000 8. . 75233302 94. 29000000 267 . 62000000 50. 061 15393 0. 59000000 0. 32000000 0. . 721QS03 l i e . cooooooo 220. aoaoooco 6 , . 753478 1 7 78. COOOOOOO 100. cooooooo 1. . 759449S9 86. 50000000 158. 00000000 6 . 36737CSO 94 . 29000000 294. 53000000 16 . 37215509 0. 4 7000000 0. 82000000 0. .02305320 32000000 2. 47000000 0. , 1 1061857 2. 3300DOOO 4 . 4 300000D 0. . 6537534 z. 4 2000DOO 5. 30000000 0. .25045741 0. 34000000 1 . 53CODOOO 0. 062*0405 2. 20000000 5 . 28000000 0, . 236 15727 2. 20000000 6. .58000000 0, . 35333254 12. .55500000 32. 60000000 I. 54532433 13. 35BOOOOO 31 73000000 1 ,06 ) 154q2 4 . 2QC00000 9. .03449275 0. 4 1072234 4 . 12941i76 7. 7500COOO 0, . 2366ei55 1 . 54300000 10. .64000000 0. 47223154 5. . 32500000 14 . 28000000 0, .549 12525 3 .58750000 18. .60200000 a . .61 100406 10. . 57500000 24 , 5 1960000 i . 1 1513133 12. .30500000 30, .66360000 i . . 53547627 40, .35500000 85, . 11600000 3, , 46144255 46 . 98600000 154 , 32200000 7, ,46261525 55. .32500000 I 18 , . 5 1550000 4 , 307EB594 56. .56720000 160. .50650000 7. . 75 1 33 180 63. . 34000000 128. 040000GO 6 . .52454831 . 2. 13886BOO 4 25751425 0. . 16616467 3. . 19034940 11 , .20377720 a. .59260018 4 . 34907000 12. .58451040 0, ,66982927 5 .552020*8 18, . 16933560 0. .95733032 7 58633600 18. . 530H284 0. 94354 758 4 1 . . 27250000 127, .57400000 7 . . 77045 -3 1 2 . 39400000 124 , . 44600000 7 , . 1697QS70 38. .31000000 163, ,56440000 10. . 80818445 40 .87230000 161 . .92000000 9. .52757694 33 .59520000 167 , 54O00D0O f i . . 70683230 76. . 52000000 106 . 50000000 2 , 56082407 84 . 35000000 105 .84000000 l , .33992436 85 . 50000000 1 16 , . 40000000 2, . 476535 1 1 32 .09000000 125 ,56000000 2. . 75435307 95 .42000000 129 , 54O0C000 2 .55350139 I . . 12 196462 2 . 19368 376 0, . 09953144 0 .52535854 t . 5327474fl 0. . 074721 i i 0 . 48106359 1 .20743055 0, 05392553 0 . 233 195 1 7 I ,02162344  .05C70C23 a . 3 15346 16 0 ,80183948 0. .03703255 0 . 55 15693 I 3 .33(596 1 • 0, .2CI03 125 0 .35427366 3, .20975020 0 . . ! 90022* i 0 . =5762g12 3 .91542573 0. , 253 305 35 I .00049407 4 . 203 1 7757 0, . 2*334531 ) . 12401185 4 , 40390675 0 . 2542D09S 45 .56352112 96. ,31045532 4 04745129 55 .27433040 216 . 384 1 3552 11. 72552324 71 527 1 3360 18G . 12452335 e. . 13355024 35 234 . 45*04 304 11, , 3 7 9 7 9 * 19 93 . 52508925 203 .44 150432 10 .03 3 13GS5 5 .55321125 1 1 . 5B942534 0. . 44225 = 7  0 .23360000 0 . 35 100000 a. .04412533 0 . 48 100000 1 .43500000 0 .07354221 0 .57340000 2. .00900000 0. . 10235310 0 .35530000 2 .58300000 0 13237539 4 49848289 15 .62533227 0. 3 MOS203 9 , 333 14582 19 10753333 0. . 7548355 = 3 : 774 16026 17 . 35 1714(>b 0  73785505 12 . 22210521 19 .46050758 0.  7 1597503 5 .08000000 9. .4 1600000 c. -39 15 1222 6 .35200000 13 . 15000002 0 . 5 146275 5 7 . 35320000 17 . 25520000 0 . 7C2587 i ! 10 . 16600000 23 . 1S0Q000Q ] ,07351273 12 . 74000000 30 . 45C000C0 1 . 520?1015 12 .30200000 34 . 76O00CCO 1 . 365 I 1533 15 .52590000 27 ,01600000 3 . 2E501B42 12 .90200000 34 76000000 I .73734503 57 03480000 f25 .27 200000 5. . 52J46247 67 20940000 180 . 3202C0Q0 9  35070585 75 =5420000 173 .7 72CGOOO 3 , 7 3 4 " i?50 53 .534JQCaO 132 . 2O75OG0C 3 . 555 ; 7 755 73 . ! 12B0000 225 .07500CCO 1 1 32242951 32 .5G510CCO 189 .25600000 12 . : 15734J6 7 7 31780000 165 , 3244C0CC 26 ,24739622 77 .31790000 188 . 79 120000 9 .55033467 3 .09235400 7 . 74047360 0 . 35055007 4 59375533 12 .33523420 0 .55257258 5 . 3795 1QC0 13 , 5?567200 0 - 7 1275525 5 . 39254712 19 ,040156 '9 1 ,03574g12 9 .30215190 24 19556250 1 .25375557 9 .54425240 2* .97246944  .54959352 10 .11470765 20 .37551532 3 -2*642535 1070 .0000000 24 .730759 1303. ,6 000  257 .502554 26 7 7 . 1300000 3623 .637505 8 .0000000 0 .006244 2259 .0000000 623 . 102554 I D S ; . 0000000 24 3 1C2S5 1482 ,6000000 360 .877532 2573. . 7300000 4364 , 507241 8. .5600000 0 .011847 2006 .OOGOOOD 556 6545 5 935 .0000000 49 .800000 (362, , 4Q00000 589 852727 2084 .3500000 3799 . S789 76 7. . 440000Q 0. .010525 568. ,0000000 951 . 332333 258. .0000000 28 .000000 362 . 1000000 229 .8 10000 538 . 1 100000 7518  358500 2 .0300000 0. .015533 2400. .0000000 592 922077 1 106. .0000000 40 . 243590 1830 . 9000DOO 527 .054359 2575 .2200000 3484 .617009 8 .4 300000 0 .010231 24 .4500000 0 . 159074 39 .3300000 0 .357552 43 .3000000 0 .31554 1 ts . 1600000 a 03327544 . B400000 1 .064741 48 .400C000 t. .769456 29 i , 4540000 31 .044355 292 .0780000 13 .512552 81 .5670730 2 . 193554 79 .S215B72 1 .068422 86 . 12! 1000 2 .393772 129 .5691000 3 .920001 155 . 5536000 8 .550459 213 . 13B9000 18 . 135732 2S6 ,6371000 30 .549936 753 .6019000 143 . 7790 15 1 102 . 404700O 668 2375 11169 .60 11000 289 .048133 1245 .9358000 721 .008899 1214 . 7 146000 51a . 833454 41 . 3740277 0 .331323 82 . 4353431 4 .214100 103 .9766909 5 .3B4055 129 .0230987 11 .228725 145 ,3570249 10 .685551 905 . 323 1000 724 .559430 983 -S153C00 516 . 955331 997 .5687000 1401 .802214 1040 . 6932000 1112 .282854 I 127 .7254OO0 1644 .59907 1 1 165 .5300000 85 . 251659 1235. . 4GC000Q 51 .396094 1340. .3500000 79 .731940 1401 . ,5400000 101 . 5 10408 1469 ,9 700000 91 .533940 17 . 3760750 0. .094 160 10, . 1439056 0 066S93 8 . 5754757 0 .034755 7 .3709425 0 .030346 5 . , 7020007 0 016457 20. . 754 r 324 0. . 485252 20, ,5492433 0. . 283897 24 . 1 753 7 '0 0. 769553 24 ,6392255 a . 713525 26 .2523705 0. 7754 19 90 i . 4 1525 15 195 = " 1 1 = 1436 .36244 17 1650. 723927 '632 . 5372540 805. 75 1489 I B ? I , .Z30S 125 1593. . 253016 1853, . 3522?'i9 1207 . 375050 39 . 7325323 2. 347 : 14 7 , . 7703000 0. 025312 12, ,3505000 0. 070310 18 . 1307000 0. 137807 23 .3103000 0 . ,227304 117, . 3327739 10 . .025551 143 .5737202 6 .333223 163 . 576 1472 '6 . 533151 183 ,2485553 6 . .201377 85. .6357000 1, .992554 122 .5352000 3. 442940 157 . 1 15 1000 6 . 4 17 172 20S ,12030CG 1 4 . 39275 1 26 1 ,8455000 30, C 71 I 30 25 1 ,0237000 39. .09027= 69 , 1358000 2, 274035 304 ,6867000 39. .£5 1372 1045 . 7776000 396 . 755057 1375. .6691CC0 1133 .095523 1527 .0375000 93 I , 3595=5 152* .335 1C00 1154. .532401 1662, .25*5000 184 7, 375552 1399 .0221000 16 14. / 14 5G3 347 ,2002000 2055 . 77 7 425 1634 2003000 1185, 7 15600 60 ,9235334 1. . 598735 101 . 4602509 5 , 7 12205 130 . 1695461 5 .50425l 162. ,3000901 13. 5 7 3034 185. .5565079 20. 3 31773 163. .9 1632 M 26. 4 1 7224 4 1 ,5542308 31 . 6 I78S1 8.042 15.331 14.75. H . 33? S.0B1 16.557 33.359 16.530 12.938 6.302 19.609 32.523 15.240 16.376 fl . 153 12.560 48.341 1B . - 7 8 13. 190 7..157 18.300 29.799 15.298 21.205 19.520 27. 113 25.479 29.9 15 35.723 24 . 352 15.103 23.519 16.313 25.121 19.255 22.948 2-1 . 522 26.392 19.094 28. M O 1 7 , 4 4 3 25.7 7 9 22.328 16.595 29.3B2 26.779 31.166 26 . 302 35.579 30.294 45.03d 36."55 43. 153 10.298 7.596 8.557 9 . 345 8.'62 20.599 30.520 26.032 28.593 22.970 40.25? 35.2d 1 4 3 , 4 1 . 1 39 40.25^ 18.555 33.929 20 3 78 27 T 1 3 22.50.' 20 48C 26.6 17 26.5 17 25.0 17 25.5 17 32.271 21. :20 16.:9J 15.37.1 21.182 19.5 13 20.950 24 15 1 27.£25 27 . 298 ' 24 590 25.735 24 . ."37 31.37 1 25.312 27.55 1 33.519 31.322 39.292 27.392 25.981 30.52? 25.555 29.343 31.550 33.2" 40.488 231 VARIABLE N MEAN STANDARD UlMIUUM UMIUUM SID ERROR SUM VARIANCE OEVUrON vat.L'E VALUE OF M £ A N COPSTP ESVPSTR ESVPST1 ESVPST 2 ESV»ST3 ESVPST4 ESVPST5 ESVPSTS ESVPSTo MAPPSIR MIP^ST1 MAPPST2 UAPPST3 M4PPS7 • MAPPST5 UAPPST5 MAPPSTP T P R D S " TF=F£~ i TFPPS7Z TPf !PSr3 TPRPST4 TPRPST5 rpPPSTB TPPP3TP PVRPS f» p,.'RPST ! °vpr -s ' 2 PVPFST3 PVRP5T4 PVPPS75 P V R P C T5 PVPPS1P LVSWPSTR LVSWPSTI LVSWPST2 LVSWPSf} LVSViPSTJ LVSWPST5 LVSWPST5 LVSHPSTP LVOPST30 LVOPST50 LVOPST70 LV0PST30 AVDPSTR AVOPST1 AVDPST2 AVDPST3 AVQSSTi AVOPST5 AVDPST5 AVQPSTP 13 15 53794£77 4 45257336 10 4 147C765 1 3 74 1755-5 15 23 50 155799 29 06 720000 13 84 3 12U5:5 26 72373057 27 45?C0000 13 83 22 ! 7 2"77 32 423 10 19B 21 42530000 1 3 80 3 7 =; 34 570 16523 2 1 5 2550000 1 3 7C 1 1 '- 131 • i 35 76722705 12 52550000 1 1 53 2 5 7 C 5 '• 3 2 29 W 7533S9 12 45250000 3 53 535 5C-C03 43 01224503 16 37220000 1 3 72 33 5 1207 7 32 42402433 16 97220000 12 S7 2 2 15354 5 7 65546637 71 5500DDOO 13 94 235-2 205 8 40591236 75 50000000 13 99 3S2075C2 5 72729 19 1 63 350COOOO 13 107 2607=323 9 15735282 94 30000000 13 1 12 53322-7 7 10 574332 1 3 6 09000000 1 1 1 17 * 3CCCCG0 1 1 34259172 10 1 10000000 3 120 J0000C00 13 1520 1886 5 74000000 13 1 17 3245 1533 1 1 59250808 101 rooooooo 1 3 1 :27t;550 0 30562908 0 56244003 1 3 0 ' •'• 3 - ' 3 5 2 0 2165240 7 0 44305153 13 0 0 I707G279 0 -14050522 13 0 5 2 C 3 r. 5 £ 3 0 15524732 0 309 1 36 12 13 0 46552-50 0 13402097 0 29334934 t T 0 4 7 75254 7 0 14840620  25018022 3 0 525 1 1503 0 15451143 0 37258258 H 0 465=05'3 0 12342322 0 25018022 13 1 .'~-Zz 0 99 197932 1 C022C4B5 • 3 1 7 5 54.422 0 333007 1 ! 0 53239 190 '3 2 Q?i32:02 1 457 19569 0 30042020 I 3 2 392=0312 ; 47575757 I 03140916 13 3 5 3 3 " 4 S d 3 0344 1486 1 1 10 2 7 S 7 9 1 1 & '•4 3200 1 Z 3 50492997 1 35001205 3 5 ! - '• 1 Z v 5 3 5 2074654/ 2 16331377 13 3 2 7352 1 M2 1 3500 1205 13 95 535=5032 27 05 1 1 1905 54 50330810 l 3 135 34255775 47 11672019 86 204 204 16 13 159 527^5=35 46 39 190281 95 9157135C 1 3 1B3 0 5 2:: 13 4 55 49340021 BB 70575497 13 195 405=3532 72 51 103068 1 17 94032955 1 ! 200 17 37 i530 63 70474156 n o 43453154 3 19 1 30335431 31 464g5100 129 3372 1584 13 200 34623533 54 35434383 129 33721534 !2 0 65=20000 0 IS 133096 0 20300000 12 ' 1 1 1023233 0 26996493 0 50500000 12 1 55445567 0 37643690 0 70700000 12 1 593EOGC0 0 4839923B 0 30900000 13 5 573 104 15 1 44976908 3 22977653 12 9 195 1794g 3 23709001 4 59100308 12 12 Oe027443 4 521 15399 5 38770921 12 13 15433372 3 31358370 8 53749058 •<2 15 5 05952272 . 3 27253131 10 13 325 2--07 5 27655555 943.10355 3 15 177=2537 5 5135E454 3 32355474 12 13 57501559 4 17352944 7 34340356 24 37246944 1 23492166 201 9932951 19 3254 ic 100 74 7C0CC0 6 518 167 74 964 3224000 552 324633 133 15F.C0U00 7 36552949 l 102 5709000 825 052G98 1 4 < ? 930DCOOO a 39255052 1081 8825000 1051 257542 ' . 4 0 1 3030000 3 5 157 7J02 1052 7349000 1202 0204 30 *2 30580000 g 925590J3 91 i 4455000 80 725520 123 70250000 8 79735763 595 8279000 S5 1 334320 101 595500CO 24 33313133 190 9098DOO 1850 053309 131 72620000 5 27015544 941 O1970CO 1117 165406 101 55C00O0O 2 12352730 114 1 6800000 58 621814 1D3 20000000 2 33133079 1225 B60D000 70 559373 107 16O00C00 1 85581507 1291 7200000 45 2S54S6 '23 OCCOOCCO 2 54255620 1394 3900000 84 04035S 129 60000000 2 96055574 U 6 3 6600000 I 1 3 95204 1 139 60000000 3 4 133 1 705 1298 4300000 123 C 416C13 1 55000000 7 59332153 360 3000000 172 975500 133 50C0C000 3 2 '5'8325 1533 0200000 )3J 395244 7 1000*17 0 OB50J350 14 5547259 0 094021 05425=03 0 0505354 l 9 5644 14 7 0 04 7 73R 00^5 239! 0 04 7 25 PC3 7 8350888 0 029 160 0 5359 1=57 0 04 3 33521 6 8950 157 0 0244 1 3 0 71497223 0 037 17073 6 3130334 0 1 79620 72257539 0 04474615 5 2540011 0 022024 0 679B0755 0 09920721 1 6083481 0 023374 0 57930735 0 03423144 6 0554797 0 015233 4 4525?'?3 0 24739029 22 7570532 0 795525 4 72464?:? 0 27404505 22 9503851  3 75 3 J £ 5 S 2 7 5 2 2 a, 3 0 40415337 27 22535B2 2 1234 19 6 3 32 1 =950 0 403 30151 31 1065056 2 177650 1 2 3335 1542 0 25546275 45 9339403 9 5 U 6 15 1 4 58029577 1 14722955 45 84 12013 14 4 77492 1 1 19 4 7 7,-34 3 C0553 153 15 545 1895 27 1 1 7697 1 1 194 77 7 34 0 77247556 45 3040395 7 757403 155 34633553 7 50253052 1254 3634620 731 763042 245 423541Q5 13 05732537 1767 2546808 2219 385321 254 57659 120 13 0054 7 334 207 1 2595 195 2198 850549 299 93092504 15 65933564 2379 6 8 0 4 i g 3 3 192 063227 390 2705 1450 20 1 1034 147 2553 2696522 5257 349570 315 34675204 19 20770223 2201 9 108633 4058 294099 296 87459 127 52 3073 U 0 8 575 7 100544 9365 337252 296 e7459127 15 075 1825 1 2604 5278392 295J 394699 0 93SOCOOO 0 04657224 7 9944000 0 02502B 1 55000000 0 07762039 13 3240000 0 •72299 2 13400000 0 10666355 18 5536000 0 14 1706 2 80800000 0 1397 167 1 23 9832000 0 234249 8 0B44e991 0 4O20935O 73 3283541 2 10 1330 U 757 15247 0 93446739 1 10 354 1539 10 473752 19 90129626 1 30514474 144 9632937 20 440333 20 30354399 1 10OB8679 157 B5207B7 14 543421 213 55 725 77? 1 7 49252-40 182 00677 11 36 719027 22 --423023 ' 1 56=52500 139 2534J07 2 7 34 3 0 j -19 63B35075 3 15331571 40 5334Q09 30 400*97 19 69835075 1 20479417 162 9001371 17 4 18348 28.555 33 25; 35.960 67. 46 . 9.584 10.351 9. 930 27.301 23 108 23.323 23.458 27.59B 31.071 2B.a21 25.497 50.354 55 359 59.57£ 51.575 . 234 31 702 100.497 79.322 28.022 34.559 29.431 30.355 35.319 31.325 47.562 27.130 24.217 24.217 24.217 24.217 25.523 35.200 37.428 25 391 33 =52 34.0E2 30.744 232 VARIABLE STANOARD OtVIATION MINIMUM VALUE M A X I M U M V A L U E O F M E A N ID H T AGE W T P R E 8MIPRE SOSPRE WHRPPE SOTSPRt FPCCPRE FPCIPRE PFSVPRE AVOPRE ARERPRE AWLPRE AVTRHRPR AVTVORPR LVOPRE LRERPRE LWLPRE LVTHRRPR LVTVORPR AHRMPRF APHRMPRE ASTPRE LHRMPRE LPHRMPRE LSBPPRE LSTPRE HOLFRE LDLPRE CHOLPRE TGPPE SBPPRER DBRPRER HRPRER EOVPRER EFPRER SBPPRE! 08PPPE! HRPRE 1 EDVPRE1 EFPRE1 SBPPRE2 D8PPRE2 HRPRE2 EOVPRE2 EFPRE2 SBPPRE3 DBPPRE3 HRPRE3 EDVPPE3 EFPRE3 S E » P R E 4 0BPPRE4 HRPRE4 EDVPRE4 EFPRE4 ERPRER ERPRE4 FRPRER FRPRE4 WTPST 8MIPST SOSPST WHRPST SOTSPST FPCCPST F P C I D S T PFSVPST AV0P3T APERPST AWLPST AV1HPPPT AVTVOPPT LVOPST LRERPST LHLPST LVTHRRPT LVTVORPT AHRMPST APHRMPST ASTPST LHRMPST LFHRMPST LSBPPST LSTPST HOLPST LDLPST CHOLPST TGPST SBPPS7R OSfpSTR HPPSTR EDVPSTR EFPST3 S 3 0 DS T l DBPPST1 HRPST I EDVPST1 EFPST1 SBPPST2 DBPPST2 HRPST2 EDVPST2 EFPST2 SBPP5T3 5 . O O O O O C O O 1 7 : . 2 8 9 6 9 5 9 ^ 5 5 33333333 78.611111]) 26.07333333 6S . 5 5 5 5 5 5 5 5 0 . 9 9 2 7 7 7 7 8 37 . 5.56333333 2.33875000 81,19777778 1.31522222 0.97777778 36.33333333 83.71111111 62.33333333 1.91822222 0.99444444 134.28000000 81.55555556 6B.36656667 117.65655667 85.400C000D 0 11111111 133. i 1 11 1 1 1 1 73.35555558 160. 11 1 11 l 11 0. g4444444 4 1.944 4 44 I 4 8 1 3 3 3 2 ' 7 1 0 0 0 0 C 0 0 1 2 7 6 2 2 2 2 : 2 2 1 U . 44444444 7 5 . 5 5 5 5 5 5 5 5 7 2 . 6 0 0 0 0 0 0 0 138.gg444444 0,44444444 131 44444444 ?e . 3 3 3 3 3 3 3 3 91 . 70000000 172.72444444 0 . 488BBB89 139.33333333 8 1 .a88B8889 100.37777778 166 . 83868889 0. 50555556 152.33333333 84.11111111 115.75668657 174.50555555 0. 51555556 1 6 0 . 7 7 7 7 7 7 7 3 126.3111111! 172.27000000 0.5D666667 1.77333333 2. 94000000 1 . 23333333 2 . 38777778 78.88889889 26.14444444 58.36656667 0.30444444 3B.44444444 6.2842357 1 3.152357 14 94.8 1 42957 1 1.52200000 1.04838889 45.86556567 83.90000000 72.47777778 2 . 17350000 1 .03525000 14 7 05000000 85.05555556 76 .95555555 125.00000000 71 , 55555556 0,OOOOOOOO 136.37500000 77.750CCOOO 169 . 250QOOOO 0 . 38889889 41 15555556 155.488B8889 226.35555556 119. 40000000 109 . 33333333 75.55555556 68 . 52222222 175.04444444 0 45222222 130 . 5 6 5 6 6 5 5 7 7 7 . 99386999 35 05596969 191 . 25 M1111 0.491 1 1 1 11 142. 11111111 79,55555556 95 17 77 7 7 78 205.53CCOOOO 0.53555556 152.OOOOOOOO 2 73E5I279 6 O43053OG 9 75519230 12 T 8 1 0 P 4 1 i 3 . 4 9 3 4 7505 22 . 30M272E 0.C90 1 7729 U 7 3 « 3 P 5 5 1 .01319904 0. 4B191397 18. 346404 1 3 0 42355103 0.05995031 1 1 .3885449 1 * 47393687 10.05392Q7 1 0.55505997 0.0745 1696 35.30455495 7 17323343 9.71450B28 2? EQ57d25S 16 75523767 0.33333333 37 11955I8Q 21 27011466 23.29939006 1 .53S23386 3 ' ( 1 5 3 1 9 9 3 2 4 27 . 5 " 3 £ 5 7 R 77 120^0796 10 341CZ29T 7.24750497 1!.03741530 44 93424922 0 10736749 10 22S4B650 5 . O O O O O O O O 15 524 I4999 63.14 105887 0.08343327 15.37042015 7.63944442 19.31752946 60.50053516 0.09342258 24 13503577 5.96750460 27 55911373 6.5 .94056918 0 11948966 30 . 4533 7 255 6.31 356554 29.50445256 54 42327627 0. 12479984 0.38082449 0. 90543467 0. 19306735 0 . 30648586 1 1 . 94445487 3,03507934 14.25350237 0 OB3532B0 9 25487859 1.04 198702 0 . 57267543 21 32099345 0 4734ig48 0 06827233 14 99699436 7.74 774 161 B.76352009 0 70455453 0 08593934 46 6 1 1 15862 11,078 14415 10 36642551 25.24375235 12.52053001 O.QOCOOOOO 31 35057567 16.05015473 30 12711166 0.60092521 7.99 1 7 3 184 37.07547857 2g R4941446 68.4614 7380 15.49193338 4.37772817 12 . 7 76 1 279 1 35 10444557 O 0964*037 20. 14944 158 5 . 6665666 7 15.57509525 36 7363881! 0 09662355 19 29655062 6 40529295 18 .62865922 35 17B95743 0.08651858 2) 40677463 I . o o o o o o o o i r r . a o u o o o c o 35 O O O O O O O O 54 .7 D D 0 0 O O 0 21 . 1D00G00O 39 . 500OUUOC 0 70000000 1 7 . O O O O O O O O 4 . 3BGCG00G Z 07000000 5 3 .40000000 0.83900000 0,98000000 12.50000000 78 9 0 0 0 0 0 0 0 4 9 . 5 0 0 0 0 0 0 0 1 0 3 3 0 O O Q O 0 .33000000 6 5.40000000 71.60000000 5 3 50000000 73.00000000 45 O O O O O O O O 0.oooooooo B5.OOOOOOOO 4g oooooooo 134.OOOOOOOO 0 . O O O O O O O O 2 8 . O O O O O O O O I 1 • C Q G O O C C O 1 8 G U D O Q C O C O 33 £0000000 96 O O O O O O O O 60.00000000 59 .60000000 92. 170000GO 0 . 21000000 122 aaoooooo 7 o . o o a o o o o o 74.00000000 89 5Q0D000U 0 33DO00O0 1 2 2 . 0 0 0 0 0 0 0 0 7 0 . 0 0 0 0 0 0 0 0 74. 3 0 0 0 0 0 0 0 87. 7 9 0 0 0 0 0 0 0.30000000 130 OOOOOOOO 7B .OOOOOOOO 79. 2 0 0 0 0 0 0 0 9 8 . 0 1 0 0 0 0 0 0 0 . 3 3 0 D 0 0 0 0 130 a o o o o o o o 7 5 . 0 O O O O C O Q 8 3 , 2 0 0 0 0 0 0 0 96.6000DOOO 0 . 3 1 0 0 0 0 0 0 0 9 9 0 0 0 0 0 0 2.00000000 0 96000000 ! .3 7000000 58 . 3 0 0 0 0 0 0 0 22,50000000 45. 5 0 0 0 0 0 0 0 0. 7 2 0 0 0 0 0 0 25 . OOOOOOOO 4 . 7 1000000 2 45000000 56 10000000 0 . 9 0 8 0 0 0 0 0 a . 3 9 o a o c c o i8.eoooooao 64 90000000 59 60000000 1 . 10000CCO 0 . 8 6 0 0 0 0 0 0 65 40000000 8 2 . 2 a a o o o o o 56.50000000 9 4 . 0 0 0 0 0 0 0 0 5 5 . 0 0 0 0 0 0 0 0 0 OOOOOOOO 95,00000000 5 5.00000000 1 4 0 , 0 0 0 0 0 0 0 0 0 . 0 0 0 0 0 0 0 0 32 OOOOOOOO B6 60000000 193 7 0 0 0 0 0 0 0 4 4.00000000 90.OOOOOOOO 7 0 . 0 0 0 0 0 0 0 0 5 7.50000000 139.6 3000000 0 .23000000 10'J DOOOOOOO 70 OOOOOOOO 70 9000GCC0 1 5 ? .90000000 0,29000000 125 OOOOOOOO 70.00000000 7 3 . 3 0 0 0 0 0 0 0 159 03000000 0 3 5 0 0 0 0 0 0 134 OOOOOOOO 9 . O O O O O C O O 1 7 $ 4 0 0 G C G C G 5 8 . O O O O O O O ? 9 5 . 4 0 0 0 0 0 C C 3 1 l a o o c c o o 1 1 2 . 5 0 0 0 0 C 3 C 0 9 6 5 0 0 C 0 0 5 9 . 0 0 0 9 0 0 0 ? 7 . 9 7 0 C U C G C 3 . 8 4 0 0 G U C O 1 0 2 . 2 0 0 0 0 0 0 0 2 . 2 6 7 0 0 0 C O 1 . 0 7 0 0 0 0 0 0 5 0 . 0 0 0 0 0 0 0 0 9 2 C O O O O O O O B O O O O O O C O O 2 . B 8 D 0 0 0 0 0 1 . 1 0 0 0 0 0 0 0 179 7 0 0 0 0 0 0 0 9 2 4 0 0 0 0 0 0 C 8 0 . 6 0 0 0 0 0 0 0 173.00000000 9 7 . O O O O C C C O 1 . O O O D O O C G 2 0 0 O O O O O O O O 1 1 3 . D O O O O O O O 2 0 7 . O O O O O O O O 4.50000aC3 5 3 , 0 0 0 0 0 0 0 0 193 C O O C G C C C 2 5 7 O O O O O C O O 2 4 0 . D O O O O O O O 1 3 G . O D O O 0 C C O 8 3 . 0 D 0 O 0 C 3 C 9 0 . 1 0 0 0 0 G C G 2 3 6 3 5 0 0 0 O 0 G 0 . 5 9 0 0 0 0 0 0 1 5 0 . 0 0 0 0 0 0 0 0 8 5 O O O O O O O O 1 2 3 . 6 0 U U U U O Q 2 6 1 . 4 2 O 0 0 U 0 0 0 . 6 2 C Q 0 0 G 0 1 6 2 . 0 0 0 0 0 0 0 0 9 0 . 0 0 0 0 0 0 0 0 1 3 6 . 2 0 O 0 0 O C 0 2 6 3 . 8 3 0 0 0 0 0 0 0 . 6 3 0 0 0 0 0 0 1 9 3 . 0 0 0 0 0 0 0 0 95 .00000000 1 6 0 . 0 0 0 0 0 0 0 0 3 2 0 . 5 4 0 0 0 0 0 0 0. 7 1000000 210.00000000 95 . O O O O O O O O 1 7 2 , 0 0 0 0 0 0 0 0 2 8 8 . 9 2 0 0 0 0 0 0 0 . 6 9 0 0 0 0 0 0 2 . 1 7 0 0 0 0 0 0 4 . 0 6 0 0 0 0 0 0 1 . 6 7 0 0 0 0 0 0 4 . 3 3 0 0 0 0 0 0 9 3 . 7 0 0 0 0 0 0 0 31 , 1 0 0 G 0 0 C 0 B 9 O O O O O O C O 0 . 9 7 0 0 C O O O 5 1 . 5 0 0 0 0 0 0 0 7 . 9 1 0 0 0 0 0 0 4 . 1 2 0 0 0 0 0 0 1 1 6 . 3 0 0 0 0 0 0 0 2 . 4 8 0 0 0 0 0 0 1 . 10OOOOOO 6 8 . 8 0 0 0 0 0 0 0 9 1 . 5 D 0 0 0 0 0 0 8 4 . 2 0 0 0 0 0 0 0 3 . 0 S 0 C C 0 0 0 1 . 1 5 0 0 0 0 0 0 212 4 0 0 C 0 0 0 0 9 9 . O O O O O O O O 91 .80000000 1 6 9 . D O O O O O O O 9 5 . O O O O O O O O 0 . O O O O O O O O 1 8 3 . O O O O O O O O 1 0 3 . 0 0 0 0 0 0 3 3 2 1 5 . 0 0 0 0 0 0 0 0 1 . 5 0 0 0 0 0 0 0 S B O O O O O O O O 2 0 8 . O O O O O O O O 2 8 4 . 0 0 0 0 0 0 0 0 2 4 0 . 0 0 0 0 0 0 0 0 1 4 0 . O O O O O O O O 8 2 . 0 0 0 0 0 0 0 0 1 0 0 . 7 0 0 0 0 0 0 0 2 6 7 4 2 0 0 0 0 0 0 O . 5 6 0 0 C 0 0 0 1 5 2 . C O O O O O O O 8 5 . 0 C O O O O G O 1 2 4 . C O O O C G G Q 2 5 6 - 1 3 0 0 0 0 0 0 0 - 6 1 0 0 0 0 0 0 1 8 0 . 0 0 0 0 0 0 0 0 go.oooooooo 1 3 5 . 0 0 0 0 0 0 0 0 2 8 4 5 2 0 C O O O O 0 G 4 0 0 0 0 0 0 1 8 5 . O O O O O O O O 0.91297093 2 0 1 * 3 5 4 3 5 S . 2 C 1 7 3 0 S 7 4 . 2 5 0 3 5 1 3 7 1 . 1644g?02 7 43370909 0 . 0 3 0 0 5 9 10 4 . 9 1 3 2 1295 0 . 3 3 7 7 2 3 3 5 0 . 1 7 0 3 3 2 3 2 6.11546804 0. 1412 1701 0.02332010 3.96284830 1 . 49 1 3 1229 3.35464024 0. 18535332 0.02483899 1 1 .758 18498 2. 39 107781 3 . 23B26943 3 36859090 5.58509922 0. 11 M 11 11 12.37318387 7.09003822 7.76646002 0,50307695 3.03530664 Z 31 = t;f?103 9 17 5 9 9 5 2 5 25.70696932 3.5 1 357430 2 , 4 1536832 3.67914543 14.9780B307 0 .03578916 3 .60982883 1 .60668667 5.5DB049G6 21.04702236 0.02781109 5. 12347538 2.54648147 6 . 43917649 20,20017839 0,031 14086 6 ,04501226 1.98916820 9.28970458 22,31352306 0.03982989 10, 15132419 2. 10452188 9 .86815085 18. '4109209 0 .04159995 0. 12567483 0.25B47822 0 06435578 0. 25882B62 3.94815 162 1.01202645 4.75450079 0.02759420 3.08495953 0.39379628 0.21645097 8.05857806 0 . 15790649 0.02275744 4 . 99555479 2 58255054 2 . 32294003 0 . 2 4 9 1 3 3 0 0 0.03070234 17 1 6 6 6 4 3 4 9 3.6927 1472 3.45547517 8.41625412 4.20684334 0 . O O O O O O O O 1 1 . 29523435 5 67312217 10.5515-1248 0 20030340 2 66391061 12 . 35B49286 9.BB 3 t 38 1 5 22.15382460 5.16397779 1.55924272 4.25870930 13.088 1 4852 0.03292012 6 . 7154B055 1 .388*8389 5 . 22503 1 75 12 . 24546270 0 .032207B5 6 .43222021 2. 1 3509765 5. 20955307 12.05951914 0.02337235 7.13559154 45.OOOOOOO ' 5 5 9 . 5 C 0 0 0 C 0 496.OOOOOOO 707.5000000 234.5600000 825.OOOOOOO 8.0350000 335.OOOOOOO 50.S7C0C00 23.5 100000 730.7800000 11.8460000 8.3000000 331.5000C00 753.4000000 5B1.OOOOOOO 17.2640000 B.950OD00 1208.5200000 734.OOOOOOO 537.3000000 1059.OOOOCOO 586.50G00C0 1 .OOOOOOO 1198.0000000 865 .5000000 144 1.0000000 B.5000000 375 . 5 0 0 0 0 0 0 13JS.5CCDCOC 1953 3 0 0 0 0 0 0 1 148 . 5 0 0 0 0 0 0 103D.OOOOOOO 63D.OOOOOOO 553 . 4000000 1250.950GOOQ 4.OOOOOOO 1 183.GOOOOOO 705. a o o o o o o B25.3000000 1554.5200000 4.40000QO 1254.0000000 737.OOOOOOO 907.9000000 150!- 5500000 4.5500000 1371.OOOOOOO 757.0000000 104 1.9000000 1570.5500000 4.6400000 1447.0000000 764.OOOOOOO 1136.8000000 1550.4300000 4.5600000 15.9600000 25.5600000 11 . 1000000 25 .9900000 710.0000000 235.3000000 620.7000000 8.1400000 346.OOOOOOO 43 .9900000 22.0700000 663 . 7000000 13.6980000 9 .4400000 412 . BOOCOOO 755 1000000 652 . 3000000 17 . 3880000 8 .2900000 1176. 400000U 765.5000000 692 6O0C000 1125.0000000 644.OOOOOOO 0.0000000 109 >.OOOOOOO 622 .OOOOOOO 1354 OOOOOOO 3 . 5000000 370.40CQ000 1399.4000000 2041.7000000 1074.6000000 984 OOOOOOO 680.0000000 517 6000000 1575.4000000 4 070000D 11 7 5 OOOOCOO 701 OOCCOOD 765.9000000 172 1.2600000 4.4200000 1279 OOOOOOO 7 16 OOOOOOO 856 .6000000 1850.2200000 4 . 8200000 1368 OOOOOOO 7 . 5 0 0 0 C G 3 6 . 5 186 1 1 95 - 75000C 163 . 356111 12.204375 497 340270 0.008132 217. 255544 1 -025550 0.232241 336.590544 0. 179480 0.004894 14 1 .337500 20.0161 11 1D1.282500 0.309203 0.005553 1246.4 1 1600 51.455278 94,37 7500 876.500000 280 740000 C. 111111 1377.86 ! 1 1 I 452.4 1 7778 542.86 1111 2.277778 82.917778 0 2 2 . 3 4 C C 0 0 '57 7 3 0 0 0 0 5947 334444 117.527778 52 . 527779 121 .325COO 2019.086753 0.01 1523 117 277778 25.000000 273.04 750U 3986.794578 0 .006961 236.250000 58.36 1 1 1 1 373.166944 3672 424861 0.008728 582.500000 35.611111 776 .687500 4481 .039803 0.014278 927 444444 33.661111 876.423611 2961.893000 0.015575 0. 144875 0.648725 0.037275 0.550419 140 . 29 11 11 9.217778 203.447500 O.OD7C03 35 . 552778 1.085529 0 . 327957 454.5847G2 0.224 12£ 0.00 4 5 5 I 2 2 4 . 6 1 Q 0 0 G 6D.O275G0 7 6 . 9 8 5 9 4 4 0 . 4 9 5 5 3 3 0.00754 1 2363.045714 122.725278 107 462776 637 500000 159.277778 a . o c o o o o 1020.333286 257.929571 907 .54295' 0.35 11 1 1 53 86777? 1374.591111 879.OB7773 4 417.127500 24G.CGGOOO 24 777773 163.229444 1535 385553 0 .00^694 405.000000 33. m i n 245 7Q85H 1349.5G22 t 1 0.009336 372,36 1 1 ! 1 41 027775 347 025944 1308 909725 0.007503 458 250000 54 772 3 . 4B7 1? . 6 R J 16 .259 32 1C 10 i 35 5 " c 1 7 . B S C '6 . 33 2? 595 32. 137 7. 155 32. 27 7 5 . 344 16 145 26 , 988 7 . 493 25 292 8 796 14 . 638 25 16 1 25 . 5 EC 300. 000 27 . 386 28 75 1 14 . 552 159 . 801 2 ' . 76 1 16 . 773 12 . 530 60 . 429 9 . 47 3 9 . 532 15 203 1Z . 329 24 . 158 8. :3S 6 . 38 J 16 . 020 36 . 555 17 , 066 1 1 . 031 9 . 329 1 9 I 49 36 . 323 18 . 4 79 15. 844 7 . 095 24. 074 38. 350 23. 177 16 , 942 7 . 437 23. 436 31 . 592 24 .632 21 .464 28 . 360 15 .654 27 329 15 .014 1 1 6 1 3 20 582 9 . 252 24 .073 15 .575 18 . 164 22 . 487 3 1 . 105 P 32 .5 75 9 . 2 3-5 1 Z.09" 12 4 2" E . 380 1 3 .025 1 j .47 1 20 195 17 .537 23 42? 20 . 55C 1 7 B U G 154 52^ 1 9 . H P 23.84* 13.C7C 5 1 . 6 6 3 14 163 5.565 I E . 5 1 3 ZZ 39." 21 773 19.671 1 3 579 8 05 1 19.57? 17 . 598 1G 174 14 083 233 STANOARO DEVIATION MINIMUM VALUE MA X I MUM VALUE STO ERROR OF MEAN OEPPS73 9 79 HRPST3 g 106 EDVPS' 2 9 199 EFPST3 g 0 S3PPST4 e 165 DBP D5T 4 5 82 HPP3T4 a 1 15 EDVPST4 8 95 EFPST4 e 0 SBPPST5 5 1E3 DBPPST5 s B4 HRPST5 5 13! EDVPST5 5 210 EFPST5 5 0 SBPPST8 1 192 OBPPSTB 1 90 HRPSTB 1 137 EDVPSTS 1 191 EPPST5 1 0 SBPPSTP 0 165 OBPPSTP g 63 HRPSTP 9 12" EDVPSTP  209 EPFSTP 9 0 ERPSTR g I ERPST4 9 2 ERPSTP 9 2 FPPTTP 9 FPPST4 9 2 FPPSTP 9 2 LRPPUDDE 9 21 LPPPMPST s 23 RATIOPRE 9 5 RA7IOP5T 9 5 RPPPRER 9 B RPPPRE! 9 12 RPPPPS2 9 13 RPPPRE3 9 7 RPPPREA 9 20 SVPPER 9 59 SVPRE1 9 84 SVPRE2 g 83 SVPPE3 9 89 SVPPE4 9 88 COPPER 9 A C0PRE1  7 COPRE2 9 8 COPRE3 9 10 C0PPE4 9 11 ESVPFER  79 ESVPPP • 9 33 ES7PFE2 9 83 ESVPPE3 9 84 ESVPRE4 9 84 MAPPRER 9 88 MAPPRE1 9 95 HAPPRE2 9 100 MAPPRE3 9 105 MAPPREJ  109 TPPPRER 9 1 TPPPRE 1 9 0 TPRPRE2 9 0 TPRPRE3 9 0 TPFPRE4 9 0 PVPFP.ER 9 I P V R P P E 1 9 1 PVBFRE2 9 1 P V R F P P 3 9 2 PVPpFr.''. 9 2 LVSWFPER 9 72 UVSrtP=E' 9 109 LVSWPOE2 g 1 15 LVSVIPPE3 9 134 L V S * a c = J g 13G A'.'DrFSP. 9 6 LV0PPE20 9 0 LV0PPE50 9 0 LVGPFE70  1 I.VOPPE90 9 1 AVDPRE 1 9 B C P-2 9 12 AVPPFE3 9 1 4 AVDPF=4 9 9 RPPPSTP Q 7 RPPFST1 9 10 RPPPST? Q 13 RPFPST3 9 16 B P P P C T J 2 19 RPPPST 5 5 24 RPP ° S T 5 1 26 RPPPSTP 9 21 SVPSTP 0 77 SVPST 1 g 94    S T 2 9 1 1 1 SVPST3 9 1 12 S'.PSTJ a 10? SVF375 125 SVPSTE 1 118 SVPSTP 9 i ie CCPSTP 9 5 CCPST1 9 7 COPSTc 9 10 CO°S T 3  1 1 C0PS14 B 12 COPST5 5 16 COPST6 1 16 .55555555 .53333333 .77656567 .55333333 .37500000 250CC0C0 .9125C0OO .23500000 .54125C00 .80000000 .50000300 .38000000 .75200000 .59200000 OOOOOOOO . OOOOOOOO 20000000 .62000000 .82000000 . 77 7 7 7 7 73 .11111111 80000000 .26666557 .55333333 .80000000 .55444444 . .' 10CCOCO OS222322 7 4CCO00O 94553555 38255555 .29637:00 .48588581 .52508973 2431C000 .01155556 .96834444 57142222 33322222 .83590000 .10500000 D8B56667 56645555 .09643333 .23805884 .55447543 .26440211 .09938101 .02916360 . 15754444 Q I 844444 . 75022222 .93910000 . 17355667 .388BB8B9 .86OO00OO . 84555556 .62444444 .93222222 .238467B9 .83862397 .79634980 58725924 .67851549 .65045672 .72IBI080 .93921502 . 11270690 24905793 .87370E96 .24521566 .47008453 .25723114 . 375218 10 . 25774654 . 57546667 .959111 1 1 . 34275556 .72640000 .31453946 75160917 73005991 1654 1632 .63575555 99844444 39231 1 1 1 09721111 .79935000 14316O0O . 34240000 244S2222 72243333 23201333 .35105550 23803333 55471250 49132000 .30440000 .20510000 .16136307 .77545934 24930560 .49874e56 .42042359 .15948876 .29996368 5 7903W59 70 CCOCCCOO 90 OOOOOOOO 1 9 20 10596 715 OOOOOOO 22 47620964 75 20000000 150 OOOOOCOO 7 492069BB 953 700C000 44 14 142131 136 75000000 290 B9000D00 14 71380710 1797 9900000 0 '0735455 0 32000000 0 6 7000000 0 02576495 4 9800000 28 90247235 140 OOOOOOOO 210 OOOOOOOO 10 21392055 1331 COOOOOO 4 =222223 ' 75 90 OOOOOCOO 1 70959624 658 OOOOCOO 29 S313004S 32 302.20700 165 OOOOOOOO 10 44091262 95B socooao 54 52057531 134 7SO002OO 297 2000COOO 19 31132495 1569 8800000 0 12240686 0 33COOOOO 0 70000000 0 04327907 4 3300000 37 15104305 140 OOOOOOOO 222 oooooooo 1 6 6 1445154 919 ooooooo 5 76756973 75 OOOOOCOO 90 oooooooo 3 02654919 423 ooooooo 24 24607185 104 oooooooo 168 oooooooo 10 84317297 656 9000000 88 24684453 142 23000000 354 22000000 39 465 I88BA 1053 7600000 0 09148770 0 45000000 0 70000000 0 0 4 0 9 H 5 5 2 9600000 192 192 oooooooo 192 OOOOOOO 90 oooooooo 90 oooooooo 90 OOOOOOO 137 20000000 137 20000000 137 2000000 19! 5 2000000 191 62000000 19 1 6200000 34 0 520CCCOO 0 6200DOOO 0 6200000 54935342 135 OOOOOOOO 222 OOOOOCOO 11 5 1552781 15 19 OOOOOOO 5 32551510 75 90 oooooooo 1 77517170 748 OOOOOOO 29 42539122 82 90000000 158 oooooooo 9 80879707 1123 2000000 64 71107054 14 1 72000000 354 22000000 21 57035565 IBB3 AOOOOOO 0 11000000 0 33000000 0 70000000 0 03666667 4 9800000 0 41593269 1 01000000 2 300000D0 0 13964423 16 2000000 0 89175545 1 4 30000000 0 29725182 23 8900000 0 93024190 i 55000000 4 32C00OOO 0 31OOB063 24 3900000 0 •-315B39 0 =5000000 29000000 0 04!15613 9 7 400000 G 52313722 1 32020000 3 30000000 0 20771241 24 8600000 0 6 7 4 7444 1 1 320O0OOO 4 18000000 0 2S1S6147 26 5100000 5 50470353 13 C0500000 30 OOODOOOO 2 201S57B8 192 4 4 30000 7 0422334O 13 30000000 30 !0400000 2 48980550 186 2950000 1 77354412 3 39522642 9 53571429 0 59121471 49 3819313 0 24105934 4 224 13793 7 02941175 0 3 1368545 50 5347985 1 01025501 7 13 700000 9 9110C000 0 3676200 74 1879000 2 080531B3 g 52COOCOO 15 57360000 0 69351061 108 1049000 2 53591529 10 2534OG0O 17 37B40000 0 84553843 125 7151000 4 54222431 10 92360000 23 13240000 1 5I407A77 I5B 1428000 5 98848980 12 31350000 23 56350000 1 99615327 183 0530000 18 36673364 34 0=200000 93 35040000 6 22226121 538 5321000 33 422937 15 4 1 203 30000 13B 08640000 11 1A098905 756 95A0000 30 95569475 43 C 7 1 0 0 0 0 137 575BOOOO 10 32196492 747 7980000 39 33735474 40 3 7000000 169 9 3920000 13 11245491 806 09B1000 36 95110402 4 0 5 7000000 153 12760000 12 31703467 792 8679000 1 05755735 2 E012I960 5 91841536 0 35252245 39 1425277 2 65543704 3 04930320 1 0 78341960 0 88514568 68 OB027BB 2 81B60124 3 19617053 12 95964036 0 93953376 7 4 3796190 4 36959671 4 34693952 10 74693504 1 45553224 90 S94429I 5 05903328 3 93318880 21 6216I71J 1 56634443 9 9 2534724 4 1 54987391 45 =5010000 1B6 71650000 13 BB329IJ7 712 4 179000 3? 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'.'400OCO0 17 232!'943 876 7S77000 55 56533053 54 02330000 212 53200000 24 55423261 627 1565CGO 116 =0440000 1 IE 30440000 1 IB 8044000 46 97756655 46 7 7C90OOO 212 53200000 1 5 65923885 106 3 8459000 0 72647680 4 43396200 6 47248448 0 24215960 46 4522576 1 75143837 6 09669516 10 59496428 0 687I46I2 69 9791340 2 25554g34 8 9=567640 14 503 15750 0 75228331 92 2437504 3 54S83476 S 73947500 20 5515S365 1 .21652825 103 4B87371 5 14403S93 7 71719B50 24 25748400 1 .31969240 99 . 3633387 7 56445175 10 75636BOO 20 64B21400 3 42764703 80 7974438 IE 29996368 16 299353S8 16 .2999637 33.527775 505.180000 1948.465075 0.011525 B35.410714 23.357143 872.101250 2983.416171 0.0149S4 1380.200000 45.500O0D 587.972000 7787.505570 0.00837D 1 193 694444 25 361 111 865 9125DD 4187 522650 0 012100 0 173000 0 795225 0 365350 0 0 15244 0 3BS3C0 0 765178 43 622 10 49 59 3051 3 145613 0 885533 1 020578 4 328613 5 435933 20 531802 35 B62010 359 739682 1117 094733 95B BB6B37 1547 428265 1365 3B408B 1 118449 7 051346 7 944513 19 093375 25 593818 1734 711996 1587 059937 1820 38595E 1639 305157 1075 B34140 65 551411 2 2 427925 84 280225 120 249678 168 959219 a 080337 0 171441 0 152E32 0 087933 0 112855 0 22734! 0 427985 0 491822 0 799878 1 064085 675 047731 1844 363403 2428 698030 5469 346902 5140 704 747 2 801536 0 027828 0 077301 0 151509 0 230454 11 545104 30 486331 31 254033 67 94234 1 3 52 '095 3 650433 5 055330 10 7 2 ! 4 1 a 23 8984 73 36 560545 46 75CS52 358 553541 927 952057 1017 55AJ65 1575 772533 2403 210« 12 3032 523C22 2206 319946 0 .527771 3 102555 5 092372 13 32'353 25 46 1135 58 743321 7 . 2 7 8 2 1 . 0 7 8 2 2 . 0 9 5 1 9 . 4 0 ! 1 7 . 3 7 2 5 . 8 7 6 2 4 . 6 4 6 2 7 8 3 4 2 2 . 5 1 6 2 0 . 2 1 3 7 . 9 9 9 1 8 . 4 5 5 4 1 . B 7 2 1 5 . 4 5 4 2 0 . 4 7 1 6.408 2 3 . 5 7 9 3 0 . 9 2 3 I 9 . 8 B 0 2 3 . 1 0 7 3 3 . 5 9 5 3 4 3 2 6 1 1 . 4 0 9 2 2 . 7 4 2 2 9 . 8 9 7 3 0 . 8 8 8 3 0 . 2 4 1 3 2 . 3 2 5 1 6 . 7 2 7 1 2 . 2 5 6 1 7 . 3 2 1 1 8 . 1 6 2 2 5 . B S 0 2 9 . 4 4 3 31.697 3 9 . 7 3 9 3 7 . 2 6 8 4 3 . 9 2 0 4 1 . 9 4 4 2 4 . 9 5 4 3 5 . 1 0 4 3 4 . 1 0 5 4 3 . 2 6 6 A 5 . 8 7 4 5 2 . 6 1 6 4 4 9 5 5 5 0 . 9 4 4 4 7 . 8 6 8 3 8 . 9 6 7 9 . 1 6 0 4 . 9 4 0 9 . 1 0 3 1 0 . 2 6 5 1 1 . 3 2 4 2 2 . 9 6 6 4 9 . 3 7 3 4 9 . 0 6 7 3 7 . 9 3 8 4 9 . 5 1 2 2 8 . 8 8 9 3 7 . 9 9 5 3 6 . 1 6 4 4 2 . 3 3 2 4 5 , 8 6 5 3 5 . 5 5 3 3 9 . 3 1 2 4 2 . 5 7 9 5 5 . ' 8 1 5 2 . 5 7 5 2 5 . 7 4 7 2 8 . 9 8 8 2 8 . 9 0 8 2 8 . 9 8 8 2 8 . 9 8 8 4 0 6 6 6 4 3 . 3 0 0 3 7 . 3 7 1 4 5 . 3 7 3 2 4 . 9 9 7 1 7 . 3 7 2 16.790 2 0 3 4 ' 2 4 . 6 8 5 2 5 . 0 4 5 234 STANDARD DEVIATION VALUE UA X I MUM VALUE STO EP.POR OF MEAN CCPSTP ESVPSTR ESVPST 1 ESVPST2 ESVPST3 ESVP3T4 ESVPSTS ESVPST6 ESVPSTP MAPPSTR MAPPST1 UAPPST2 UAPPST3 MAPPSTJ WAPPSTS UAPPST6 UAPPSTP TPRPSTR TPRPSTl TPOPST2 TPRPST3 TPRPSTd TPRPST5 TPRPSTB TPRPSTP PVPPSTR PVRPST1 PVRPST2 PVRPST 3 PVRPST4 PVRPST5 PVRPST6 PVRPSTP LV5WPSTR LVSWPS T1 LVSWPST2 LVSWPST3 IVSWPST4 LVSWPST5 LVSWPST6 LVSWPSTP LVOPST 30 LVOPST50 LVOPST70 LVOPST90 AVOPSTR AVDPST1 AVDPST2 AVDPST3 AVQPSTc* AVDPST5 AVDPST6 AVDPSTP 95 100 103 1 10 I 17 123 II 1 0 .27307606 .32201 1 1 1 .319D7776 . 22894444 .53863333 .64028750 . 26058000 . 8 1560000 .05 156557 . 70222222 .20555556 124 153 150 168 204 199 183 0 46222222 01 125000 33600000 66000000 39 111 U 1 96451442 7 1754 1 4 7 573502 13 53985735 55064312 45264 145 43678625 49629908 23885833 42253552 55051054 85395544 07435395 5109D313 .63579761 036 13309 . 35905321 83959352 .68227135 . 5734Q690 .98091849 94829191 . 8023986 1 . 32956554 . 65205000 ,08675000 .52145000 .95515000 .92382132 .79185603 .21691660 . 15922101 24467602 .69405379 . 99574317 .111 10193 6.35B74g65 34 . 4094Q253 20.57352016 16.69731517 20.29081542 20. '5592041 37 .02332738 25.91095322 7 .5633084 l B,59352252 8 .59015332 9.36635583 12.0578S53B 16 . 35020367 14 . 40935355 0.15210311 0. 1 143B593 0.09585355 0. 1032 1537 0. 13252400 0. 13560608 0. U5977 17 0.42574453 0.45023557 0. 35093512 0.55525222 0.e3235!22 1 .25803 1 28 0.97213593 22.90U540) 47 .93 1 76027 54 . 6 3 3 4 i g j 5 6/.99303550 92.32900053 110.1 3225664 90 .9 1 179875 0.2 1 1 39536 0. 35232725 0. 493253 17 0.534 18907 0 .64370094 3.50335350 4. 16422535 5.20222737 7 . 12593735 5.47532321 6 .6404 1 1 7 1 7 . 7 17 19550 68 . 41670000 65.5487GOOO 70.51760000 55.24520C0O 55 44550000 50.007COOOO 72 . ?1550000 50.00700000 76.50000000 33.20000000 89. 14000000 92.44000000 96 450QOOOO 96 . 45000000 123.55000000 95.45000DOO 0. 73510282 0.50547153 0. 14357584 0.32775642 0. 303 19390 0.250 17082 0. 43678525 0. 250WDB2 0-56393053 0.32433183 1 .02094934 1 .03043483 1.253 1 7338 1 40724 157 2.535 7976 1 1 .253 W338 54 . 39S23455 57 . 2 12 14923 85.05093269 77 . 54 147 123 54 .530748 15 9 1.2 1 1 43960 199.30238851 64 , 530746t5 0.3300COOO 0. 55000000 0. 77COOOOO 0.39000000 3.e625Q443 3.08556430 5. 10975794 6.31909320 7.07334039 8. '2932510 15.99574317 7.07334033 29. 6482 14C0 2. 122916=5 123 . 4576847 40. 560972 163. 12620000 11 . 46990089 875. 8961000 1184. 005369 129. 92350000 6. 35784 335 866. 87 1 7000 423. 270 143 122 . 44700000 5. 55577 1 72 848. O6O5C00 276 . 300334 124 • IRdO'JOO S . 75350647 787 . 8477C00 4 11. 7 17353 1 IC. 395C0000 12551220 5S3. 1223000 06 . 2974C7 14 1. £3300000 16 . 55957142 425 . 3034CCO 1371 . 037023 72. .2 1550000 72. 8155000 14 1 . £3600000 3. 63598941 8 13 . 554 (CO? 57 1. 37627.: 99. aooooooo 2 . 554602B0 780. 3200000 63. 422244 103 . 4 3000000 2. . 99797427 857 . 7 500000 75 . 575073 1 16 . 35000000 2. 39672777 901 . 7900000 75. 5 192S5 117. 33000000 3. .25973394 331 . 1600000 57 . 345 194 129 . 60000000 4 . 25564157 880. 0900000 145. 633370 133. 55OCO00O 3 1203509 5B5 . 680CC00 25 7 . 329330 123. 5 6000000 123. 6500000 133. . 550DOOCO 4 , 90312122 1002. 43000C0 207 . 62975 1 1 . 15923830 0. .05070270 8. 6805293 0 . 023137 0. .84670650 0. .035 12295 6. .4573722 0. 01 2090 0. . 7 5307 '99 0 .02226552 5. ! 6 15 ! " 2 0. .003252 0. 65745952 0. .03440523 4 . 85B9B52 0. 0 10554 0. 7498S352 Q. .04695431 4 . 4051450 0 . .0175=3 0. .55107724 0. 06054483 2. .3132072 0. .0 18389 0. 43676625 0. . 4357S52 0. 74938352 0 .04855906 4 . 4666917 0 021303 2. .04622420 0 . 14224621 1 1 . 149 7250 0. .182111 2. 46763024 0. . 15007355 12 .8017237 0.  2027 2 2 . 33552500 0 . 1 1697337 13. .954595= 0. . 122 155 3. . 32452522 0. . 2 57540 16 . 68 55 3=0 0. .43071= 3. . 75 1 35716 0. 16 594831  0. .592325 4 . . 399394C9 0. .557 103 13 12 . 5545 1 = 7 1. .503020 2. .53575761 2 .536 7 3 75 4 . 399384U9 0. . 32-1Q.1528 18. .325 1973 0, .34504 8 134 . 1535837! ; .53332134 922 .2315233 524 . j?7r.t • 2 1*. . 267234.10 15 .97725342 1123 . 5503417 2297 . 4 525 4 2 270 . 12784Q32 18 .27947292 1363 . 140445? 3007 252 1 33 310 . 993687!5 22 .654 35517 1445 .160662! 4623. .06 1035 355 . 53258240 32 . 32000794 1351 . 8473460 B6 17 . 223353 3B5 . 04652531 19 . 25254695 1024 . 74 14595 12129 . 115 155 199 . 3023855 1 199 8023355 3B6 .04652531 30 . 30393292 1649 .9660953 B2B4 ,955 152 0. .31800000 0 .07473350 5 .2164000 0 ,044530 1 .5 3000000 0. .12456650 8 . 6940000 0 . I2'.i 34 2 . 14200000 0 .17439310 12 . 17 16000 0. .243304 2 .75400000 0 .22421970 15 .5492000 0 ,402195 5. .63194729 0 .2U55698 44 .3143915 0 .4 14 35 1 14 . 1435 1975 1 .24039031 70 .3348482 12 . 308545 18 .91954223 1 . 47227705 89 .7513323 17 . 340798 19 54673905 1 .33526512 113 . 2737631 27 .C53170 27 .99943166 2 .51971769 137 .9574082 50 .731818 22 .3244 i 5 IS 2 .44 590 7 3 1 78 .4702550 29 .385735 16 . 395743 1 7 16 .3957432 27 . 93943 156 2 .34774007 120 .3853154 44 .035056 .021 35.256 2 >.350 17 7 20 23 . 17n 23.26 5 4 3.430 26.'454 9 . !e5 9. 122 8.673 9 . 535 10.970 1 3 935 15.770 15.939 11.23? 19. 1 16 24.057 29.3 1 1 29.4 13 34.447 31.546 22.534 35.399 .10 . 125 50.503 47.74 4 25.063 30.395 35.583 42.34a 54.935 53.737 49.509 32.420 32.420 32.420 32.420 13.073 39.905 37. 1 18 36.741 4 1.328 34.892 43.944 235 U I I J.'.'JM MAXIMUM STD ERROR VALUE VALUE OF U£AN ID 7 4. 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2L8SOO 0 0000063 2 52902CEO 0 OO0OOG29 0 OOOOQGOI' 0 U E 5 S 2 9 0 0 /5555I37 0 21O6E0 £271 OGOOOEE 2611 £1279999 SI 00OO0OP9 792 00000017 97! 27061032 BE 2555312; 261 Z9SC35 581 oooooor 655 2720IS29 5 OOOOOOO1 511 00000002 SB 090ESB22 E l 35 259991 201 GGGGOCO £67 03227921 7 oooooooo 06 OOOOOOOO £9 OB2522C! 01 23555591 29 SiSeDO r i S d O D E:Sd03 i i S a O D biSaOD c i S d A S S i S d A S S i S d A S 7iSs .*.S C.Sri\S SiSclAS . i S a A S diS - c d a S i 3addd S i Sosdti E i S d a d U Bi-Saadd i iZzadH d l S e o d U i r ^ d Q A T DJSadDAT CS 3 "3=0 AT bdsdCAV EHdo'.'.SAl d3adrV5AT rdadHAd EBddaAd 2==aMAd .SaddAd aasdMAd P a a d c d i tB^dtidX i s a a a d i i a s o o d i d 2 d d a d i LsaddflH S3ddd*H t adadTH uadddvn PaodAS3 EaadASB 23ddftS3 1 aba.A S3 = = dd.*£3 faddCD £ 3 U d O D S3dd03 . 3ddOD batidOO ratidAS catidAS H3ddAS .3tidA3 b3ddAS P 3 d d d d « EBddddtl HBadddd !aSdddU ei3addd« i S d J l i V H 3 a d O I i V a iadi'idddT andi'iadUl dl-SdHa r L S d b d d i S d b 3 n s d a a d i S d d 3 d l S a d 3 c i SdAQS diSdaH d i S d o a O a l C a d B S a i S d d a SiSdAQ3 SISriBH B l S d a a O 9 i S d d S S Sl5ad3 &iSdAG3 5 i S a H H GiSddBO S l S d s S S ? i 5a 22:3 PiSdAGB P i S d d H 7 i = c a 3 0 U S c 3 = £i.5dAG3 i l i i d a H S!i3a = aQ rVV3ft 40 UOUtia QlS 3mvA N0I1VIA3Q 9ZZ 237 57i>iCH"0 U1NIKUM DEVISI ION VALUE COPSTP ESVPSTR ESVPST 1 ESVPST3 ESV'F-74 MAPPS71 MAPPST2 MAPPS7 3 MAPPS7A MAPPS75 MAPPS75 WAPPS7? TPPPSTP TPPP37 1 TPPPS7E TPPPST3 TPPPS7 A 7PPPST 5 7PPPS7E TPPPS7P PVPP37P 7 1 72 PVRPS7P LVSWOSTS LVSWPS7I LVSMPS7 2 LVSWPE7 3 LVSVJPSTA 75 76 AVDPS7P AVDFS71 AVDPS72 = 73 AVCFS7; AVDPS70 AVDPS7P 101 33525714 102.00232257 105 .5 = 5=1-29 102.5=-33323 2=.332=0222 95-3351422S 90.531=2257 96.07 142257 97.OOOOOOOO 105. 14 111. 105.291=2=57 1 . 223 = 35 1=, 0.225:42 12 0.7850i713 0.59567147 .31125342 . 1 = 22;= 10 .25 7 '5355 .2:2 = 54 14 . 505:-2 = 7- .=7345554 2 . 134:533 1 62.98547335 115.13 10=749 '. 15 .04653 134 137.0=5=3275 i17.51245334 124 02334143 55 14 1 .557257 1 4 5.0512133B 7.67145335 1.62425 142 4.332:5205 3.711:: = 7; If.533:=2=0 31.5''122 = 5 27.0440?;:= 38.417:0002 8. 12:::454 6 .2332 = 733 7.25=24=02 9.2057:755 12.32120=53 11 32:'.25=1 0. 1323 725; 0. •54 27- 74 5 0. 2= :322-2-2 0 . 22722215 1 . 15242235 .73:422:3 .20722:10 47:27:0: . .1:227:?' .2322 242= .;4=5:=3! 1 7:-3=722 15 2=*-: = =f5 10. =25=122 7 5 32.42=7=402 32.:72::575 77.22:57406 53.43250514 0.'5=2:213 0.2'542=?" 0.3::= 1154 0.45=7=533 1.02340524 2.2025SC56 3.442:9703 3.=1737427 3 1 .2224 ;: 10 30 2 4=00000 •;7j .'-94QCOC0 73 25:20000 ': 22;2'7730 37 ;=740C20 30 ,73740700 7:,:5000000 64 44C0ODC0 = =.23700CCO 90.2 500CCCO 9 7 TOOOOOOO 13.50932250 135.2S50000O 169.252OCO0O 139.35370000 15 7- 13 1 70000 12 4.c 3 = 00200 13=.33750000 9?.=0000000 103.'5000000 103.10000000 113 :0GCC030 .12 I .C7C00COO : 7:27:5 3 7 7 0. = 2 1957=1 •2 ::=0:244 0 . =.2:92702 0 42-257543 .47357:43 2:53=6=3 :'=-04?'-» :::;4709 . 2 4 7 4 0 5 0 4 33:=.05 = 1 0 ." = 74=03 52.=='70254 ICO ="32226 1 74 '7:7=Q9i '02.75424000 3D.715515=3 30 .:: 10" 1659 O.4600GC00 .6 17 = 3912 .73:=9=23 . 22039-:=! 2.5=233257 1.2=274223 2 . -7717 = 0C 2-1 2.022175 = 3 2 . 24:030 : 4 5.3:445=73 5 2144557= 100.70335737 1=0 O-'.p^eiA 155.-122: 2040 165 4:P;3255 1 74 . =25: 74 1 2 . 1 1653259 ./3A80CCO 1 . =3 23.44743532 . 237010S5 .34040699 .75317101 .50249952 •22 = 27334 12.53177224 7 .5301 5577 12 .05546657 17.05558903 19.55353517 59.=07=0051 1 . 415053E5 7 .055 = 025: 1 1 . 3 1 2 2 4 4 yj 10.23155072 12 437345=2 2= =4423=12 14.=2045015 3.0749=05= 2.45953105 2. 73135 15 = 3.79504345 6.372 4 .53033502 0.-J72 = 0'=: 0.05:31705 0 : : c:;i20C 0 03577042 0.5 7 170759 0.2772 0.-77244 127 0 :5 2:7 5 : = 3.:7;0:322 0 2-05-7-5552 1 .4 7043549 0.5.1546537 = . 157525 73 5 252=9512 12.22=2=952 13 2314025= 44 3=701425 2 0 . 1 9 5 7 4 157 0.06245321 0.10410536 0.14574750 0.18738964 0.3B945557 0.B7044495 1.30129275 1 .47678635 1 9 . 0 7 3 0 5 : 5 2 50.1997537 713.2243000 7 14 0 1G300O 74 ? ,32 = 5000 523 3=53000 25-3. 79P.40C0 57;. 533.7 20COOC 572.500C000 673.OOO0000 535.3800000 333.4700000 744.0400000 3.537=6=2 5. 7753 = 4 = 3.49511=5 4.17522:2 3.5558420 9.Z252227 9.5702543 r.540=530 9.532=343 3 5204866 7 560.892353! 313.3375324 325.3239334 S22 . 27 1335: 353.740251= 65 1575301 3.6335000 47B4C00 10 14,015233 349.445294 993.327623 731.279237 935.332554 2535.241720 1475.304311 65. 137248 42.531314 42.3534973 53.7001735 81.3729400 86.3572053 13335C3 86.=36397 145 355533 143.657548 0.037202 0.023=05 O.OS4723 0.0551B7 1.353=75 04 307 1 1547-1 1 . 233343 .48-332 2.325437 255.414574 275.4 1 1 255 105 1.5 164 30 1055.373344 5954.003=21 2355.075544 0.027312 0.245304 1.051735 5.303721 11.353540 13.085397 379.205C5 1 43 . 53-1 18.347 30.396 25.3 1 1 25 44 = 57.'25 . 75 7 .859 .277 .5 30 073 .053 '3.132 17 2 = 3 23.54? 3= =7 = 3 : .220 32.525 30. :43 19.532 43.033 3 1.537 3 1.337 31.337 31.337 17.020 30.020 23.6 I 7 23.133 154.1 32 = 007 421.202709 v e n t i l a t o r y t h r e s h o l d 1 /min 02 VARIABLE N MEAN STANDARD STD ERROR DEVIATION OF MEAN GROUP=1 AVTVOPRE 13 0 . 8 2 9 0 .212 0 .059 AVTVOPST 12 0 .292 0 .084 LVTVOPRE 13 y.a&a. 0 .334 0 .093 LVTVOPST 12 1 . 755 0 .404 0 .117 AVOPRE - 13 1.353 0 .319 0 .088 AVOPST 13 1 .454 0 .325 0 .090 LVOPRE 13 1 .994 0 .530 0 . 147 LVOPST 13 2 .265 0 .524 0 . 145 GR0UP=2 AVTVOPRE 9 0 . 8 1 6 0 .254 0 .085 AVTVOPST 9 1 :09 3 0 . 326 0 . 109 LVTVOPRE 9 T. 309 0 . 325 0 . 108 LVTVOPST 9 1 . 590 0 .489 0 . 163 AVOPRE 9 1.316 0 . 424 0.141 AVOPST 9 1 . 522 0 .473 0 . 158 LVOPRE 9 1 . 940 0 . 575 0. 192 LVOPST 9 2 . 1 1 0 0 .686 0 . 229 GR0UP=3 AVTVOPRE 7 0 .894 0 . 270 0 . 102 AVTVOPST 7 0 .908 0.221 0 .084 LVTVOPRE 7 1 .224 0 . 370 0 . 140 LVTVOPST 6 1 . 285 0 . 331 0 . 135 AVOPRE 7 1 . 229 0 .420 0 . 159 AVOPST 7 1.313 0 . 353 0 . 133 LVOPRE 7 1 .834 0 . 364 0 . 138 LVOPST 7 1.730 O. 551 0 .208 MAXIMUM VALUE MINIMUM VALUE 1 .200 1 .500 1 .800 2 .400 2 .020 1 .770 2 . 870 3. 120 0 .404 0 .460 0 . 728 0 .880 0 .692 0 .600 0 .962 1 .010 1 . 297 1 .640 1 .900 2 .400 2 . 267 2 .480 2 .880 3 .060 O. 484 0 .663 0 .774 1 .010 0 . 839 0 .908 1 .033 1 . 100 1 .200 1 . 140 1 .730 1 . 750 1 .755 1 .820 2 . 320 2 .616 0 .440 O. 580 0 .640 0 .900 0 .600 0 .880 1 . 295 0 .920

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