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Central, peripheral, and generalized adaptations in cardiac rehabilitation Goodman, Leonard Stephen 1988

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CENTRAL, PERIPHERAL, AND GENERALIZED ADAPTATIONS IN CARDIAC REHABILITATION By LEONARD STEPHEN GOODMAN B.P.H.E. The University of Toronto, 1979 M.P.E. The University of British Columbia, 1982 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Interdisciplinary Studies, Medicine, Physical Education, Sports Medicine) We accept this thesis as conforming to the required 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 this study was to investigate whether central adaptations are responsible for. a transfer of fitness to untrained limbs in 13, 9 and 7 CAD/post-MI patients exercising in a walk/jog (WJ) (Legs only) , an aerobic circuit (CT) (arm+legs) program, and a low exercise intensity control group (LC) respectively, for 6 months. Graded exercise tests to determine maximum arm and cycle (leg) aerobic capacity (VC>2peak) and ventilatory threshold (VT) was measured using a SensorMedics Metabolic Measurement Cart, and an arm ergometer and electronically braked cycle ergometer, respectively. Left ventricular (LV) function and absolute volumes (calculated by non-geometric methods) during cycle ergometry were measured by gated bloodpool radionuclide angiograms (RNA). Cycle maximal aerobic capacity (VC^peak) increased in CT and' WJ:. 1.96. ± 0.58 to 2.17 ± 0.70 (P<.01) vs. 1.93 ± 0.51 to 2.22 ± 0.54 (P<.004) l-min-1, respectively. Arm VC^peak increased from 1.32 ± 0.42 to 1.52 ± 0.47 (P<.001) vs. 1.35 ± 0.32 to 1.45 ± 0.34 1-min-1 (P<.01)for the CT and WJ groups, respectively. In both exercise with arm and legs, VT was increased in the WJ and CT groups, but the greatest changes were for VT as expressed as absolute VO2. Both arm and leg VC^peak data were correlated with arm and leg VT. The LC group demonstrated no changes in VC^peak or VT for arms or legs. Peak LV Ejection Fraction (LVEFpeak) increased more in 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 Ejection 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 significantly at rest and exercise in the WJ and CT groups, but Peak total peripheral resistance (TPR) however was related to SV and LVESV (r=-.69 P< .003, r=-.42, P<.05), obscuring . apparent intrinsic cardiac adaptations. In addition, neither group demonstrated alterations in body composition and blood lipids as a result of training, despite significant increases in functional capacity. Results suggest that transfer of fitness to untrained limbs in these patients is due in part, but not solely to increased LV function. TPR or other unidentified contributing factors could still account for these effects. iv Table of Contents Abstract ii Table of Contents iv List of Tables vList of Figures viAcknowledgment x 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 Lipid Analysis2.4 Nuclear Imaging: 2.4.1 Supine Left Ventricular Radionuclide Angiogram (RNA) 17 2.4.2 Exercise Gated Bloodpool RNA 18 2.5 Statistical Analysis 23 3.0 Results 3.1 Physical Characteristics 26 3.1.2 Exercise Training 23.2 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 First 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 Ventricular Function; Effects of Exercise Training..69 V 4.0 Discussion 4.1 Body Composition 7 6 4.2 Blood Lipids 7 4.3 Lower and Upper Extremity Aerobic Capacity: 4.3.1 Lower Extremity Changes in Aerobic Capacity 82 4.3.2 Upper Extremity Changes in Aerobic Capacity 8 4.4 Cardiac Function: 4.4.1 First Pass Radionuclide Angiography: ...93 4.4.2 Gated Bloodpool RNA Exercise Testing; Submaximal Hemodynamic and HR Responses... 93 4.4.3 Reliability and Validity 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 7 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 vi List of Tables Table 3.1 Physical Characteristics of Subjects. 29 Table 3.2 Body Composition and Lipids After 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 in 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 in Ejection Fraction After Exercise Training 56 Table 3.10 Changes in Left Ventricular Volumes After Exercise Training 58 Table 3.11 Alterations in Peripheral Resistance: Effect of Exercise Training 71 Table 3.12 Derived Left Ventricular Function Variables: Effect of Exercise Training 72 Table 7.1 Cardiovascular Adaptations After Exercise Training 147 Table 7.2 Change in V02max After Training in CAD 173 Table 7.3 Indirect Indicies of Myocardial Oxygen Consumption and Training in CAD 180 Table 7.4 Factors Affecting Cardiac Morbidity and Mortality; Postulated Cardiac Mechanisms 194 Table 7.5 Reasons for Failure to Identify Intrinsic Cardiac Adaptations After Exercise Training...204 vii List of Figures Figure 3.1a Arm Peak O2 Uptake Before and After Training 34 Figure 3.1b Leg Peak O2 Uptake Before and After Training 34 Figure 3.2 Ventilatory Threshold for Leg and Arm Ergometry After Training 37 Figure 3.3 Arm VC^peak vs. Absolute Arm Ventilatory Threshold 43 Figure 3.4 Cycle (Leg) VC^peak vs. Leg Ventilatory Threshold 4 Figure 3.5 Plot of Cycle VC^peak vs. Total Peripheral Resistance 45 Figure 3.6a Arm Crank HR Response at 25W 4 9 Figure 3.6b Cycle Heart Rate Response at 65W 4 8 Figure 3.7 Alterations in Submaximal Heart Rate After Training 54 Figure 3.8 Ejection Fraction Before After Exercise Training 61 Figure 3.9 Peak Ejection Fraction vs. Peak Systolic BP After Exercise Training 62 Figure 3.10 Cardiac Output Before and After Exercise Training 63 Figure 3.11 Change in Submaximal Stroke Volume vs. Systolic Blood Pressure 64 Figure 3.12 Changes in Stroke Volume vs. Systolic Blood Volume Before, After Training 65 Figure 3.13 Plot of Stroke Volume (WL-90) vs. Total Peripheral Resistance at WL-90 66 Figure 3.14 Changes in Stroke Volume vs. Total Peripheral Resistance After Exercise Training 67 Figure 3.15 Changes in End Systolic Volume vs. Systolic Blood Pressure at Peak Exercise 68 Figure 3.16 Changes in Stroke Work and LVEDV After Exercise Training 73 viii Figure 3.17 Systolic 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 Intrinsic Cardiac Contractility 155 Figure 7.4 Summary of Acute Exercise Responses in The Cardiac Patient 165 Figure 7.5 Exercise Training and Increased Capacity in Cardiac Patients 177 Figure 7.6 Exercise Specificity and Transfer Effect of Training 218 ix Acknowledgments It would have been considerably beyond the limits of my personal skills and resources to have successfully attempted a Ph.D. thesis of this type without the help and encouragement I have received from many individuals both on and off the UBC campus. I especially would like to thank my academic advisor/research supervisor Dr. Don McKenzie for initially agreeing to be my advisor at short notice at a particularly dark time for me back in 1984; he has come through with the ultimately important factors which make a Ph.D. possible: financial, academic and personal support. His supervision and direction during both my Masters and now Ph.D training have been I feel, directly responsible for my maturation from an inexperienced graduate student to a beginning scientist. I would like to acknowledge the B.C. Heart Foundation and Health and Welfare Canada for the personal financial support during my tenure at UBC through graduate awards. Dr. Mike Plyley at the University of Toronto was my supervisor for my first year, completed at that institution. Many thanks go to him for support through that year and encouragement all the way through. This study would not have been possible without the help of a great many staff at the UBC-HSCH. I would like to especially thank Dr. Walter Ammann and his technologist staff (Christa McRae, Shelia Woloshyn, and Tony McLintock) who always made me feel part of their Nuclear Medicine department, and who tirelessly but gave their expertise and skills to the study. Many thanks go to Dr. Max Walters, who while retired from Medicine and my committee, was initially a strong support in the beginnings of the study. More recently, the exceptional support of Dr. Colin Nath and the Division of Cardiology during all the (volunteer) supervision of all the upper and lower extremity stress tests must be acknowledged and thanked. I would also like to thank the staff in Respiratory Medicine (Mary-Ann, Carmen and Louise) for the privilege of using the exercise laboratory and Beckman MMC for the testing, and the support during trouble-shooting. Thanks is due Marylin Harkley and Anna Bozak who helped with the data collection in the lab. This help considerably reduced the strain during these days, and certainly made this process much more enjoyable for me, as well as the patients due to their wonderful nature and energy. I would like to thank Peter Schumacker at SCARL for the invaluable consultations with the statistical aspects of the study, as well as the additional help and the wonderful open-door policies of Frank Ho (Statistics) and Susan Mair (with the Telegraf plots) in the Computer Science Department. X Finally, my love and admiration goes out to my family, the closest to me of course, my wife Risa, who has stood by me all this time throughout all the frustrations and achievements with patience and love. To her I am forever grateful. In addition, the love, support and confidence of the Korsch's, and my wonderful family back home in Toronto has given me the strength to go on when it all seemed uphill. 1 1.0 Introduction One of the many issues still not completely resolved in cardiac rehabilitation is the effect of chronic exercise on the adaptation of the left ventricle (LV) in patients who have suffered a myocardial infarction (MI), with angina, or after recovery from coronary artery bypass surgery (CABS). Historically, the mechanisms responsible for the improved functional capacity, reduced symptoms of coronary insufficiency, and reduced frequency of electrocardiographic abnormalities universally observed after three to 12 months of endurance training have been ascribed to mostly peripheral effects occurring in the exercised muscles-(Clausen and Trap-Jensen, 1970, Detry et al., 1971, Ferguson and Taylor, 1982, Ogawa et al., 1981, Sim and Neill, 1974). There is however, rapidly accumulating data to suggest that there might be a component of central (left ventricular) adaptation which might occur as a response to prolonged and intense endurance training in these patients. While increased exercise training capabilities and improvements in aerobic capacity would no doubt be expected with improvements in LV function, even more important prognostic survival variables could be also expected, according to the data of White et al., (1984). 2 Although the studies which have demonstrated large increases in maximal aerobic capacity (VC^max) and parallel improvements in intrinsic LV function are impressive (Ehsani et al., 1986, Ehsani et al., 1982, Williams et al., 1984, Hagberg et al., 1983, Jensen et al., 1980), these are countered by other studies which have shown either no changes (Verani et al., 1981, Ditchey et al., 1981), or minimal changes (Froelicher et al., 1984) at either rest or submaximal exercise. It has been suggested that the studies which have demonstrated LV adaptations have included subjects who were unusually motivated and minimally compromised and thus represented a sub-sample of post-MI patients which were capable of achieving very high exercise training frequencies (5-6 d/week) and intensities (75% - 90% of VC^max). Other confounding factors in these studies include the variations in the size of the infarcted area of myocardium, the use of differing techniques for measuring LV function, the roles of varying medications on LV performance, the heterogeneity of the patients studied (post-MI vs. CABG, angina, angioplasty, etc.), and the modes of exercise training employed. Nevertheless, the question remains whether myocardial hypertrophy, alterations in chamber size, and general improvements in intrinsic LV contractile function, which have been observed routinely in healthy normals post-3 training (Barnard et al., 1979), can be achieved in the average post-MI patient, even considering necrosis-related decreases in myocardial compliance and the amount of viable remaining myocardium. One method of isolating and uncovering the contributing central and peripheral effects of habitual exercise is to train one limb, and then subsequently test the untrained limb. It has long been understood that the effects of exercise training are largely specific to the muscle groups trained, but that in some cases, improvements in the VT^max or maximal work, load achieved in the untrained limb (barring habituation effects), or reductions in the heart rate and blood pressure response at an equivalent work load, would imply a central training effect by virtue of a greater cardiac output and hence, O2 delivery. This classical experimental design has been used numerous times with normal subjects, with general divergence of results. Clausen et al., (1973) found a small ( 10% improvement) in arm VT^max after training of the legs, and concluded a central effect, as did McKenzie et al., (1978), by demonstrating lower submaximal heart rates for the untrained limbs. Saltin et al., (1976) also observed increases in VT^ntax in the untrained legs after one-leg cycle training with no 4 evidence of peripheral training effects (mitochondrial enzyme changes). These authors concluded that the effect was not due to improvements in cardiac output, but rather to the greater efficiency of other organs to oxidize lactate after training. Other general findings relating to the transfer effect suggest that the initial level of fitness, training frequency, intensity and duration determine the extent of cross-over of training effects (Lewis et al., 1980, Franklin, 1985) . It has been only recently that this research model has been extended to the cardiac patient. This is because traditionally, walking and jogging was the only mode of training considered appropriate for this population, with fears that upper body exercise was largely static in nature, and would place excessive hemodynamic loading on the myocardium and dangerously elevate myocardial oxygen consumption. Today, it is well documented that programs utilizing a combination of upper and lower body aerobic training are not only safe hemodynamically, but effective in increasing functional capacity of muscle groups used in occupational and leisure settings (Hellerstein, 1977, LaFontaine and Brackerhoff, 1987, Magder et al., 1981, Ben-Ari et al., 1987). This has resulted in the formulation of a new research model to uncover central vs. peripheral training mechanisms in cardiac patients. 5 Only a few studies have trained the arms or legs and tested the untrained limbs in coronary artery disease (CAD) patients. Increases in the untrained limb (arm) VC^max after leg training has been reported to range from 8% (Thompson et al., 1981) to 13% (Wrisley et al., 1983), in addition to decreases in the HR x systolic blood pressure product (RPP) at a matched submaximal workload (Ben-Ari et al., 1987). While all these studies report improvements in achieved work load, RPP, HR, and VC^max, none have utilized techniques able to quantify direct changes in the central component to determine whether the adaptations were intrinsic to the myocardium, or isolated to the periphery. Therefore, the objective of this investigation was to apply the training specificity model to determine the contribution of peripheral vs. central components before and after six months of exercise training in average CAD patients. Specifically, the research goals in this study were to: 1. Determine the cross-training potential between patients exercising the whole body (arms + legs) in an aerobic circuit training program, and patients exercising only the lower extremities (walking/jogging), by testing the legs and arms in both groups using standard open circut gas analysis arm and cycle ergometry. Observing an increase in arm 6 fitness in the walking/jogging group would imply factors other than muscle-specific (peripheral) mechanisms to explain the training effect. 2. To quantify the above implied central (cardiac) component of training adaptations in both groups, by using nuclear isotope imaging techniques during rest and exercise. 3. To determine if lipid profiles and body composition measures are altered by exercise training by either circuit or walking and jogging training methods. 4. To compare the efficacy of whole body vs. legs only modes of cardiac rehabilitation exercise training in terms of overall training adaptations. 7 2.0 Methodology 2.1 Subject Recruitment Prospective patients were identified through referral from cardiologists in the Greater Vancouver area. Patients were screened for the usual medical contraindications to exercise training (American College of Sports Medicine, 1986). For the purposes of the study, additional criteria were established. These included: (1) Resting left ventricular ejection fraction 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 prior to entry into the study. (3) Subjects had no musculoskeletal limitations to exercise. (4) Subjects had either no supraventricular arrythmia or were otherwise controlled by medication. (5) Subjects had no aortic regurgitation or significant mitral valve abnormalities. (6) Subjects were willing to exercise a total 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 leisure activities or work, including swimming, nordic skiing, rowing, and calisthenics (permitted arm activities included golf and household activities only). 8 All subjects signed a waiver and consent form before entering the study, which was approved by the University of British Columbia's Human Experimentation Ethics Committee. The subjects were permitted to continue with their regularly prescribed medications (see Table 3.1 in Results section for patients' individual medications) both throughout the training and testing periods. They were asked to notify the experimentors if a change in medications occurred. A withdrawl and/or change in medication resulted in the exclusion of that patient's data in the experimental analysis due to changes in metabolic and hemodynamic function that would follow. 2.2 Exercise Training The subjects were randomized into one of two training modalities, WJ (YMCA) or aerobic circuit training (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 training logs from both the WJ and CT programs, were identified at the three-month period, and included in the study. The criteria for their selection were failure to maintain their target heart rate above that representing 60% of V02Peak, and failure to attend three consecutive weeks of 9 less than 2 sessions/week. They were maintained on low-level walking, cycling or circuit training exercise programs (less than 3 sessions per week and an intensity 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 carefully designed home program, similar to that offered at the YMCA. Since true statistical randomization was not possible due to the few numbers of available subjects, the most feasible method of subject recruitment employed was based upon geographical proximity to the centres. Of the total 40 patients initially recruited, 13 were assigned to the CT, and 20 were assigned to the WJ programs, respectively. Both the WJ and CT programs utilized a standard 10 minute warm-up period consisting of generalized light calesthenics and stretching exercises, followed by 30 to 45 minutes of endurance training and a 5 to 10 minute concluding cool-down period. The aerobic phase in the WJ program consisted of walking progressing to walking/jogging intervals at the predetermined target intensity, as described by Kavanagh et al. (1973, 1975). Outdoor cycling and cycle ergometry was permitted in this group as supplements to walking and 10 jogging. The CT group utilized a variety of aerobic exercise equipment, randomly assigned upon each session to achieve a balance between upper and lower body fitness by including a minimum of one upper extremity exercise station. Each session included 3 X 10 minutes of either treadmill walking, stair climbing, rowing, cycle ergometry, arm ergometry, wall pulleys, medicine ball throwing, and a cross country ski simulator at the previously determined target intensity. Subjects were required to move rapidly to the next station, to maintain the pulse in the target range. In this group, outdoor cycling and walking/jogging was also permitted as a supplement. The frequency of exercise training was held at 3/week for the first 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 cycling 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 light walking or cycle ergometry, or with circuit training in the case of three non-complying subjects originally randomized to the CT group. Exercise intensity was determined by recognized methods 11 (American College of Sports Medicine, 1986, Karvonen et al., 1957), based on results of the initial cycle ergometry tests, signs and symptoms. An initial training intensity representing 60 - 70% HRpeak reserve, and the heart rate representing 70% of VC^peak, or in the case of angina-limited patients with or without beta blocking medications, a HR just below the anginal threshold was assigned. Resting HR was determined during the 10 minute resting period in the nuclear medicine evaluations (See 2.4.2 Gated Blood Pool Exercise Studies ). Over a 3 month period, or as exercise tolerance improved, exercise intensity was gradually increased to 75-80% HRpeak, barring signs and symptoms. Because maximal HR achieved on cycle ergometry is 5 - 7% below that of treadmill testing (Wicks et al. 1978), the intensity was adjusted upward in patients who achieved a true VC^max (plateau of VO2, respiratory exchange ratio (RER) > 1.15) during cycle testing by this amount for the WJ group subjects. Upper body exercise intensities for the CT group were also determined by these methods, yielding training HR's 50 - 70% of that attained for cycling and walking (Franklin, 1985) . The energy expenditure of each session for the WJ and CT groups was. estimated to ensure that each group was performing the same amount of work per session. Based upon a 70kg subject exercising at an average target intensity, the total energy expenditure per session for the CT group was 1184.4 kj, and 12 1146.6 kj for the WJ group (eqvivalent to 273 and 282 kcal, respectively) including the 10 minute warm-up for both groups. The calculation' of energy expenditure for the CT group was based upon an average of two lower-extremity and one upper extremity 10 minute sessions per class. Calculated training heart rates for the groups were as follows: WJ: month 0 to 3: 100 - 105 bpm, months 3 to 6: 111 - 118 bpm. CT: month 0 to 3: 109 - 112 bpm, months 3 to 6: 110 - 115 bpm. LC: month 0 to 3: 97 - 103 bpm, months 3 to 6: 94 - 97 bpm. In the CT group, pre-training treadmill maximum tests (Bruce protocol without gas analysis) were performed as a requirement for attendance at that program. The data from these tests is not included in this study, but was used to determine training' intensites along with the other methods described above (75 - 85% of symptom-limited HRmax). All subjects recorded in-class and at-home exercise sessions on log sheets. These sheets were examined regularly by the investigators and individual program staff, and included information on exercise pulse, duration and symptoms. Dietary and behavior modification education was not included in the study. In the case of participants on a home walking program, contact was maintained by regular telephone calls, bi-weekly mail-in of logs, and several visits to the 13 exercise laboratory for low-level submaximal exercise testing for the purposes of monitoring and exercise prescription updating. 2.3 Exercise Testing 2.3.1 Maximum Oxygen Uptake The following testing procedures were performed in 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 first obtained. Subjects were prepared for 12-lead ECG, and first performed a graded arm ergometry test with open circuit gas analysis. After calibration, the arm ergometer (Monarch Rehab Trainer) was adjusted so that during the phase of maximum reach, a slight bend in the elbow occurred, and a line between the crank arm and the olecranon was in a line parallel to the floor (Franklin, 1985). After an initial warm-up work load of 0 W, increments of 6.25 W were applied every 2 minutes at 50 RPM (paced by a metronone) until termination of the test. Subjects were continuously monitored by ECG using an oscilloscope, and 12-lead recordings were made in the last 15 seconds of each work load. Blood pressure was not recorded during arm ergometry tests due to the potential unreliable nature of popliteal artery blood pressure determinations, and the need 14 for a continuous test protocol for determination of ventilatory thresholds (discussed in the following sections). Criteria for determining the termination point of the test are described in greater detail elswhere (American College of Sports Medicine, 1986, Ellestad, 1975), but briefly included: 1. Failure to maintain the desired pedaling cadence, 2. Muscular fatique, 3. Syncope, 4. Pallor, 5. Nausea, 6. Failure to increase VO2 when work is increased, 7. RER > 1.15, 8. Attainment of age-predicted maximal HR, 9. Failure to increase HR with increasing work, 10. ECG abnormalities (including > 2 mm horizontal or downsloping ST-segment depression or elevation), 11. Grade 3+ angina, and 12. exhaustion. Subjects breathed through a two-way Hans Rudolf valve (Volume = 70 ml) into a SensorMedics Horizon MMC for continuous measurement of expired gases. The MMC was calibrated prior to the tests with gases of known concentration, and was also calibrated for temperature, barometric pressure, and volume according to the manufactuer's specifications. The test protocol was continuous in nature, allowing for determination of ventilatory threshold (Wasserman and Mcllroy, 1968, Skinner and McLellan, 1980), in addition to the peak oxygen consumption (VC^peak), minute ventilation (VE), volume of 15 expired CO2 ( VCO2)/ respiratory exchange ratio (RER), end-tidal partial pressure of CO2 (PETCO2), and end-tidal partial pressure of O2 (PETO2). Ventilatory threshold (VT) was defined as absolute workload (Watts) or VO2 (absolute or relative percent of VC^peak/max) where the relationship between VE and VO2 becomes alinear (Wasserman et al., 1973, Kinderman et al., 1979, Davis et al., 1976, Skinner and McLellan, 1980). VT's were determined by the same observer, and no reliability/validity studies were performed on the determinations of VT's. Due to lack of available laboratory time which would have enabled arm and leg testing on separate days, a rest period of 60 minutes between the arm and cycle tests was included, with the cycle test always following the arm test in an attempt to minimize subject fatigue by first testing the smaller muscle mass first. The cycle ergometer test was performed by utilizing a magnetically-braked ergometer (Quinton Uniwork Model 245). The ergometer was individually adjusted so that upon leg extension there was a 5^ flexion at the knee. Initial pedal load was 32.7 W, and increased 16.3 W every 2 minutes until termination. Twelve-lead ECG was recorded at the end of each stage. The observed and derived gas exchange indices and calibration procedures described for the arm ergometry test, as well as termination criteria (but with the addition of the failure of systolic 16 blood pressure to increase) , were repeated for the cycle test. Subjects were instructed to maintain a pedal rate of 70-80 RPM to minimize local quadriceps fatique, and blood pressure was determined at the second minute of every exercise level. Subjects were asked to not voluntarily hold their arm up for the experimenter during blood pressure measurement, and were requested not to grip the handlebars tightly while cycling to minimize changes in blood pressure. 2.3.2 Body Composition The Third Edition of the Canadian Standardized Test of Fitness body composition protocol (1986) was utilized to characterize changes in fatness/muscularity, and fat distribution patterns over the 6 month period in these patients. After determining landmarks, the following measurements were recorded: triceps, subscapular, biceps, suprailiac and medial calf skinfolds, and waist, gluteal (hip) girths. Derived variables from these raw measurements included: Body Mass Index (BMI) {kg/m^}, Sum of 5 skinfolds (SOS), Waist/Hip girth ratio (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 after an overnight (14 hr.) fast and abstinence from 17 alcohol. Blood was drawn for analysis of total cholesterol, high and low-density lipoprotein cholesterol subtractions (HDL-C, LDL-C), and triglycerides (TG) using an enzymatic method (Kodak Ektachem, Seragen Diagnostics, Indiana), (Allain et al. 1974). This was repeated after 6 months of exercise training. 2.4 Nuclear Imaging 2.4.1 Supine Resting Left Ventricular Function Within 1-3 days of maximal testing, subjects reported to the Nuclear Medicine Laboratory in the morning; they were asked to avoid food and caffeine for 3 hours before testing. After administration of stannous fluoride to prepare the red blood cells for in-vivo labeling by the tracer, subjects were placed in the supine position, and a gamma camera (Picker dyna 4/15) with a parallel hole collamator was placed in the left anterior oblique (LAO) 40° position over the chest. Technesium-99m (99mTc) (370 MBq combined with 0.5ml saline) was injected as a bolus into the basilic 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 in the LAO 4 0° projection were obtained at a framing rate of 0.6 seconds per image for a total of 128 images. The images were saved on a Winchester hard disc on a 64 x 64 x 8 matrix. Immediately after acquisition of the dynamic images, a 1 18 minute static 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 dividing the injected activity by the area under the first pass curve (excluding re-circulation) according to the basic indicator dilution therapy (Alazracki et al., 1975, Fouad et al., 1979). The CO program determines the initial activity by relating equilibrium count rate to blood volume, and excludes recirculation from the first pass curve by extrapolation of the downslope of that curve. The program assures a good fit statistically 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 total activity to 740 MBq, and allowed to reach equilibration for 10 minutes for the in-vivo labeling of autologous red blood cells. 2.4.2 Gated Blood Pool Exercise Studies Immediately after the supine imaging studies, and allowing for maximum labeling of the red blood cells with ^^mTc, subjects were fitted onto the cycle ergometer (Collins 19 Pedalmate controller, Atomic Products Corporation elecromagnetic ergometer) in the semi-erect position. A scintilation camera (Siemens LEM 6607) equiped with a low energy 140 KEV all-purpose parallel-hole collimator was positioned over the patient's chest in the LAO 40° position for best ventricular separation. Some deviation from this angle was required to optimally visualize the ventricles in some patients. Count data was obtained in a frame mode of 16 frames per R-R interval of the ECG in a 64 X 64 pixel matrix, and processed using a CDA MicroDelta computer/terminal and software for manual calculation of Global and regional left ventricular ejection fraction (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 left-ventricular end-systolic and end-diastolic regions of interest (ROI) were then manually drawn with a joystick. A background region was manually drawn 2 pixies lateral and inferior to the LV ROI (Holman and Parker, 1981, Gerson, 1987) (See Appendix II). Attenuation (e-^) of the activity of the isotope by chest 20 wall structures and distance to the camera was calculated using the formula: e"Pd 2.0 Where -u is the linear attenuation coefficient of water (given at -0.15), d is the distance from the centre of the LV to the scintillation camera divided by sin 40° , as measured and processed by a 1 minute acquisition (after the exercise studies), in the anterior position with a labled marker positioned over the centre of the LV (Links et al., 1982). Left ventricular end-diastolic volume (LVEDV) for each level of exercise was then subsequently calculated utilizing a non-geometric method (Links et al., 1982, Slutsky et al, 1979, Holman, and Parker, 1981). This method has been validated against standard contrast angiographic methods with reliability coefficients of .87 (LVESV) and .85 (LVEDV) for both rest and exercise. (Slutsky et al., 1979). Validation studies carried out in the present testing facility between angiographic vs. RNA - determined resting LVEF and SV yielded reliability coefficients of .83 ( P < .04) and .93 ( P < .006), respectively for resting studies only, since exercise contrast angiography is not performed at the present institution. The count rate of blood in the LV was calculated by drawing 21 two 5 ml samples of the patient's blood soon after exercise, and imaging these in petri dishes for 5 min. The count rate for the average of these 2 blood samples, plus an area drawn with a joystick for background counts was processed. To account for the decay of ^^mTc over time, a standard table for decay rate of 99mTc was used to adjust the LV count rate for each level of exercise by multiplying each factor by the recorded time of each exercise acquisition. LVEDV was calculated as: LVEDV = LV count rate/ e^Rd 5 ml count rate 3.0 Exercise was preceeded by a 10 minute resting acquisition while the subjects sat quietly on the ergometer. Resting blood pressure was recorded at the end of this period. The exercise levels were determined by the previous cycle maximum tests, and were set at 30, 50, 70 and 90% (WL-30, WL-50, WL-70, WL-90) of the maximal work rate and/or corresponding HR at that workload. Pedaling rate was maintained at 70 RPM and the levels were continuous. Each level consisted of 1 minute to achieve a steady-state, and 2 minutes of acquisition for a total of 3 minutes at each level. The ECG was continually monitored and blood pressure was recorded at the end of the first and second minutes of acquisition (2nd and 3rd minutes). Because the semi-erect 22 position neccessary for gated blood pool imaging, the biomechanics differed from that on the standard ergometer. This occasionally required adjustments of the workload downwards in some patients if it was noticed that the energy and HR requirements were above these levels. In this case, a target HR corresponding to the workload representing these percentages was used to gauge the workload setting, and the workload was noted. Upon post-testing, the identical procedures were utilized, except in the case of determining the workloads. Depending upon the extent of improvement in the cycle maximum test, the subjects pedaled at the same absolute workloads representing 30, 50, 70, and 90% (WL-30, WL-50, WL-70, WL-90) of the pre-testing maximum, and then two additional levels representing the new 70 and 90% (WL-70post and WL-90post) of (relative) maximum. To minimize investigator bias effects during the processing and drawing of the ROI's, the investigator was blinded to the identity of the subjects by assigning code numbers to each individual. Measured parameters at each level of rest and exercise were as follows: LVEF (calculated automatically), LVEDV, derived Stroke Volume (SV) : LVEF X LVEDV, Left-Ventricular End-systolic volume (LVESV): LVEDV - SV, and Cardiac Output (CO) : SV X HR. Rate-pressure product (RPP) (HR X Systolic blood pressure X lO-^) was calculated at each exercise 23 level, as was total peripheral resistance (TPR), calculated by: TPR = MAP 4.0 CO " where MAP is mean arterial blood pressure calculated as diastolic blood pressure + .33 (systolic - diastolic blood pressure). TPR is expressed as Peripheral Resistance Units (PRU), where 1 PRU = 1 l/min_1/mmHg_1 (Burton, 1972). Intrinsic myocardial performance parameters were also estimated by utilizing the calculated parameters expressed as Systolic Blood Pressure/End-Systolic Volume Ratio (P/V Ratio) (Sagawa et al., 1977, Iskandrian et al., 1983) as: P/V Ratio = SBP 5.0 LVESV' Where SBP = systolic blood pressure ( an estimation of LV end-systolic pressure), and LVESV = left ventricular end-systolic volume. Left ventricular stroke work (LVSW, g • m) was calculated as SV X MAP X .0136 (Kragenbuehi, 1985). 2.5 Statistical Analysis Data was analyzed by SAS (Statistical Analysis Systems Inc., Cary Id.) software on The University of British Columbia's 24 48-megabite Amdahl 58 60 mainframe computer using the Michigan Terminal System. Metabolic, body composition, and blood lipid data were analyzed using a 3 X 2 General Linear Model of Analysis of Variance design for unbalanced cell data, for mean differences of scores from pre to post training. Students paired t-tests were utilized for some analysis for pre-vs. post differences of scores within groups. Upon finding a significant F ratio, post-hoc tests using Scheffe's test was utilized to determine the between groups differences. The minimum of a 0.05 level of significance was used as the criteria to determine a statistically significant difference. To minimize the probability of excessive type I and II experimentwise error rates due to the extent of the data collected in this project, for many of the data, only the WL-70, WL-90, and WL-90post exercise levels were quantitively analyzed in this thesis. Some data not statistically analyzed does appear in figures (resting, WL-30 and WL-50). Pearson Product Moment Correlation proceedure was used to estimate the relation of one physiological variable to another. The 0.05 level of significance was used. Plotted correlational data was generated using SAS plot proceedure. 25 Plotted data for figures (See List of Figures, page vi) were computer-generated by Tell-a-Graf Version 5.0 software on The University of British Columbia's mainframe computer using raw data input. A QMS printer was used to produce camera-ready plots. 26 3.0 Results 3.1 Physical Characteristics of Subjects Twenty-nine of the original 40 subjects completed the training study. Of the 11 drop-outs, 3 were for non-medical reasons, and 8 were for medical reasons. None of the remaining patients were smokers. Description of the physical and medical characteristics of the patients are listed in Table 3.1. 3.1.2 Exercise Training Thirteen patients comprised the walking/jogging (WJ) group, 9 in the circuit training (CT) group, with 7 remaining in the low-intensity exercise control (LC) group. All testing proceeded without event except in two cases of hypoglycemia, where administration of fruit juice immediately prior to the testing resolved the problem. In one additional patient, testing was postponed due to an episode of acute unstable angina immediately prior to the RNA exercise procedure. 27 Subjects in 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 training durations were initially 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 training. Exercise training diaries were monitored for each patient to maintain compliance. Exercise intensities (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 Lipids Body weight did not change for any of the groups before or after training, nor did body mass index (BMI) , waist-hip ratio (WHR) or sum of five skinfolds (SOS) . The total cholesterol to HDL cholesterol ratio and HDL cholesterol (HDL-C) did not demonstrate any changes due to training in either group (Table 3.2). 28 No significant correlations for any of the body compositon or blood lipids were found, including any of the metabolic variables. Only when the complete pre-testing data (n=4 0) was analyzed did significant correlations result between WHR and HDL-C (r = -.74, P < .03). BMI and HDL-C were not correlated (r = -.18, P < .32). The best correlation obtained between lipids and body composition was BMI and LDL-C (r = -.25, P < .18). There was a mild but significant correlation between HDL-C and VC^peak for all 4 0 pre-test data (r = .45, P < . 01) . 29 Table 3.1 Physical Characteristics 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 CDS 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 Ar 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 MI-Myocarcial Infarction A-Angina BA-Balloon Angioplasty CABS-Coronary Artery Bypass Surgery TPA-Tissue Plasminogen Activator Treatment As-Aspirin/Platelet Inhibitor Ar-Anti-Arrhythmic B-Beta Blockade C-Calcium Channel Blockade D-Diuretic I-Inotropic Agent L-Lipid Lowering Agent N-Nitrate S-Sedative WJ-walk/jog group CT-circuit training group LC-low-intensity control group. 30 3.3 Aerobic Capacity 3.3.1 Lower Extremity Aerobic Capacity The maximal external workload for the WJ and CT training groups increased from 131.95 ± 33.64 to 144.30 ± 36.73 and 134.28 ± 19.84 to 147.32 ± 48.60 Watts, respectfully (P < .04). There was no significant change for the LC group. Table 3.2 Body Composition and Lipids After 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 Circuit Training Group VC^peak increased significantly for the two groups by 13% (1.93 ± 0.51 to 2.22 ± 0.54 1-min"1) and 9.7% (1.96 ± 0.58 to 2.17 ± 0.70 l-min-1) for the WJ and CT. groups respectively (P < .004). The LC group's VC^peak was reduced by 6% after the 6 months training. Both the WJ and CT groups were significantly different than the LC on post-testing differences in scores, but there was no difference between the WJ and CT group (Table 3.3, Figure 3.1a). There was no difference in VO^peak between the groups on pre-testing. To verify that the increased V02peak values were due to real exercise training effects and not to habituation or motivation, analysis was performed on the RER at maximal exercise. There was no significance for pre to post differences for all three groups ( P < .32 ). Maximal RPP increased significantly in the WJ and CT groups after training from 21.57 to 24.35 mmHg/HR x 10~3 (P < .05 ) and 22.35 to 23.29 mmHg/HR x 10-3 (P < .04), respectively (Table 3.3). When the data in the three groups was pooled (n=2 9)., VC^peak was significantly correlated with RPP (r = .69, P < .001). 32 The groups differed upon pre-testing, however for maximal workload (P < .03), RPPmax (P < .05), and HRmax (P < .05). There were no differences in maximal HR due to training in any group, however, the LC group had significantly lower maximal HR than the WJ and CT groups at both pre and post-testing (P < .05) . 33 Table 3.3 Lower Extremity Aerobic Capacity after Six Months of Endurance Training 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 training pre-testing vs. LC. V02peak (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 (VC02/V02) P < .004 pre vs. post training, 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. 34 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 Ventilatory Threshold After Training Break points in the deviation from linearity in the VE vs. V02 and VE/V02 curves were identifiable in 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 lost due to disk and software problems encountered on that testing 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 V02 increased significantly only in the WJ group, from 1.38 ± 0.33 to 1.76 ±0.40 l*min-1 ( P < .001), but was not significantly different from the CT • or LC groups (Table 3.4, Figure 3.2). When expressed as percent of V02peak, the changes were non significant for all groups despite a trend towards significance, increasing from 70.18 to 80.65 and from 66.37 to 7 6.96 percent of V02peak in the WJ and CT groups respectively. VT expressed as a percentage of HRmax increased significantly in the WJ group only, from 79.86 + 5.97 to 85.08 ± 5.42% after training ( P < .05 ). 36 Table 3.4 Lower Extremity (Cycle) Ventilatory Threshold Alterations After Endurance Training 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 %V02peak 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 37 38 3.3.3 Upper Extremity Aerobic Capacity The following upper body metabolic values are reported in Table 3.5. Arm ergometry was completed in all subjects without incident. Subjects in both the WJ and CT groups increased the maximal workload achievable from 41.70 ± 14.2 to 45.87 ± 12.9 W ( P < .003 ) and from 36.83 ± 11.9 to 45.87 ± 14.9 W ( P < .002 ), respectively. The LC group increased significantly from 34.77 ± 11.9 to 40.20 ± 7.90 W. VC^peak values for arm ergometry increased significantly for the WJ and CT groups; 1.35 ± 0.32 to 1.45 ± 0.34 (P < .05), and from 1.32 ± 0.42 to 1.52 ± 0.47 l-min-1 (P < .003), respectively. There was no significant increase reported for the LC group. Only the CT group was significanly different from LC on differences of pre-post scores (P < .05) (Figure 3.1b). Maximal RER values pre vs. post were not different for the WJ and CT groups for arm ergometry, however, the LC group had a significant increase in post-testing RER ( 0.95 to 1.07, P < .05). There were also no changes in maximal HR except for the CT group, who increased from 117.7 to 125.0 bpm (P < .05). 39 Table 3.5 Upper Extremity Ergometry Aerobic Capacity after Exercise Training Variable Group Pre (Mean, SD) Post (Mean, SD) Maximal Work load (Watts) WJ 41.7 14.2 45.9 12.9 ** CT 36.8 11.9 45.9 14.9 * LC 34.8 11.9 40.2 7.90 ~ Pre vs. Post: ** P < .003 * P < .002 ~ P < .05 4 VC^peak (l-min-1) WJ 1.35 0.32 1.45 0.34 ** CT 1.32 0.42 1.52 0.47 * ¥ LC 1.23 0.42 1.31 0.35 ** P < .001 * P < .0003 Pre vs. Post ¥ P < .05 vs. LC RER (VC02/V02) WJ 1.04 0.06 1.04 0.07 CT 0.98 0.07 1.05 0.07 LC 0.95 0.06 1.07 0.07 * * P < .05 pre vs. post HRmax (bpm) WJ 115 20.4 118 14.9 CT 118 29.6 125 25.5 * LC 111 28.8 118 23.2 * P < .05 Pre vs. Post 40 3.3.4 Ventilatory Threshold and Upper Extremity Exercise Training The VT as expressed in absolute l-min-1 02 increased significantly in the WJ group, from 0.829 ± 0.21 to 1.075 ± 0.29 l-min-1 (P < .001). The CT group significantly increased VT from 0.816 ± 0.25 to 1.093 ±0.33 l-min-1 (P < .001). There were only slight changes in the LC for absolute VT (Table 3.6) (Figure 3.2). The CT group was significantly 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 V02peak, significant increases were observed in 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) after training, respectfully. Only the WJ group differed from the LC group on differences of scores (P < .05) . VT Expressed as a percent of maximal HR increased only in the WJ group (76.48 ± 11.0 to 83.38 ± 7.5%, P < .02), and was significantly different from the LC group on differences of scores (P < .05). Full data for VT data is presented in Table 3.6. 41 Table 3.6 Alterations in Ventilatory Threshold after Upper Extremity Training Variable Group Pre (Mean, SD) Post (Mean, SD) Arm VT (IO2-min-1) WJ 0.829 0.21 CT 0.816 0.25 LC 0.894 0.27 1.075 0.29 * ¥ 1.093 0.33 * ¥ f 0.908 0.22 P < .001 pre vs. post ¥ P < .05 vs. LC, f vs. WJ Arm VT (%V0^peak) WJ 62.43 12.1 74 .66 10.5 * ** ¥ CT 62.33 10.1 72 .48 8.8 * LC 75.23 9.45 68 .46 5.83 * p < .001 pre vs. post ** p < .05 vs. LC ¥ P 05 WJ vs. CT Arm VT (%HRmax) WJ 76. .48 10 . 9 83. .38 7 . .54 *•** CT 83. .71 4. 77 83. .90 7, .75 LC 84. .49 9. 54 77. .74 8. .89 * P < .02 pre vs. post ** P < .05 WJ vs. LC 42 The VT expressed in l-min 02 was positively correlated with VC^peak for all groups pooled for arm ergometry (r = .87 P < .001) and for cycle ergometry ( r = . 91 P < .0001) (Figures 3.3, 3.4). The correlations for V02peak with VT, expressed as a percentage of HRmax or V02peak were weaker and inversely related, with arm VT %V02peak (r = -.47 P < .01), and arm VT %HRmax (r = -.33 P < .07). Cycle VT %V02peak was also inversely correlated with V02peak (r = -.47 P < .007), as was VT %HRmax (r = -.64 P < .001). Arm V02peak was correlated with Cycle V02peak (r = .77 P < .003), as was arm VT with Cycle VT when expressed in l-min-1 02 (r = . 68 P < .01). There was a significant correlation between the Cycle V02peak and Total Peripheral Resistance (r = -.53 P < .002, Figure 3.5). Arm Ventilatory Threshold (1 • min"1) FIGURE 3.4 rH 25 •rl 6 • rH „ OO cd 75 p. CN o •> t 50 01 1 I—I a >-. O i 25 Cycle (Leg) VCVjpeak vs. Cycle Ventilatory 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 Ventilatory Threshold (1 •min--'-) 45 TPR Units 46 3.3.5 ST-Segment Alterations After Training The level of ST-segment depression at peak cycle exercise increased non-significantly from 0.54 ± 0.51 mm to 0.67 ± 0.98 mm in the WJ group and decreased from 0.94 ± 1.5 mm to 0.39 ± 0.60 mm in the CT group ( P < .05). There was an increase in ST-segment depression in the LC group, from 0.57 ± 0.93 mm to 0.93 ± 1.5 mm after the 6 month period (P < .05) . The ST-segment at maximal arm workload decreased in both the WJ and CT groups after training, but non-significantly (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 Effects 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 after training in the three groups. These workloads were chosen because they represented low enough levels of work to be considered submaximal for most of the subjects. However, 2 of the subjects in the LC group, one in the CT group, and one subject in the WJ group failed to reach these workloads on pre-testing, and their data is not included in this 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 significant reduction in 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 respectively), 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 in Submaximal Heart Rate for Arm and Leg Ergometry Variable Group Pre (Mean, SD) Post (Mean, Cycle HR @ 65.4 W WJ 98 ± 14.2 92 ±16.4 * (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 49 Figure 3.6a Arm Crank HR Response at 25W 110-1 T . 105-X 80-75-70-S Q. XI TO X 120 115 110-105 100 95-( 90 85-80-75 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 First Pass Radionuclide Angiogram First-pass cardiac output radionuclide angiograms were available in 24 of the 29 subjects. Technical problems in one subject, inability to establish a good venous line for the injection, and poor bolus quality for subsequent analysis of the time-activity curve were reasons for the remaining missing data. There was a significant difference for all subjects in resting SV from the supine position using this technique, to the semi-erect position during gated bloodpool radionuclide angiograms (88.44 ± 19.24 vs. 62.28 ± 15.5 ml, P < .001). There was no difference however in resting supine CO or SV after training. 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 All Gated Bloodpool RNA's were completed successfully, except in two cases, where all the subjects' data stored on disk were accidentally erased. Their data is not included in the overall analysis of cardiac function, except for the remaining HR and blood pressure variables. Resting HR, recorded during the 10 minute erect position Gated Bloodpool RNA demonstrated no changes after training in all groups. At the absolute submaximal workload representing the pre-training 70% of maximal VO2 (WL-70), HR was reduced from 104 ± 16.8 to 100 ± 16.0, 115 ± 28.0 to 107 ± 22.5 (P < .05), and 100 ± 18.2 to 98 ± 13.8 bpm for the WJ, CT and LC groups respectively. HR at the workload representing the pre-training 90% of maximal VO2 (WL-90) decreased significantly for only the WJ group (122 ± 22.2 to 114 ± 19.0 bpm, P < .05). The CT group demonstrated HR decrease of 126 ± 29.6 to 120 ± 29.5 bpm, (non-significant), while the LC group had an increase in HR at this workload (Table 3.8, Figure 3.7). 52 There were "no differences in RPP at WL-90 for all three groups, although there was a trend for smaller values for the WJ and CT groups on post-testing. At a WL representing 70% of pre-testing maximum, only the CT group demonstrated a decrease in RPP from 17.57 ±4.54 to 16.10 ± 3.27 mmHgXHR X 10-3 (P < .05). The levels of systolic blood pressure (SBP) were unchanged at WL 70 for all groups, but the level of peak SBP was significantly increased after training only in the WJ group (166.62 ± 18.23 to 184.62 ± 24.35 and 160.80 ± 30.45 to 168.80 ± 34.60 mmHg, for WJ and CT, respectfully. The LC did not demonstrate an increase in SBP at peak exercise after training. 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 Ejection Fraction and Absolute Cardiac Chamber Volumes After Exercise Training. Resting LVEF increased significantly in the WJ group from 46.4 ± 0.08 to 52.7 ± 0.09% (P < .001). There were also significant differences between the WJ group with CT and LC groups with respect to resting LVEF (P < .05) . At the same absolute workload representing the pre-training 90% level (WL 90) , only the WJ group increased LVEF; upon post-testing, at this submaximal exercise level, LVEF was 65.8 ± 0.11% compared with 53.3 ± 0.11% at this same WL pre-training (P < .001). The CT group also increased LVEF at WL-90, but the change was not significant (Table 3.9, Figure 3.8). Peak LVEF increased in both the WJ and CT groups, with the magnitude of change greater for the WJ group (53.3 ± 0.11 to 64.8 ± 0.10%, and 50.7 ± 0.12 to 55.3 ± 0.11%, P < .001, and P < .02, respectively). When Peak LVEF was plotted against peak SBP, there was an upward and right shift for the WJ and CT groups, but not for the LC group, indicating improved cardiac function when an estimate of afterload (using SBP) is taken into account (Figure 3.9). There was no significant correlation between peak LVEF and VC^peak for the groups combined (r = .23). 56 Table 3.9 Changes in Ejection Fraction after 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 vs. CT, LC Data for SV (rest, WL-90, WL-90post), CO (WL-90post), LVESV, and LVEDV (WL-90, WL-90post) are presented in Table 3.10. Resting CO (Figure 3.10) increased, but non-significantly in the WJ and CT groups after exercise training, 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, respectively). 57 Submaximal CO (WL-90) was increased after training for only the WJ group from 12.20 ± 3.27 to 15.54 ± 4.54 l-min-1, (P < .05) and was greater than the CT group, and statistically greater than the LC group. At peak exercise (WL-90post vs. WL-90) ,. CO increased significantly for both the WJ and CT groups to 15.54 ± 4.45 and 14.27 ± 6.37 l-min-1 (P < .03) (Figure 3.10). CO at WL-90 and WL-90post were significantly correlated with TPR (r = -.67, P <. 0001, and r = -.66, P < .0007) . 58 Table 3.10 Changes in L. Ventricular Volumes After 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 significantly greater at all levels (rest, WL-90, peak) in the WJ group after training, with only peak SV statistically greater after training in the CT group. The LC group did not display any changes at any level. Resting SV increased from 62.8 ± 11.99 to 80.50 ± 19.9 ml (P < .02) in the WJ group, and non-significantly in the CT group ( 59.84 ± 18.87 to 77.72 ± 18.9 ml). At WL-90, SV increased in the WJ group from 101.23 ± 22.6 to 127.87 + 42.9 ml (P < .02), and this change was greater than for the CT and LC groups (P < .05). At peak exercise levels (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 still significantly greater than pre-training peak levels (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 indirect estimate of afterload (TPR) was plotted against changes in peak and submaximal SV from pre to post-training, the curves shifted upwards and to the right for the two training groups (Figures 3.11, 3.12), suggesting improved contractile function. TPR (WL-90) however, significantly correlated with WL-90 SV (r = -.69, P < .003, Figure 3.13). When plotted against TPR for rest, WL-70, WL-90post, SV shifted upwards and to the left for each group except the LC group at peak exercise (Figure 3.14). 60 There were no statistically significant reductions in LVESV at WL-7 0 for any group, but at WL-90 and peak levels, LVESV decreased significantly in only the WJ group after training (93.97 ± 40.6 to 70.11 ± 35.8 ml at WL-90 [P < .01], and 93:98 ± 40.55 to 72.39 ± 33.42 ml at WL-90post [P < .03]). Peak TPR was mildly correlated to peak LVESV for combined groups (r = -.42, P < .05). The plot of changes in LVESV against SBP demonstrated a shift upwards and to the left for the WJ group, indicating an improvement in ventricular emptying against a greater afterload (Figure 3.15).. LVEDV increased from rest to peak exercise at post-testing for the WJ group only (154.70 ± 33.4 to 198.10 ± 59.0 ml, P < .002). There was no change in LVEDV at WL-90 exercise levels for the WJ group (195.20 ± 51.5 vs. 197.97 ±66.10 ml or at the new peak level (WL-90post) 198.10 ± 59.0 vs. 198.20 ± 51.5. The CT group however, displayed a trend towards increasing LVEDV at these two levels of exercise (172.27 ± 54.4 vs. 196.24 ± 54.6 ml (WL-90), and 172.27 ± 54.4 vs. 209.30 ± 64.7 ml (WL-90post) (P < .07). TPR at both levels of exercise (WL-90 and peak) was significantly and negatively correlated with LVEDV (r = -.67, P < .0004, r = -.69, P < .0003). In Figure 3.16, LVEDV for rest and three exercise levels is plotted against LVSW to assess the contributions of the Frank-Starling Mechanism to ventricular 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 Systolic BP After Exercise Training 70-60->, 50 CL 40 30 130 140 150 160 170 180 190 Systolic BloodPressure (mmHg) 200 . P • P p < .001 05 vs.CT, LC WJ • CJ 0 LC _ :02 c.05 (SBP) 20 n Figure 3.10 Cardiac Output Before and After Exercise Training 18H e p < .05 vs. WL-90pre +. p < .05 vs. LC 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 15o^ 140 -20 -10 10 SV (ml) 20 30 • WJ • CT • LC _ # P < .02 (SV) * P < .02 (SBP) P < .05 (SBP) FIGURE 3.13 Stroke Volume (WL-90) vs. Total Peripheral Resistance (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 Total Peripheral Resistance (TPR Units) Figure 3.14 Changes in Stroke Volume vs. Total Peripheral Resistance After Exercise Training 140-| 130-120 -110-E ioo-o > a) o i_ •t—' CO 90H 80-70-60-If. + P < .02 + P < .05 (vs. LC) 50-1—r i—i—i—i—i—i—r~ 0.80.9 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. Ventricular Function; Effects of Exercise Training Systolic Blood Pressure/LVESV ratio (P/V Ratio) WL-90 increased but non-significantly in the WJ group from 2.19 ± 0.88 to 3.53 ± 1.08 mmHg/ml"1 (P < .08) after training. There were no changes for the CT or LC groups (Table 3.11, Figure 3.17). At WL-90post, P/V ratio declined in all groups, with the WJ group demonstrating a non-significant increase in this variable pre vs. post (Peak P/V ratio = 2.19 ± 0.88 to 3.48 ± 2.78 (P < .06). Left Ventricular Stroke Work (LVSW) increased significantly at the WL-90 level in the WJ group (154.45 ± 34.76 to 196.41 ± 72.51 g-m, P < .04), and increased, but non-significantly in the CT group ( 136.38 ± 71.70 to 168.98 ± 92.83 g-m ), with the . LC group demonstrating a decline in LVSW at peak exercise after low-intensity training. Comparison of pre vs. post peak LVSW, demonstrated significant improvements for both the WJ and CT groups with a decline in 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 related to LVSW at both WL-90 and WL-90post exercise levels ( r = -.58, P < .001, r = -.62, P < .002) (Figure 3.18). 70 An indirect measure of contractile function, Ejection Rate (ER) was improved only in the WJ group at WL-90 (2.81 ± 0.67 vs. 3.06 ± 0.59 EDV/Sec.-1), but non-signif icantly. There were no changes in ER after training in either the CT or LC group. At peak exercise levels after training, only the WJ group demonstrated a significant change in ER (2.81 ± 0.67 vs. 3\33 ± 0.90 EDV/Sec-1 (P < .01), which was also significantly greater than the CT group (P < .05). The LC group demonstrated a significantly reduction in ER from 2.26 ± 0.55 to 1.98 ± 0.64 EDV/Sec-1 (P < .05). For all groups pooled, ER at WL-90 was positively correlated with LVEF WL-90 (r = .85, P < .0001), as was SV at this exercise level ( r = .50, P < .02) . The estimation of diastolic filling, Filling Rate (FR) increased marginally at WL-90 for only the WJ group after training (3.15 ± 0.99 vs. 3.45 ± 1.03 EDV/Sec-1), and increased significantly at peak exercise pre vs. post (WL-90 vs. WL-90post) in only the WJ group (3.15 ± 0.99 vs. 3.72 ± 1.33 EDV/Sec-1 (P < .01). P/V Ratio was correlated with FR WL-90 and FR peak ) r = .55, P <.007). Total Peripheral Resistance (TPR) was reduced with increasing levels of exercise for all groups, but reversed slightly at peak exercise levels. At the WL-90 level after training, the WJ and CT groups demonstrated reduced TPR; 0.558 ± 0.13 to 0.485 ± 0.13 and 0.678 ± 0.34 to 0.551 ± 0.13 PRU's for 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) in 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 Alterations in Total Peripheral Resistance: Effect 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. Ventricular Function Variables; Effect 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 Filing 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-' •qwi-hwl-70 4 I / ^flwl-90 ••wl-90post oWl-90 Qwl-70 4 , p -= .001 vs.wl-90pre(LVSW) • P < .002 vs.rpost (LVEDV) • P < .04 vs wl-90pre (LVSW) • P -c .01 vs wl-90pre(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-90pre 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 failure to lower body fat levels contrasts with the majority of the literature in this area (Kavanagh et al., 1973, Hellerstein, 1973) . A lowering of body fat would reduce the external work required during work or exercise, and thus lower myocardial 02 consumption for the same given level of work. In theory, this concept is physiologically correct, providing there is a potential for considerable body fat loss initially. This group of subjects however, displayed average body fat levels compared to large populations at pre-testing, and thus further reductions in body fat might have been unrealistic for subjects who could have achieved most of the potential body fat losses immediately after the MI due to changes in diet/lifestyle. On WHR scores, the data reveals that all the subjects ranked in the top 90 to 95tn 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 all groups on pre-testing was 64.9 mm, in the 35tn percentile for the general population, but outside the "health risk zone", where increased risk for CAD and diabetes is most correlated (Lapidus et al., 1984). 77 Other factors to consider in the failure of body composition to change are the time frame from MI or surgery to the onset of exercise training; many changes in body composition can take place during hospital stay (mainly an increase in fat to muscle mass ratio) due to chronic bed rest. If pre testing measurements are taken at this point, the apparent body fat losses could be highly exaggerated. Secondly, the exercise training programs, although sufficient to provoke increases in aerobic fitness, were probably too short in duration/session to affect weight loss in a group of patients with already normal body fat levels. Impressive fat losses have only been recorded in CAD patients who train extensively, such as marathon running (Blessey et al., 1981, Kavanagh et al., 1974). 4.2 Blood Lipids Alterations in cholesterol and its subfractions has been well documented in the healthly population, but also in exercising cardiac patients. The patients in this study had total cholesterol/HDL-C ratios above what would be considered desirable for this population (values below 4.5 representing reduced risk). The results of this study conflict with other studies which have demonstrated increases in HDL-C and/or reductions in the Total Cholesterol/HDL-C ratio. Streja and co-workers (1979) 78 observed a significant increase in HDL-C, which has been associated with reduced CAD risk and linked with an arterial plaque "scavenging" effect as well in healthly and at-risk populations. Their patients increased HDL from 35 to 39 mg/dL after 13 weeks of training, which however, failed to induce a training effect. None of the exercise groups in this study demonstrated an increase in either HDL, or a decrease in total-cholesterol/HDL ratio, and LDL-C, despite an increase in fitness levels for the WJ and CT groups. Heath et al., (1983) also demonstrated a decrease (9%) and and increase (11%) in LDL-C and HDL-C respectively, after training, and the change in LDL vs. change in VC^peak was significantly related (r = -.73). In our patients, the relationship of VC^peak to HDL-C was not as strong, but significant, (r = .45, P < .01), still indicating that aerobic fitness is related to HDL-C levels. A study by Erkelens et al., (1979) also demonstrated an increase in HDL-C in 83 training CAD patients from 35 to 40 mg/dL, but found that after 6 months, there was no further increase in HDL-C. As our patients were recruited 4 -6 months after MI, it is possible that maximal changes in lipids had already been attained by dietary changes that subsequent exercise and the lack of controlled diet changes were unable to affect. Thus, these results seem to indicate that without dietary manipulation in these patients, relying 79 entirely upon exercise to improve lipoprotein profiles seems to be ineffective. There is documentation however, of lipids remaining unchanged, even in normal individuals after exercise training which produced an increase in VC^max. (Allison et al., 1981). These authors linked the failure of a HDL-C increase to a failure of TG to also reduce. Upon further analysis, it is revealed that in our patients, TG was reduced in all groups (20% in WJ, 6 % in CT, and 20% in LC). Thus in our patients, the inability for HDL-C to increase must be related to other factors which can influence HDL and LDL-C, namely alcohol intake, diet, exercise intensity, duration, and initial fitness level. Some literature has linked the fat deposition and body composition to blood lipid changes (Ribeiro et al., 1984, Melish et al., 1978). In the first study, the authors demonstrated that only in the CAD patients that recieved dietary counselling and exercise (vs. exercise only), did body fat levels and total cholesterol levels decline. However, in their study, HDL-C levels were unchanged in both groups after exercise. The Melish study demonstrated a significant decline in LDL-C in normals subjects, with a significant relationship between the^ change in LDL-C and a decline in adiposity. 80 In our group of subjects, Waist-Hip ratio was negatively related to HDL-C, indicating some degree of association with body composition. Thus, the mechanisms of this link between body fat and blood lipids needs further investigation and research. An additional factor to consider in evaluating the complex interrelationships between lipids, diet and exercise, is that there exists significant reliability and variablility problems in the measurement procedures (Superko et al., 198 6) . Any significant changes in HDL-C could be masked by the wide inter and intra-laboratory measurement and quality control measures which have not been adequately standardized in Canada and the U.S. Finally, it must be emphasised that the actual measures themselves are still controversial; the subfractions of HDL, HDL2 and HDL3 have been identified recently, and have differing metabolic roles. The HDL2 unit has been identified as the cardioprotective unit, with the HDL3 unit being non-protective, but positively correlated with alcohol consumption. Also, the apolipoproteins associated with HDL and LDL (Apo A-I, A-II) have been recently identified more strongly with atherogenisis risk than the lipoproteins themselves (Superko et al., 1986). The unavailability of the measurements of these lipoprotein subfractions and their 81 related apolipoproteins renders this a limitation in this aspect of the study. 82 4.3 Lower and Upper Extremity Aerobic Capacity 4.3.1. Lower Extremity Changes in 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 in efficiency for cycling 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 training. The advantages of cycle ergometery testing are more easily measured and reliable systolic blood pressures, and equal RPP for the two modes (Wicks et al., 1978), suggesting that the patients responses could be validly compared and equated to their medical and physiological status. The increases in cycle VC>2peak in both the WJ and CT groups is consistent with changes found in the literature after exercise training. A search of the literature demonstrates that directly measured VC^peak values increase from 0 (Sullivan et al., 1985) to 46% (Hagberg et al., 1983), with the 13.1 and 9.7% (for WJ and CT groups, respectively) increases for the two groups of patients in this study representing an average increase in functional capacity. 83 Detry et al., (1971) demonstrated 21% improvements, as did groups of patients from the Toronto Rehabilitation Centre (Kavanagh et al., 1973). A select group of marathoning CAD/Post-MI patients from Kavanagh's patient program have reported values of 43.5 ml'kg-1-min-1, with up to 55% increases, but using estimated VC^max (using a nomogram). It is noteworthy that the studies that were primarily intended to demonstrate intrinsic changes in cardiac function after training also demonstrated the largest increases in VO2 (Ferguson et al.,: 41%, Hagberg et al., : 46%) . To ensure that VC^max as opposed to VC^peak has significantly improved however, RER and other physiological variables must also be considered in the exercise test results (Roberts et al., 1984, Taylor et al., 1963). It is uncertain in some studies whether RER and other indicies of true attainment of VC^max have been reached. CAD patients, particularly those with ischemic symptoms, will often attain a higher VO2 upon re-testing due to motivational and patient-physician/tester interactions (Taylor et al., 1963). Measurement of RER at peak effort will often differentiate between a true VC^max or VC^peak. However, higher RER values upon re-testing after a period of exercise training should not always rule out attainment of true training effects; some patients who have higher peak RER values at post-84 testing might have increased their myocardial oxygen consumption capabilities, and thus are able to work closer to their true VO^max before termination of exercise. On the other hand, some patients might be limited by an early onset of anaerobic metabolism in the working muscles, increasing excess CO2 production, and thereby increasing RER at low exercise intensities. However, it would follow that in this case, high RER values would not be acccompanied by an attainment of age-predicted HRmax and a plateauing of VO2 • Clearly, it is apparent from this discussion that this issue has not adequately been resolved in the cardiac rehabilitation literature, and needs further examination. It can be seen from the present data that the true criteria for attainment of VX^max (RER 1.15, a plateauing of VO2 with increasing workload, age-predicted HRmax) were not accomplished due to the usual reasons associated with this medical condition, and agreeing with other data (Taylor et al., 1963). However, the RER values were significantly unchanged at pre and post-testing, indicating that the motivation level and physiological stress at peak exercise during both testing situation was similar. Other parameters (maximal workload achieved, and RPPmax) also indicate a training effect in the WJ and CT groups, and an absence of any effect in the LC group. However, the LC group had lower values for maximal WL, HR, and RPP at pre-85 testing, suggesting that they might have represented a different group of patients. Their inclusion into the LC group based upon the above listed criteria (See Methods section) could have been due to a progression of their disease, initially poorer functional capacity due to more extensive myocardial disease, or a greater number and/or extent of coronary vessel occlusion. Since more detailed medical records were not available on these patients, correlating information on the extent of coronary occlusion and/or percent of LV affected by the MI, to current group classification was not possible. The observation that the slightly greater increase in V02peak in the WJ vs. the CT group is probably a reflection of the greater time spent performing lower limb training in the WJ group, compared to the CT group, who spread the training time between the upper and lower extremities. It is interesting in that, although the CT group on the average spent between one-third and two-thirds of the training on lower extremity training compared to the WJ group, the increase in VO2 for the WJ group was not significantly greater. It is speculated that the specificity of walking and jogging became uncovered during cycle testing in the WJ group, offsetting the reduced lower limb training time factor. Overall, the physiological changes demonstrated are 86 consistent with improved functional capacity after exercise training in these patients. The fact that ST-segment depression at peak exercise did not decrease in the WJ group, but did in the CT group (.94 to .39 mm) would also suggest an exercise specificity effect, and a failure in the WJ group to increase peak myocardial oxygen consumption, using electrocardiography alone as a basis for this interpretation. However, maximal RPP (as were many cardiac function parameters discussed later) was increased in 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 after training. It must be recognized that there exists a high false positive and false negative rate in ECG evaluation, and these results in isolation of other physiological 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 level in the two training groups, thus agreeing with the classic effects of reduced myocardial O2 demand and symptoms of ischemia at a given external workload previously reported in the literature (Clausen et al., 1969, Detry and Bruce, 1971, and Sim et al., 1974). Ventilatory threshold for cycling demonstrated improvements, 87 but only in the WJ group when expressed as absolute l-min 02 (Table 3.4). These findings are in contrast with those by Sullivan (et al., 1985), who failed to demonstrate an alteration of VT after 12 months of exercise training, whether expressed as VE vs. VO2 or ventilatory equivalent for 02- However, unlike the present findings, the authors also failed to demonstrate an improvement in VC^peak after exercise training in their subjects. Although the VT as expressed as percentage of VC^peak or HRmax failed to improve to the same extent as expressed as absolute VO2, the variability of the measures could have rendered these changes non-significant. As the majority of these patients were on some form of Beta adrenergic blockade medication, the VT's occurred at relatively higher percentages of HRmax than is usually found for normal or even athletic subjects. Increases in VT have been previously documented in normal middle-age males (Davis et al., 1979) (44% improvement in absolute VT) , but not in exercising CAD patients. Since the VT (absolute VO2) was correlated with VC^peak (r = .87), it seems that VT is a parameter which accurately describes aerobic fitness without the pitfalls of relying upon "maximal" physiological values. However, the relationship becomes altered, and is flawed when percentages of HRmax and V02Peak are compared, probably reflecting the altered HR response due to medications. Since HRmax values 88 are low due to Beta-adrenergic blocking medications, the patients with the highest relative VT's are those that have a low VC^peak, (who terminate the exercise test early) and the patients with the highest functional capacities (and VC^peak), have the lower relative VT's, since they terminate exercise later. Thus in evaluating the effect of exercise training on VT in CAD patients on Beta-adrenergic blockade, only the VT expressed as an absolute HR or VO2 should be compared. 4.3.2 Changes in Upper Extremity Aerobic Capacity Arm VC>2Peak for the groups represented between 65 and 70% of leg VC^peak. This agrees with data from Franklin (1985), and Astrand et al., (1965), who found similar percentages in testing arms and legs in both normal and cardiac populations. Schwade et al., (1977) found that maximal arm workloads represented approximately 41% that of the leg. We found that this percentage was lower, with arms representing only 33% of leg maximal workload. The small but significant improvements in arm ergometry VC^peak and workload were demonstrated in the WJ group who did not train the arms (Table 3.5). The small reductions in submaximal HR for leg exercise after leg training was observed for both the WJ and CT groups, since they both trained the legs. However, (although the differences were 89 non-significant), a slightly greater relative decrease in submaximal arm HR at 25 W for the WJ group than that for the CT group, who did train the arms (Figure 3.6) was observed. It is speculated that since the WJ group demonstrated the greater overall training effect (greater cycle VG^pea'k after training) than the CT group, this was reflected in the greater but small transfer effect to the untrained limbs. The CT group's training stimulus, spread over three relatively discontinuous 10 minute sessions, each on a different apparatus, might not represent enough of a metabolic stress to uncover changes at submaximal workloads. McKenzie et al., (1978) and Savard et al., (1987) have suggested that the transfer effect is greater from the trained, larger muscle mass to the' smaller untrained muscle mass than the reverse. It is speculated that since in the present study the WJ group spent a greater percentage of time training with the larger muscle mass than the CT group, this could have expedited this transfer effect. The possibility that the WJ group could have derived some upper extremity training effect due to the more vigourous use of the arms during walking and jogging can be ruled out, since the relative contribution of these limbs to the training effect would be negligable in active individuals at this phase of rehabilitation. In addition, the CT group supplemented their training with walking/jogging, and they too would therefore have benefited equally. 90 Another factor to consider in explaining the relatively small submaximal arm HR responses found in this study compared to other indicies of arm fitness is that many of these patients were on Beta-adrenergic and/or Calcium antagonist medications. This contrasts to most studies, where the patients were weaned off their medications during testing. This most likely resulted in lower absolute changes in HR from rest to exercise and hence, would explain the failure to uncover these changes at submaximal levels of work. Nevertheless, the CT group still demonstrated the greater absolute increase in arm VC>2Peak (13.2%) vs. the smaller but significant transfer effect for the WJ group (7.0% increase in arm VC^peak). These results generally agree with other literature. The improvement in arm VC^peak in the CT group is similar to that found in other studies. Wrisley (et al., 1983) found that patients who also balanced training of the arms and legs improved arm and leg VC>2Peak 11 and 13%, respectively. Lewis et al., (1980) found a 9% transfer effect to the untrained arms in healthy normal subjects, as did ROsler et al., (1985). Clausen et al., (1973), found a 10% transfer effect to the untrained arms. Thompson and Cullinane (1981), studying this possible transfer effect in CAD/Post-MI patients, revealed an 8% improvement in arm cranking after cycle training only, but the training effect 91 for the group who had the arms tested after arm exercise training was only 10%. The speculated mechanisms for these transfer effects have been increases in cardiac (central) function, supplying a greater cardiac output to the untrained limbs, changes in catecholamines, alterations in TPR, and most often cited, increases in lactate (H+) uptake/oxidation by inactive but trained skeletal muscle, heart and kidney (Saltin et al., 1976). ROsler et al., (1985) has argued that the central hypothesis can be ruled out since post-testing arm VC^peak is often lower than pre-testing leg VC>2, and therefore even before training, the cardiovascular system is already able to support an increased arm aerobic capacity. This would agree with the data in this study. In addition, the authors also demonstrated no evidence for local biochemical/ultrastructural changes in the untrained limbs. Unfortunately, none of the aformentioned studies have measured changes in cardiac function after training of either the arms or legs. Reports on the present study's findings relating to cardiac function appear in a later section of this discussion. For arm ergometry, both the WJ and CT groups demonstrated improvements in VT expressed as absolute level of O2 consumption, as a percent of V02peak or as a percent of HRmax (Table 3.6). The demonstration of an increase in arm 92 ergometry VT for the WJ group parallels the previously noted increase in arm VC^peak, and further reinforces the finding of a transfer effect from the trained to the untrained limbs. The relatively larger increase in VT expressed as absolute l-min-! O2 for the CT group is consistent with their greater training effect for arm exercise, and represents the concept of specificity of exercise training. A limitation in this study in completely understanding the training effects of arm exercise and the transfer of fitness to the untrained limbs in CAD patients, is the lack of blood pressure measurements during arm exercise. As a result, systolic blood pressure, which would have given insights into RPP and hence an indirect estimate of myocardial oxygen consumption during arm exercise, was not possible. It was felt that the measurements using the popliteal artery, or utilizing a discontinuous test protocol were cumbersome, or prevented VT measurements, respectively. Further studies should investigate the possible use of newer microprocessor/automated BP units (which were unfortunately unavailable for this study) when testing arm responses to exercise. 93 4.4 Cardiac Function 4.4.1 First Pass Radionuclide Angiography The data from this study are consistent with the classic finding that there are postural changes in cardiac volumes from the supine to erect position (Bevgard et al., 1960); SV decreased from 88 to 62 ml from supine to the erect position. Owing to increased venous return due to reduction in the effects of gravity, stroke volume is enhanced in the supine position. As a result, there were no changes in CO or SV in this position due to the exercise training intervention, since any changes in cardiac performance would be masked by this position, which would increase SV to near maximal values. 4.4.2 Gated Bloodpool Radionuclide Angiography Exercise: Submaximal Hemodynamic and HR Responses The failure of resting HR to decline due to the training effect conflicts with some of the literature (Ehsani et al., 1986, Clausen et al., 1970, Kasch and Boyer, 1969). It should be emphasized however, that in most studies, patients have been taken off beta adrenergic medication. Thus the potential for demonstrating a resting bradycardia is limited in these patients who have already blunted heart rate responses. Although some authors have demonstrated reduced 94 resting HR in patients on Beta-blockade (Froelicher et al., 1985, Wilmore et al., 1985), it has also been demonstrated in many populations that VC^max is poorly correlated with HR reduction at rest (Astrand and Rodhal, 197 6). The demonstration however of significant (-5%) reductions in HR at the submaximal exercise levels at the pre-testing 70 and 90% of maximal levels (WL-70, WL-90) agrees with other findings, but is less than commonly observed in other literature (Hagberg et al., 1983, Sim and Neill, 1974, Detry et al., 1971, Frick and Katila, 1968). The 90% level might have represented too high a stress, even after training to uncover greater changes in HR for the two training groups. The fact that only the CT group demonstrated a reduction in RPP and HR at WL-70 probably reflects their greater adaptive response due to the specificity of cycling, which the WJ group did not perform. On the other hand, the overall increases in fitness were slightly greater for the WJ group, as previously documented. The greater peak RPP recorded after training reflects this adaptive response, despite the fact that this group did not train using cycle ergometers. The increase in maximal RPP agrees with findings of Sim and Neil (1974), and Hagberg et al., (1983), and would suggest that the myocardial oxygen consumption has been augmented. Since it has already been established that the increases in VC^peak were not 95 artifactual, these increases' in RPPmax for the WJ group are due primarily to increases in SBPmax, and would appear (in the absence of further cardiac data) to represent changes in the myocardial fj^supply/demand relationship. This data agrees with increased RPPmax found by Ehsani and co-workers (1981), who found highly significant increases, but also with accompanying increases in ischemic threshold and reduced ST-segment depression at peak exercise levels. 4.4.3 Gated Bloodpool Angiography: Reliability and Validity The correlations for determination of LVEF and SV using standard contrast angiography vs. RNA's found for this study (.85, .93, respectively) agree with others (Hindman and Wallace, 1981, Links et al., 1982, Slutsky et al., 1979). Reliability studies were not undertaken, but studies investigating the test-retest reliability of radionuclide-derived LVEF and absolute cardiac volumes have reported acceptable test-retest reliability. Hindman and Wallace reported values of .89, .89, and .94 for exercise LVEDV, LVEF, and CO, respectfully. Caldwell (1981) found exercise LVEF had an intraobserver variablility of 1 - 3%. Ehsani and co-workers (1986) found better reproducibility for exercise LVEF (1.7 ± 0.9% , r = .92), and LVEDV. (7 ± 3 ml, r = .92). Drawing incorrect regions of interest about the ventricular 96 borders and the background regions (despite built-in computer algorithms to check errors) can contribute to small errors which can result in increased LVEF and volumetric data if performed by a biased or unskilled operator. To minimize these effects, only one experimentor was used to draw these regions after practicing on unrelated data. Furthermore, blinding the identity of the subjects reduced the bias effect. 4.4.4 Left Ventricular Ejection Fraction The baseline levels of resting LVEF (46, 44, 43% for WJ, CT and LC groups respectively) represent values commonly found in patients with CAD or previous MI (Values for normal range between 60 and 80%) (Nivatpumin et al., 1979). The increase in resting LVEF in the WJ group after exercise training is not commonly found in the literature, even in the studies which demonstrated greater metabolic and cardiac function adaptations than this present study (Ehsani et al., 1986, Williams et al., 1984). Only Verani et al. (1981) found an increase in resting LVEF after only 3 months of training. It is speculated that the significant findings in resting LVEF in this study were due to differences in RNA processing techniques from other studies, combined with the training effects in the two training groups, and the fact 97 that our patients remained on their medications, augmenting ventricular function by decreasing systemic resistance. Consistent with the greater overall aerobic fitness adaptations in the WJ group was the observation of significant (19 and 18%, respectively) improvements in LVEF at the pre-testing 90% level (WL-90) and at peak levels. This result is similar to those by other investigators (Ehsani et al., 1986 and Williams et al., 1984,). Williams and co-workers reported peak LVEF to increase from 50 to 54%, while Ehsani et al. (1986) reported an increase in the intensely trained group from 52 to 58%. Our findings of changes from 53 to 64% (WJ) and 51 to 55% (CT) are slightly larger changes, despite the lower exercise training intensities than the former study, whose subjects trained for 12 months for up to 1 hour per session, five sessions per week, at up to 90% of V02max. The known variablility of LVEF measures, coupled with the use of a different method of LVEF determination used by the above authors could explain in part, the greater changes in LVEF found in the present study. However, a more probable cause is that Ehsani's patients had higher pre-testing resting LVEF than our patients (53 vs. 46, 44 and 43% for the WJ, CT and LC groups, and thus our patients displayed a greater potential adaptive response. Also, it is uncertain whether the authors' patients were studied at the same level 98 of stress as our patients. Their patients were studied at rest and "peak" exercise. However, it would be difficult to obtain true peak exercise levels during RNA's with CAD patients, as at least 2 minutes of steady-state acquisition is required for enough count data for reliable LVEF and volumetric data. Our patients exercised at 90% of VC^peak, a level that most patients could accomplish safely. It is speculated that at the 90% of VC^peak workload, rather than a "peak" workload, our patients achieved higher and more reliable LVEF values than the Ehsani et al's patients because they had not yet decreased LVEF, which would occur at peak exercise due to ischemia. Also, the authors' exercised their patients in the supine position, which might have diminished ejection fraction and other volumetric values due to the effect of gravity on venous return; in the supine position as previously discussed, LVEDV and SV are thought be be near maximal at rest. Finally, it is suggested that since the patients remained on Ca^+-antagonist and Beta-blockade medications during testing, this resulted in a net augmention of LV performance due the greater drop in systemic resistance than depression of contractility, which these drugs would also cause. Other studies have failed to demonstrate changes in LVEF in CAD and Post-MI patients after endurance training. Cobb (et 99 al., 1982) found no improvements in LVEF at any level of rest or exercise. Similarly, 12 months of training failed to result in significant improvements in LVEF in a large group of patients, despite a demonstration of favorable peripheral adaptations and an 18% improvement in VC^peak (Froelicher et al., 1984). The latter study, however, measured patients in the supine position during exercise for the RNA procedures, and a failure to detect any significant LV performance improvements could have been due to this factor. Foster et al., (1984) and Hung et al., (1984) also failed to detect any changes in LVEF after training, despite other favourable submaximal changes in exercise capacity. As shown in Figure 3.8, although LVEF is increased at WL-90 for the WJ group, LVEF failed to increase, and actually decreased (non-significantly) at the new peak workload. This would indicate that a critical level of myocardial 02 consumption supply/balance ratio had been exceeded. At this new peak level, the ischemic threshold (now elevated from the pre-testing peak), has been again reached. As defined, LVEF is a ratio of SV to LVEDV. Although it is a useful and popular clinical tool to evaluate overall cardiac function, it can be greatly influenced by the peripherally-mediated loading conditions placed upon the heart from beat to beat. Evaluated alone, LVEF can lead to a misinterpretation of the effect of exercise training on LV 100 performance (Nivatpumin et al., 1979). To account for other factors which could influence LVEF, some measure of the contribution of afterload and preload conditions should be included in the interpretation of central vs. peripheral exercise training effects. Nivatpumin (et al., 1979) has presented data to confirm that patients with seemingly normal LVEF's have in 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 systolic blood pressure or RPP as an estimation of impedance to LV emptying (afterload). When submaximal and peak LVEF were plotted against changes in LVEF, Ehsani and co-workers (198 6) found that there was an upward and right shift in the relationship, leading the authors to conclude that since LVEF significantly increased in the face of significant increases in SBP, intrinsic improvements in LV performance was suggested. Our data, demonstrating significant.increases in SBP and Peak LVEF in the CT and WJ groups (Figure 3.9) agrees with their findings. 4.4.5 Cardiac Output and Absolute L. Ventricular Volumes There were significant increases in CO for the WJ and CT groups at submaximal exercise level WL-90 and peak exercise levels on post-testing (WL-90post vs. WL-90) (Figure 3.10). 101 These results agree with data from Hagberg et al. (1983), however, they found no increases in CO at the same absolute workloads, but did observe increases at relative percents of post-training VC^peak. Since HR was reduced at these levels of exercise, SV must have increased to account for the increased CO at these exercise levels. Stroke volume was increased at rest (63 to 80 ml) and each exercise level (101 to 127 ml at WL-90) for the WJ group. The increases in resting SV compare favorably to data from Hagberg et al., (1983) who found increases from 66 to 81 ml after training, and from 100 to 120 ml at the peak exercise level tested (approximately 65% of pre-testing V02Peak) but disagrees other studies who found no changes in SV (Froelicher et al., 1985, Rousseau et al., 1973). It can be observed that only at peak exercise levels (WL-90 post) , does SV fail to further increase, and in fact falls non-signif icantly (128 to 125 ml in the WJ group) . This finding agrees with other data which suggests that SV fails progressively up to maximal exercise in CAD and normal subjects. These data however conflict with reports of SV failing to increases past about 40% of peak capacity (Rousseau et al., 1973, Astrand et al., 1964); the CT group was actually able to increase SV from the WL-90 level to the new WL-90post workload (109 to 118 ml). The interaction 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 in compromised subjects. This effect should be persued with this particular population by further investigation. Utilizing the measurement of SBP (a non-invasive estimation of afterload) to examine whether these changes in SV were actually due to intrinsic improvements in LV contractility, Figure 3.11 and 3.12 demontrates the upward and right shift in the curves for the two training groups, which would suggest, similarly to others (Ehsani et al., 1986), that contractility has improved at submaximal and (near) maximal exercise levels. However, calculated TPR (not determined in the latter study,) was found to be significantly lower at both submaximal and near maximal workloads (WL-90 and WL-90post, respectfully, Table 3.13) after training. When the change in SV from pre to post-training is plotted against TPR (Figure 3.14), the curve shifts upwards and to the left, indicating that for any absolute SV, systemic vascular resistance is correspondingly reduced, except for the LC group, where it is increased as power output is increased, (suggesting some increased intramuscular tension at high work rates for this group). This data conflicts with that from Hagberg et al., (1983) who demonstrated an increased SV at the same measured 103 systemic resistance after training. However, the above authors measured SV at only 35, 45, and 65% of "VC^max", perhaps too low an intensity to greatly reduce TPR. It would appear that from our SV data, the falling of TPR at the higher workloads (90% VC^peak) increased SV by enabling greater ventricular emptying. It is also speculated that the significant drop in TPR in the patients was further augmented by the peripheral vasodilation effects of Ca^+ and Beta-blockade medications which they remained on during training and testing. In agreement with the data from Hagberg et al., (1983), Siconolfi et al., (1984) failed to demonstrate the expected drop in TPR with increasing exercise levels, and found no correlation with training effects, leading these authors to conclude that central effects due to training are possible, and are not always due to reductions in afterload and systemic resistance. This finding however, conflicts with many in the literature and our data, which supports the finding that systemic vascular resistance decreases as V02 increases (r = -.69, Figures 3.5, 3.13). The changes in LVESV were the most pronounced for the WJ group, which was the only training group to decrease LVESV at a greater afterload (estimated by SBP) at peak exercise after exercise training from 94 to 70 ml (Table 3.10, Figure 3.15). This result is similar to that of Ehsani et al. 104 (1986), who demonstrated a similar shift, but in patients who trained more intensely than those in the current study. Again, the same adaptive responses found with a less intense exercise program could be due to the characteristics of the patient sample, testing protocols, testing posture, medications (with their associated greater decreases in TPR), and intensities chosen during RNA acquisitions. Froelicher et al., (1984), utilizing training intensities similar to the present study however, found no improvements in LVEF and SV after training, but also demonstrated a greater LV emptying (reduced LVESV) with no change in afterload. The authors however, tested patients in the supine position. The CT group had increases in afterload at WL-90, but failed to decrease LVESV at this workload at post-testing, indicating a declining LV contractility at this new level of external work compared to the WJ group. This is consistent with the lesser improvements in VC^peak and LVEF in this group' compared with the WJ group. In addition, the LC group failed to increase SBP at this workload, and decreased LVESV non-significantly, which is consistent with their overall failure to increase aerobic capacity, as previously demonstrated. Accompanying the decrease in LVESV for the WJ training group however, was a low but significant correlation between TPR 105 and LVESV (r =-.42), suggesting that although the decrease in LVESV after training might be due to intrinsic cardiac adaptations, the drop in systemic vascular resistance, a peripheral effect, might also influence this interpretation. The pumping ability of the left ventricle can be influenced by extra-cardiac effects, such as preload, in addition to other intrinsic factors. Measurement of LVEDV during exercise testing enables the investigator to uncover the contribution of the Frank-Starling Mechanism to increasing SV and CO. End-Diastolic Volume has been equated to the magnitude of venous return (Katz, 1977, Guyton, 1976) and compliance of the ventricular walls (Port et al., 1980). The possible mechanisms underlying diastolic function are not completely understood, but might be related to factors such as age, prior myocardial damage (relating to wall tension and distensibility), peripheral venoconstriction, and blood volume. Rodeffer et al., (1984) has suggested that in the aged, SV as well as LVEDV assumes an increasingly important role in maintaining CO in the face of decreasing HR with age. The increase in LVEDV with training, and the change in this cardiac volume from rest to exercise is not clear. Iskandrian et al., (1981) found that LVEDV changed minimally 106 from rest to exercise, as did Ehsani et al., (1986). The latter group however found that LVEDV increased at rest and exercise after high-intensity training. Our data indicates a slight increases in LVEDV for the WJ and CT groups at both rest and peak exercise levels after training, but the increases were non-significant due to the wide range of values. This contrasts with Ehsani et al., who found alterations in LVEDV after training. It is suggested that their subjects represented a subset of patients with initially less myocardial damage, and hence greater ventricular compliance. However, unlike the . results from Ehsani et al. (1986), the patients in the WJ group significantly increased LVEDV from rest to exercise at the WL-90 level on post-testing (Figure 3.16), from 153 to 196 ml. Although left ventricular stroke work was significantly increased in both the WJ and CT groups after training at WL-90 post-testing, (Table 3.11, Figure 3.16), since LVEDV also increased, the role of the Frank-Starling mechanism and both peripheral and central mechanisms in supporting the improved central function must be considered in this response. This result differs from those of Ehsani et al., (1986) who found significant increases in LVSW without the augmentation of the Frank-Starling mechanism (no changes in LVEDV from rest to exercise). This conclusion is strengthened by the observation of a significant correlation between LVEDV and 107 TPR of -.67 in the present study, suggesting increased venous return possibly leading to the greater ventricular filling (Table 3.11) . This would increase stroke volume and cardiac output partially by the Frank-Starling mechanism. Since we have no data to correlate the extent of LV damage to diastolic compliance and thus filling characteristics in the subjects, the role of LVEDV in the. cardiac response to exercise training in these patients remains unanswered. Furthermore, the alterations in blood volume, which increases with endurance training in healthy subjects (Covertino et al., 1980), has not been examined with respect to its relation to cardiac function and exercise training in this population. The measurement of the LV Systolic Pressure/End-Systolic Volume (P/V) ratio has been examined by Sagawa and co workers (1977) in animal models as a valid index of myocardial contractility which is independent of preload and afterload. The use of the P/V ratio has been validated in the human model with contrast ventriculography (Nivatpumin et al., 1979) and recently, with RNA techniques, utilizing a standard sphygmomanometer for systolic blood pressure measurements and calculated LVESV (Iskandrian et al., 1983). Although both the WJ and CT subjects increased the P/V ratio at submaximal and peak exercise levels after training, the 108 changes only approached significance due to the large standard deviations in 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, resulting in values in excess of 11.0. Since P/V (expressed as a ratio) might contribute more statistical variance as measure than separate examination of SBP and SV, etc., it might not represent a sensitive enough measure for examination with a relatively heterogenious sample as found in this study. Despite statistical non-significance, the data however suggests improvement in this variable due to exercise training, and suggests that peak contractile function is attained at submaximal workloads, with impairment of contractility at the new peak exercise levels. Thus, the failure of P/V ratio to significantly increase after training, in contrast to other investigations, might: 1. be a function of it greater sensitivity as a measure than plotting afterload estimates vs. a central function variable, or 2., represent a sensitive measure only with data that displays less variation than that found in this study. The larger differences that were found in the present study in SV and LVESV after training vary from that found in studies where the exercise intensity was substantially greater (Ehsani et al., 1986, Hagberg et al., 1983, Ehsani et al., 1982) can also be explained by the posture during 109 exercise testing. The latter investigators utilized the supine position during RNA's, which would diminish the changes in absolute LV volumes from rest to exercise. In addition, most other studies have observed the exercise test responses without any inotropic or chronotropic medications. The subjects in this study were on a variety of medications (Table 3.1), and were maintained on their medications throughout the testing periods. Although it has been demonstrated that training while on beta-adrenergic blockade does not prevent attainment of a training effect (Froelicher et al., 1985), the effect can in certain circumstances be attenuated if the medication is not cardioselective (Wilmore et al., 1985). Sklar et al., (1982) found that VT and VC^peak were unchanged in CAD patients whether on or off these medications. Kalischer et al., (1984) have demonstrated some depression in LV function and volumes with propranolol, particularly at rest. The P/V ratio was depressed at rest, however LVEF and P/V ratio were unchanged at exercise. This would account for the lower resting LVEF found in these patients compared to others (Ehsani et al., 1986, Williams et al., 1984, and Foster et al., 1984) and the greater potential for the larger increases in LVEF that have been observed in this study. Calcium antagonist medications also reduce myocardial O2 110 demand, and can affect LV function, but not to the extent of the Beta-antagonist medications. (Lowenthal, 1987). Few studies have examined the influence of these medications on the training response in CAD and Post-MI patients, particularly left ventricular function. However since these medications decrease coronary as well as peripheral vascular resistance by inhibiting smooth muscle Ca^+ flux, alterations in venous return could have accounted for the changes in LVEDV, LVESV and SV in this study, in addition to the decreased TPR with increased levels of exercise. Since only a relatively small number of studies have demonstrated cardiac involvement in cardiac patients after exercise training, based on the present findings, extra-cardiac factors must still be considered. One possiblility which would account for the findings of cardiac adaptation in this and other studies using higher exercise stimuli (Ehsani et al., 1986, Hagberg et al. 1983) is the finding of an attenuation of plasma catecholamines at rest and any given level of exercise after training in CAD/Post-MI patients (Ehsani et al., 1984). The reduction in sympathetic tone serves to reduce myocardial O2 demand at any given level of submaximal exercise, enabling a greater LVEF and volume response before ischemia occurs. The patients in the present study have this accomplished by their beta-adrenergic blockade medication, and so this effect might be Ill less noticable, thus affecting many of the central and peripheral functions during exercise. 112 5.0 Conclusions In conclusion, the results of this study support the findings of some but not all investigations in that: 1. A small degree of transfer of fitness to the untrained limbs as judged by increases in VC^peak and VT occurs as a response to 6 months of endurance training in uncomplicated and medicated CAD/Post-MI patients. 2. These training effects are both centrally and peripherally-mediated, with a portion of the cardiac effects due to changes occurring in the periphery which augment left ventricular performance, despite other physiological measurements which would indicate independent intrinsic cardiac alterations had occurred. 3. The mode of training utilizing aerobic circuit training as opposed to continuous walking and jogging is less effective in producing a generalized training effect. This is probably due to the limited duration spent at each station per session, and\or the greater muscle mass utilized during walking and jogging. i 4. The failure to increase aerobic capacity and cardiac function in the group of low-intensity control patients 113 probably reflects an overall lack of training stimuli, as judged by the low exercise intensities and frequencies per week. However, deterioration in their medical condition by progression of CAD leading to these results cannnot be ruled out, and would also explain the poor exercise performance, initial pre-testing differences on many central and peripheral indicies, and their poor compliance with exercise training. 5. Favorable improvements in central and peripheral adaptations to endurance training in the WJ and CT patients were not accompanied by expected alterations in lipid profiles and body composition. The failure to experimentally manipulate the diet, the failure to measure apolipoproteins, and the previously discussed variability and unreliability of lipoprotein measurements could explain these results. Regarding the circuit training group, overall balance of upper to lower extremity fitness might be desirable with this type of training, as demonstrated by the slightly greater improvement in arm ergometry VC^peak and cycle ergometry-specific improvements in this group. However, due to the extra equipment, costs, and dependence upon a hospital or facility, circuit training might not be as feasible a training mode as walking/jogging. The latter form of training is more convenient and seems to confer greater physiological training benefits, as judged by the transfer 114 of fitness to the untrained arms in the WJ group and greater overall LV adaptation in this group. It should be emphasized however that for special groups who need to condition specific muscle groups for participation in work or leisure activities, aerobic circuit training is efficacious in providing moderate training effects. However, this is providing that the training intensities, frequencies per week and durations per mode are sufficient and equivalent to that of a graded walking/jogging programs. More work needs to be done to quantify these variables in aerobic circuit training in cardiac rehabilitation. The observation that a low-intensity/low-frequency program of endurance training of less than 1 to 2 days per week at less than 60% of VC^peak failed to confer either central or peripheral training effects in the LC group is consistent with other data. This group actually demonstrated a regression in fitness. It can be ruled out that this group did not perform sufficiently during testing due to motivational reasons, since their RER data indicated equal effort during all exercise tests. The observed central training effects in the two training groups may have been due to intrinsic cardiac adaptations (previously established in healthy populations). This finding is infrequently observed in other studies however, 115 due to technical limitations, testing in the supine position, failure to study exercise responses at multiple and higher submaximal workloads, and withdrawing patients' inotropic and chronotropic medications during testing. They however might also be due to changes in total peripheral resistance, catecholamines, changes in sympathetic tone, unknown effects of medications, or changes in blood volume. The fact that ST-segments failed decrease in the group which displayed the greatest central adaptations (WJ) despite significant improvements in many of the central cardiac function measures indicates that peripheral factors still form at least a significant proportion of the training effect, and as a result, is not possible to state conclusively that maximal myocardial oxygen consumption might have been favourably affected by the training regime. Transfer of fitness to the unexercised arms is demonstrated by the improvement in arm VC^peak, maximal workload, and ventilatory threshold in the WJ group for arm ergometry could also be accomplished through extra-cardiac alterations. Recent investigations in lactate kinetics suggests that the removal rate, buffering and oxidation of H+ in non-exercising but trained skeletal muscle, liver, heart and kidney might occur after training. This could also partially explain these findings. The failure to uncover decreases in submaximal HR for the untrained arms despite the other changes that indicate a transfer effect could have been due to the effect of Beta-adrenergic blockade and Ca^+-channel blocking drugs, which slow heart rate both at rest and at exercise, effectively masking these changes. Clearly, further research utilizing neurophysiologic, blood lactate, tracer studies, or NMR spectroscopy might shed further light on.these mechanisms in this population. 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The efforts to combat morbidity and mortality due to CAD have taken three basic identifiable directions in modern medicine; the basic scientific 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 interdisciplinary team approach to rehabilitation of CAD. This first area represents basic scientific laboratory-based investigations in the mechanism of the genesis and profliferation of the coronary atherosclerotic process (Gotleib, 1982) . Work in this area continues to strengthen the association of dietary constituents (Majno, et al., 1984, Eggen and Strong, 1987), psychoneurophysiological triggers (Lee, 1985), and neuro-endocrine influences (Sirek, 137 et al., 1978) in the initial arterial wall damage, followed by the gradual accumulation of atherosclerotic material in the coronary arteries. 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 infarction. Modalities of treatment utilized 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 latter have often been identified as major reasons for the observed decreases in short-term mortality from acute myocardial infarction over the past few decades. The third area of intensive research, and more frequently, practice, involves prevention of initial and reccurrent events through primary, secondary, and tertiary approaches (Froelicher and Brown, 1984), with the emphasis and techniques utilized being determined by the population under consideration. The main qualifying difference from the medical approaches is that prevention involves factors that can be actively altered by the individual, and that are related to "lifestyle" (ie., diet, stress, exercise). 138 Primary prevention is the attempt to prevent the disease process from initially establishing itself in the organism. This area, for example, involves pediatric screening for familial lipid abnormalities, an emphasis on physical activity during childhood, and propagating of positive health behaviours throughout early childhood and towards adulthood. Secondary prevention relates to slowing and perhaps halting the pathologic process already present, but which is still in a sub-clinical asymptomatic stage. Epidemiological investigation has convincingly documented the effect of diets low in fats and cholesterol and lifestyles which include > 2000 kcal/week of energy expenditure (either during work or purposeful leisure exercise pursuits) on subsequent development of symptomatic disease (Paffenbarger, 1986, Kannel, et al., 1986). Tertiary prevention has grown to be associated with rehabilitation after the sequlea of symptomatic disease, prevention of further progression of arterial occlusion, and most optimistically, reversal of CAD through a combination of dietary, psychological, medical, pharmacological, and health behaviour modifications. Although ideally cardiopulmonary rehabilitation (CPR) encompasses all these aspects in the achievement of a CAD patient's return to 139 productive life, it is the physiological effects of exercise training in this population which is currently undergoing major investigation, and which has formed the cornerstone of this investigation. To date, the long-term effects of exercise training on mortality and recurrance of myocardial infarction (MI) as studied by longitudinal trials have been generally dissapointing (Naughton, 1985) . Of the 7 trials that have been conducted, only one demonstrated a statistically significant decrease in recurrances in the exercise training group, but this was the only study which used a multifaceted approach (counselling, diet intervention, as well as exercise training) (Kallio, . 1979) . Most of the trials suffered from inadaquate sample sizes, poor control of the exercise stimulus, and cross-over of the controls to the exercise group. Nevertheless, there is a wealth of clinical and scientific information which contiues to overwhelmingly support the physiologic rationale for endurance (and more recently, upper body aerobic and resistance) training in patients recovering from MI, surgery, or with angina. It has been the understanding of the physiological adaptations which occur in both healthy humans as well as in animals with artificially-induced coronary occlusions after chronic endurance exercise training, where the rationale and 140 implimentation of graduated exercise training 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 is 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 physiological systems in parallel, and is best described by the Fick Conductance Equation: V02max = CO. X A-V02 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 divisions of the oxygen transport and utilization process; systems which serve to deliver O2, (central) and systems which serve to utilize O2 (peripheral). This model can be further divided into more complex components, summarized in order: 1. Ventilation ..mechanical exchange of O2 and CO2 with environment. Factors include pulmonary function, environmental content of O2 and C02• 2. Diffusion diffusion of O2 and CO2 across the alveolar membrane. 141 3. Chemical combination with Hb chemical reaction binding O2 and CO2 to red blood cells in association with hemoglobin Factors include hemoglobin, number of red blood cells, partial pressure of water, O2, CO2, acid-base balance, temperature, and iron stores. 4. Transport and Distribution cardiac performance, blood volume and hydration, sympathetic stimulation, regulation of distribution of cardiac output, total peripheral resistance, environmental temperatures. 5. Utilization factors include partial pressures of O2, CO2, myoglobin, mitochondrial number and oxidative enzyme levels, presence of fuels, number of cont ractile units, metabolic activity of contractile units, acid-base balance, extra and intracellular ion concentrations. It is clear that when a human being increases his or her activity level, all these systems must operate effectively, and in parallel so that ultimately, internal cellular homeostasis is achieved in the face of increases in metabolic rate upwards of twenty times that at rest. At the onset of exercise in the normal adult, interrelated 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 results in consistant and predictable physiological responses (Figure 7.1). Depending upon the initial fitness 142 level of the subject, the presence or absence of disease, anatominc limitations, genetic endowment, and age, subjecting an individual to this stress at frequent and regular periods constitutes habitual exposure, and will result in adaptations in most of the above systems for 02 transport and utilization. It is the extent, time frame, and parameters of this adaptation with which we are concerned and forms the basis for explorations in the benefits that CAD patients accrue from exercise training. 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 habitual exercise, profound changes occur in the untrained muscles which enables external work to be performed at generally less cost to the cardiovascular system. Clausen (1976) has examinined the relationship of the peripheral and central components to exercise, and determined that as exercise intensity increases, the peripheral resistance (TPR) declines. In addition the decline in peripheral resistance is inversely proportional to the maximal oxygen uptake (VC^max) and muscle mass size. As V02max increases, the heart rate at any given level of exercise decreases, and blood flow to that muscle decreases. But what are the specific adaptations that occur which explain these responses? Data from both morphological ultrastructural studies as well as biochemical and histological studies have demonstrated significant increases in capillarization (Parizkova et al., 1971, Hermansen and Wachtlova, 1971, and Brodal et al., 1977) after prolonged training in mostly slow-twitch fibres. Functionally, this provides greater surface area for exchange of Q>2, CO2/ free fatty acids, metabolites, lactate and fuels. Of perhaps greater significance are the adaptations in the cellular biochemical processes which produce ATP. Early 145 studies in animals (Holloszy, 1967, Bengi et al., 1975) and subsequently in humans (Gollnick and Sembrowich, 1977) have demonstrated the intracellular increases in mitochondrial mass, Electron Transport Chain co-enzymes, Krebs Cycle rate-limiting enzymes and isoenzymes, mitochondrial shuttle enzymes, and specific myosin-ATPase's in slow-twitch fibres. For a more complete review of the specific enzymes involved, the reader is referred to Holloszy's and Coyle's (1984) paper. The importance of the peripheral adaptations in the general training effect is profound in that not only is maximal capacity improved by these adaptations; the duration factor (the ability to perform prolonged submaximal exercise) is increased. This is accomplished by increasing the cell's capacity for fat metabolism, and thereby reducing the dependance upon the limited intramuscular and liver glycogen stores during exercise of 45 minutes or greater (Holloszy and Coyle, 1984). Exercise duration is improved additionally however by the complex interplay of the metabolic and cardiovascular responses after training. The classic response is a sympathetically-mediated decrease in muscle blood flow to the exercising and non-exercising tissue after training, essentially redistributing 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 training is outlined in Table 7.1. 147 Table 7.1 Cardiovascular Adaptations After Endurance Training Factor Rest Submaximal Peak Heart Rate Stroke Volume A-V02 Difference Cardiac Output V02 Work Capacity Systolic B.P. Diastolic B.P. Mean Arterial Pres. TPR Coronary Blood Flow Brain Blood Flow Visceral Blood Flow 0 Inactive Muscle B.F. 0 Active Muscle B.F. 0 -Skin Blood Flow 0 Blood Volume + Plasma Volume + Red Cell 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: + increase - decrease not applicable 0 no change Adapted from Brooks & Fahey, 1984, p. 326 148 Normal Cardiac Physiology: An Overview The heart muscle differs from skeletal muscle from histologic, metabolic and functional standpoints. These differences are . a manifestation of its challenging physiological requirements compared to skeletal muscle, which has the luxury of resting. The heart is a four-chambered organ; the right side, (right atrium and ventricle) providing pulmonary circulation, and the L. atrium and ventricles providing systemic circulation. Both atria are low-pressure reservoirs for venous and pulmonary venous return, and act more as primers for the ventricles. The ventricles are thicker muscled than their atria, with the left ventricle demonstrating a more developed hypertrophy and smaller chamber compared to the Right ventricle, which only requires a mean arterial pressure of 15 mm/Hg to pump the cardiac output through the low-resistance pulmonary circulation. Left ventricular pressures are typically 120 and 70 mm/Hg systolic and diastolic, respectfully. The myocardium is a versatile fuel user and myocardial fibres are well endowed with mitochondria. The substrates that it will oxidize are in proportion to their arterial concentration. Although the heart is unique in that lactate can be utilized as fuel, it cannot be metabolized when the 149 heart is hypoxic. In this case, the heart will break down glycogen. However, only 30 to 40% of the heart's oxygen consumption is derived from the oxidation of glucose, the rest comprising of esterified and non-esterified fatty acids (Katz, 1977, Berne and Levy, 1979). The myocardium's blood supply, the two coronary arteries, their branches and capillaries, deliver 200 ml/min at rest, and this can increase to as much as 900 ml/min at maximal exercise (Berne and Levy, 1981). Invasive studies in animals and in humans have demonstrated that coronary venous blood is almost fully desaturated at rest (about 5 volume %, that found at the level of skeletal muscle mitochondria at maximal exercise). The importance of this fact is that when the myocardial metabolic (O2) demands are increased, for example during exercise, further increases in myocardial O2 consumption must be met by increases in coronary flow. In the healthy myocardium, this is accomplished successfully by a combination of mechanisms: 1. Increases in aortic pressure 2. Variation in flow.during systole, diastole 3. Increases/decreases in coronary resistance with increasing/decreasing fibre metabolism 4. Increases in sympathetic firing 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 sited four main factors in the fundamental functioning of the heart. These are: 1. Afterload 2. Preload 3. Contractility 4. Heart Rate 1. Afterload Despite the fact that actual myocardial fibre shortening is responsible for the ventricular ejection of blood during systole, most of the myocardial oxygen consumption during the cardiac cycle is attributed to increases in pressure-work, as opposed to volume-work. An example of Pressure-work is when systolic blood pressure is 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 aortic pressure is overcome by ventricular pressure, and where ventricular pressure is overcome by aortic pressure, respectively. The amount of pressure work that the heart has to perform during systole is referred to as afterload, and can be estimated by calculating the total peripheral resistance (TPR) of aortic outflow by: TPR = M.A.P./CO. Where M.A.P. is mean arterial pressure, and CO. is Cardiac Output (Burton, 1972). 151 Afterload can be increased by structural abnormalities such as aortic outflow defects, or by increases in resistance in the periphery, such as vasoconstriction. Afterload can also be reduced by factors in the periphery, such as vasodilation. 2. Preload The amount and pressure of venous and pulmonary venous blood returning to the right and left ventricles respectfully, will dictate how much the chambers will stretch during diastole, how much potential energy will be stored in the myocardial fibres when they stretch, and finally, how much kinetic energy they will then contribute to systole. This effect was first demonstrated in isolated animal hearts preparations, and is well known as the Frank-Starling Law of the heart (Figure 7.2). When venous return is augmented, either by reinfusion of saline, increases in blood volume, or by venoconstriction in the periphery, the ventricles are stretched by the increased venous (right and left atrial) pressure, and the next beat will eject a greater stroke volume. 152 Figure 7.2 The Frank Starling Law of the Heart 20 40 GO Time-sec. As right atrial pressure (venous return is increased, left ventricular volume is increased (downward shift in top curve), leading to greater ventricular emptying upon systole. • From Berne and Levy, 1981, p 158. 153 This mechanism allows the heart to eject any volume that is delivered so that cardiac output is regulated between the two sides of the heart. It also utilizes the basic characteristics of myocardial fibres to generate force upon stretch, according to the length/tension relationship. Guyton, (1973) eloquently presents a series of curves which describe variations of venous return and the effects on cardiac output in normal and diseased hearts. These concepts have been regarded as basic to our understanding of cardiac performance in cardiac failure situations. The extent of cardiac filling and stretch is dependent upon factors which govern venous return (sympathetic and mechanically-induced venoconstriction), blood volume, and inherent distensibility of the cardiac chambers. Factors which can alter ventricular distensibility or compliance are age, myocardial calcium flux, heart rate, and extent of ventricular scaring (Katz, 1977). 3. Contractility During periods of increased metabolic activity, as found during exercise, the myocardium's contractility is increased primarily by increases in sympathetic firing. This process stimulates the adenylate cyclase system, altering calcium flux across the sarcolemal membrane (Katz, 1977) . Greater 154 calcium availability to the actual contraction machinery results in greater cross-bridge formation and greater contraction velocity, with the velocity a function of intracellular calcium concentration and the external load imposed upon the sarcomeres. Circulating catecholamines also augment this effect by increasing the permeability of calcium and therefore greater calcium inward flux during the plateau of the myocardial action potential. The sum effect is to enable the left ventricle to perform , more work for a given level of diastolic pressure (Figure 7.3). 155 Figure 7.3 Intrinsic Cardiac Contractility 60-Left Ventricular End Diastolic Pressure -cm.H20 Infusion of norepinepherine in the dog causes increased left ventricular performance due to enhanced contractility over control conditions. From Berne and Levy, 1981, p 161. 156 4. Heart Rate The frequency of cardiac contractions is a function of increased sympathetic activity to the sinoatrial node to increase firing rate. The metabolic requirements of the body will generally dictate the heart rate, and the heart rate in turn, will directly affect most of the heart's other performance determinants and oxygen consumption. The maximal heart rate possible is largely determined by age and present health, and to- a somewhat lesser extent, the state of physical fitness. Some important factors which take place during increases in heart rate are the reduction in the coronary flow period during the shortened diastole, and the impairment of cardiac filling during' diastole (Astrand, 1976) . Much work has been undertaken to delineate methods whereby the work of the heart, or more specifically, the oxygen consumption can be measured. The direct method is cardiac catheterization which is obviously invasive. However, more non-invasive methods have been used, which give close correlations to the direct methods, and utilize the above determinants of cardiac function. Gobel, et al. (1978) have demonstrated that the product of HR and systolic blood pressure (the Rate Pressure Product) is a reasonable 157 estimate of myocardial oxygen consumption (MVO2)• Nelson et al. (1974) found that the accuracy of using a blood pressure cuff or central aortic catheter for systolic blood pressure were equal when calculating RPP, producing correlations between invasive vs. non-invasive MVO2• of .85 and .88, respectfully. Other measures of cardiac function utilized to describe cardiac function are the end-systolic pressure/volume ratio (Sagawa, et al., 1977, Nivatpumin et al., 1979), and left ventricular stroke work, a product of left ventricular systolic 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 rise in anticipation of exercise, primarily mediated by cortical activity. Upon initiation of exercise, heart rate increases within 0.5 to 2 seconds, and rises in parallel to metabolic needs. Steady-state heart rates are achieved within 1 to 2 minutes. Stroke volume is larger, and close to maximal values at rest in the supine position, due to the lack of leg blood pooling effects found in the erect position. As a result, stroke volume will not increase appreciably with exercise in the supine position. In erect positions however, resting stroke volume values are smaller, but will increase at the onset of exercise. At lower intensities, stroke volume is the major determinant of cardiac output, increasing approximately 20% from resting values to peak values (70 to 90ml, respectively). Maximal levels of stroke volume are reached early in 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% in young subjects ( Shephard, 1984). After these percentages of maximum are reached, further increases in cardiac output must be achieved by increases in heart 159 rate, and to a large extent, by decreasing levels of peripheral resistance. It has been observed that stroke volume values are dependent upon the type of exercise and the total muscle mass utilized in the activity. The finding that maximal stroke volumes for arm ergometry < cycle ergometry < treadmill running is 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 is similar at rest and at submaximal levels of exercise between trained and untrained individuals, with resting values of 5.6 to 6.4 litres • min-1. Peak cardiac output values are typically 18 to 25 in healthy normals, and can reach 30 to 38 litres • min-1 at maximal exercise in elite 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 dissipation, and thus varies according to the individual's fitness level, state of hydration, and the environmental conditions. As exercise duration is extended, cardiac output remains essentially unchanged, but as more of the plasma volume is 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 in Normal Individuals after Habitual Exercise The questions concerning the limits and mechanisms surrounding central, or cardiac adaptations to chronic exercise training have intriqued exercise scientists for years. An additional argument of the relative importance of the roles of central vs. peripheral adaptation to exercise is still hotly contested, but with the utilization of more advanced non-invasive technologies (echocardiography, doppler, nuclear medicine), the answers are changing. Saltin, who has studied the cardiovascular response to exercise extensively, has convincingly reasoned that the central component is indeed (after the fast time-course in which peripheral changes have occurred), the limiting component to the adaptive response. It has been calculated that " the maximal level of perfusion of the muscle vascular bed, and thus the maximal oxygen uptake, may be centrally rather than peripherally limited at the level of the contracting muscles, [and that].. during exercise with 2 legs + 2 arms, an unreasonably high cardiac output of up to 70 litres • min-1 would be required to sustain perfusion" (Savard, et al., 1987). The investigators also demonstrated 161 that VC^max did not increase when arm work was added to already hard two-legged work. Thus in the healthy trained individual, it would seem that peripheral adaptations are already maximal, and further increases in maximum aerobic capacity must be accomplished by central cardiac changes. This is further suggested by Holloszy and Coyle, (1983) who present data indicating that over a wide range of VC^max values for recreational through to elite athletes, past a VC^max of around 50 ml'kg-1 •min--'-, mitochondrial citrate synthase levels are the same. Clearly then, the periphery does not explain entirely high levels of cardiorespiratory function. In an important paper, DeMaria (et al., 1978) demonstrated increases in left ventricular chamber diameters, stroke volume, wall thicknesses, and rates of fibre shortening using echocardiography in 24 subjects after 11 weeks of training 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 al., (1982) did not show increased systolic time intervals after a 6 month training program in males despite a 17% improvement in VC^max, cardiac output, and stroke volume improved. Nevertheless, it was the authors 162 conclusion that these changes were due to changes in preload, rather than actual structural or contractile adaptations to the myocardium. This result agrees with a more recent study, comparing very well trained vs. moderately trained runners (Crawford et al., 1985). The authors found increases in LVEDV at rest and at peak exercise, and ascribed these improvements to the fitter subjects ability to utilize the less-energy costing Frank-Starling mechanism to increase cardiac function, which could be simply due to increased venous return. Improvements in intrinsic cardiac function have been demonstrated in healthy middle-aged individuals as well (Martin et al., 1987). After 12 weeks of intense swim and circuit weight training, VC^max increased from 2 9 to 35 ml-kg-min-1, stroke volume increased 18%, and left ventricular diastolic 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 in intrinsic cardiac contractility. Barnard (et al., 1977), also studying middle-aged men, found that training resulted in favourable improvements in cardiac function, with post-training MVO2 requirements reduced by 18% vs. control subjects as measured by the tension-time index. The diastolic pressure time index was significantly 163 greater during exercise after training as well, inferring that myocardial O2 demand was reduced, effectively improving the supply/demand relationship of myocardial perfusion. It would seem then, that for healthy individuals without prior or present cardiac disease, the capacity for adaptations in the pumping ability of the left ventricle, as well as the capacity for simultaneous reductions in the work of the heart (MVO2) at any submaximal exercise load, is enhanced after endurance training. For an more complete review and summary of cardiac chamber changes in normals after exercise training, the reader is referred to Peronnet et al., (1981), and Dowell (1883) for details of proposed biochemical/cellular mechanisms. Cardiovascular Responses to Exercise in Patients with Coronary Artery Disease or Myocardial Infarction 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 in adverse environmental conditions. Since coronary oxygen extraction is almost maximal at rest as discussed above, the patient with coronary obstruction reaches a point of specific exercise intensity (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 in CAD will depend upon the extent of disease, the presence or absence of prior MI, state of aerobic conditioning, in addition to other more subtle factors. As illustrated in Figure 7.4, the CAD patient differs from the normal subject during maximal exercise testing in the following respects. A true VC^max and RER > 1.15 is rarely achieved due to premature termination of the test, caused by anginal symptoms of coronary insufficiency, associated electrocardiographic abnormalities, and reductions in muscle blood flow leading to anaerobiosis secondary to deteriorating cardiac function. (Dressendorfer et al., 1981, Taylor et al., 1963). A study by Roberts (et al., 1984) found that none of normal subjects, and only 8.6% of their CAD patients plateaued VO2 at the end of exercise tests. 165 Figure 7.4 Summary of Acute Exercise Responses in the Cardiac Patient Racing of Percieved Exertion or Absolute Workload 166 As a result, the maximal VO2 observed during exercise testing should be referred to as VC^peak as opposed to VC^max, which would imply that the patient reached a true physiological maximum. It is consequently not surprising that the changes in cardiovascular function accompaning increasing exercise loads differs in this group compared with healthy subjects. A normal increase in ejection fraction of 5% from rest to exercise as measured by radionuclide angiography has been demonstrated in healthy individuals. A failure to change, only slight increases, or a fall in LVEF can be demonstrated in CAD patients (Borer et al., 1977). Slutsky et al., (1979) attributes the fall in EF to increases in LVESV, indicating impairment of force generation and contractility. Iskandrian (et al., 1981) has observed however, that EF alone does not explain all the mechanisms of disturbances in cardiac function in the exercising CAD patient. They demonstrated a poor correlation between duration of exercise and resting EF. Gibbons et al., (1987) reports conversly that peak exercise EF is more indicative of overall cardiac function than other measures of L.V function such as systolic pressure/systolic volume ratios. There still remains the argument of which index of cardiac function(s) altered during exercise in CAD patients is 167 contributing to the abnormal exercise tolerances. Thompson et al., (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 in this parameter with exercise. As expected, submaximal cardiac output values were similar at rest, but the CAD group had lower values at peak exercise. The normal group increased their EF from 66 to 77% (rest to exercise), but the CAD group increased from 62 to only 67%. This study was unique in that it measured subjects in the supine position, where EDV is maximal, thereby leaving only HR as a mechanism for increasing CO. Iskandrian et al., (1981) found that increasing CO was accomplished by tachycardia, since there were insignificant changes in 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 inability of CAD patients to increase EDV, which could utilize the Frank-Starling mechanism to augment CO, could be due to regional myocardial necrosis (prior MI) restricting myocardial compliance, reducing stretch from venous return (Thompson et al., 1987) . This is further confirmed by recent increasing interest in left ventricular diastolic function as an equally important 168 variable in cardiac performance during exercise (Gibson, 1987). Thus, in summary, the CAD patient differs from the normal subject in terms of cardiac performance during exercise in several respects. Firstly, systolic function is impaired due to decrements in myocardial perfusion past a specific MVO2 corresponding to a specific external work load and VO2. Secondly, due to cardiac scarring from prior MI, or ischemia, diastolic function (and hence compliance) is compromised, minimizing the potential contribution of CO from the Frank-Starling mechanism. The net result is a decreased SV and EDV, and an elevated ESV during exercise. Maximum CO will be reduced. Other variables such as left ventricular stroke work and systolic pressure/systolic volume ratio will be reduced at any given level of exercise and at peak exercise. 169 Cardiac Rehabilitation-A Short Historical Perspective From an historical perspective, exercise therapy for patients with heart disease is a relatively new concept in medicine. The traditionally accepted treatment for a MI has until only the last few decades had been total bed rest. Typical treatment for the recovering cardiac patient is. best illustrated from a quotation from Lewis (1933, p.49); "The patient is to be guarded by day and night nursing and helped in every way to avoid voluntary movement of effort". After the myocardial scar had formed, the most a patient had to look forward to was a life of inactivity, which would often prematurely end a career and provoke damaging subsequent psychological problems. However, as early as the nineteen forties, the role of bed rest and chronic inactivity in the treatment of CAD began to change. It was noted by Heberden (1941) as early as 1941 that although he had .."little to advance.."for the treatment of angina he knew of one patient "who set himself a task of sawing wood for a half an hour every day and was nearly cured". Probably the first incentive for advocating activity during the recovery stage after MI was based upon the deleterious effects of bed rest on physiologicical processes and 17 0 functional capacity. This had of course been elucidated by exercise physiologists, in particular Saltin et al. (1968) who studied the effects of total bed rest on the waning of VC^max and the time course to gain it back with resumption of training. 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, Saltin et al., 1968). The resultant orthostatic hypotension produces tacycardia, which places further O2 demand on an already deconditioned and ischemic heart. Blood viscosity increases due to the decreased blood volume/RBC volume ratio, predisposing the patient to thromboembolism (Fareeduddin and Ableman, 1969). Additional changes also include decreased pulmonary ventilation and vital capacity, alterations in nitrogen balance, a 10 to 15% decrease in lean muscle mass after as early as 7 days, with parallel increases in VO2 for any given level of work. This latter effect also dangerously increases the MVO2 in the already compromised heart. Thus the beginnings of what is now commonly known as "Phase I" cardiac rehabilitation was set in motion. The more prophylactic applications of exercise, particularly endurance or aerobic exercise well after the discharge period after an MI (Today's Phase II and III) would take a few more years to develop. 171 Leaders such as Hellerstein in the mid-nineteen sixties were developing the connection between the epidemiology of physical activity in the prevention of CAD, and applying these concepts to secondary and tertiary prevention in individuals wishing to return to full and productive life. More important clinically, was the need to prevent further angina and recurrent MI (Hellerstein, et al., 1967). The London bus driver study by Morris et al., (1953, 1956) was also an important research landmark associating inactivity with increased risk of CAD. It was realized that the research pointing to some "protective effect" incurred by chronic exercise training in healthy individuals could be applied safely and effectively in CAD patients. These exercise effects 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 overall healthier lifestyle (ie., smoking cessation, stress management, dietary alterations). Many of these early principles are still routinely put to practice in the 1980's. Although many cardiac rehabilitation programs were initiated around the world, the Toronto Rehabilitation Centre is often recognized as one of the initiators and innovators of the field in North America. The use of walking, progressing to 172 jogging, and a scientific methodology of prescribing and monitoring patients' exercise programs was formulated, and produced initially impressive results. Kavanagh (et al., 1973) demonstrated increases in estimated VC^max from 27 to 38 ml•kg-1'min-1 and decreases in ST-segment depression with 2 years of exercise. A control group receiving only hypnotherapy did not demonstrate any of the beneficial adaptations. Kavanagh's Centre, and a selected group of exceptional patients amazed the world when they trained and successfully completed the Boston Marathon in 1975. These patients demonstrated an improvement in 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 al., 1977) . Ranges of values reported for peak oxygen uptake after endurance training in CAD and Post/Ml patients is summarized on Table 7.2. 173 Table 7.2 Initial Value and Change in VC^max After Exercise Training in Patients with CAD Source N, Hx VC^max Pre % change Duration (ml-- -k q ~ X: '.min "-*-) (months) Detry et al., 6 MI 27 18 3 1971 6 angina 19 31Redwood et al. 7 angina 10 56 1.6 1972 Ferguson 14 MI, CAD 22 25 13 et al., 1978 Conner et al., 6 MI 20 19 8-12 1976 Clausen & Trap-Jensen 25 angina 100 3 1970 Patterson et al., 37 MI (intense) 28 13 6 1979 42 MI (low int.) 28 -2 .6 Franklin 16 MI 24 13 3 et al., 1978 Hagberg et al. 11 MI, CAD 25 39 12 1983 Froelicher et al., 69 CAD + controls 33 -3 12 1984 59 CAD + exercise 33 18Adapted from: Thompson, P.D. 1988, p. 1539 174 More recent developments in cardiac rehabilitation include the greater variety in modes of activities for the upper and lower body and more advanced methods of prescription and patient education and motivation. However, the precise physiological mechanisms whereby the post-MI and CAD patient benefits from exercise are still hotly argued. The rationale for exercise for minimizing symptoms and reducing the psychological and pathological effects of the disease are confirmed. What is still not completely understood however, is the relationship between long-term participation after MI, and the subsequent fatal and non fatal re-infarction rate. Some research would suggest that exercise training for CAD patients is directly related to prevention of re-infarction however. Kanavagh, who has one of the largest ongoing patient data bases of any centre in the world has suggested that compliance with the exercise regimen was the most important single determinant of long-term prognosis (Kavanagh et al., 1979). The risk ratio for fatal and non fatal reinfarctions was 23.6 times higher for those patients who complied poorly, and the authors suggested that exercise was responsible for maintaining a positive behaviour towards other important risk factors such as smoking. A more recent study has demonstrated that simply the ability to 175 successfully complete a post-6 month exercise test with fewer ST-segment changes and normal blood pressure responses is associated with a significantly lower fatal and non-fatal recurrance rates (Stone et al., 1988). This would seem to indicate that exercise, resulting in the above effects in most cases, must have some favourable effect on mortality. Failure of some of the larger clinical trials to significantly demonstrate this effect was probably due to small sample sizes, statistical problems, and cross-over of the non-exercising control groups (Naughton, 1982). 176 Physiological Aspects of Exercise Training in CAD Patients; Generalized and Peripheral Effects. From the previous discussion on the training effects which occur after a period of chronic endurance exercise in healthy individuals, it is apparent that many of these principles apply to the CAD/post-MI patient as well. The early studies which examined the effects of exercise training in this population were revealing, but crude statistically and technically, but nevertheless, formed the basis for later investigations. Varnauskas (et al., 1966) investigated 9 patients after only 1 month of training and measured A-VO2 differences and CO using the Direct Fick method before and after training. Although the exercise testing was submaximal, the authors demonstrated an increase in anginal threshold, A-VO2 difference, with decreased lactate production, no change in CO and VO2.. The anginal threshold is, and will be defined in the remainder of this 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 this study, and many similar early studies are characterized by the short study periods and relative lack of precision in calculating the exercise prescription and exercise stimulis. 177 Figure 7.5 Exercise Training and Increased Functional Capacity in Cardiac Patients The raising of the ischemic threshold by increasing VC^peak via peripheral adaptations, (Lowered MVO2 [dashed line], postponing angina. Postulated increases in maximal MVO2 by intrinsic changes in cardiac vascularity (circled line) would further increase VC^peak to VC^max. 178 It has been previously mentioned that non-invasive indicies of myocardial 02 demand (RPP, TTI) can be utilized to predict actual MVO2 with surprising reliability. This has been utilized extensively in the classic research, and was demonstrated in the reductions of submaximal work RPP found by Frick et al. (1968), Kasch et al. (1969), Clausen et al., (1970), Detry et al., (1971), Redwood et al., (1972), and others (Table 7.3). Frick and co-workers found reductions in TTI at the same absolute level of work from 5.17 to 4.38 x 10~3, and similar changes for RPP in 7 patients. Kasch et al., (1969) were' able to demonstrate resting as well as exercise reductions in RPP in 11 patients. In a well quoted and comprehensive study, Clausen et al., (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 similar pattern to CO (reductions of 15%), indicating that the patients were able to more effectively redistribute the CO during exercise, thus reducing the work of the heart. Further studies by Clausen et al. (1969), with very little control over the exercise intensity ("adjusted individually according to the working capacity of each patient") were able to demonstrate lower systolic blood pressure at the 179 same submaximal workloads, with a 34% improvement in functional capacity as tested on cycle ergometers. 180 Table 7.3 Indirect Indicies of Myocardial Oxygen Demand Before and After Physical Conditioning by Male Coronary Heart Disease Patients Study Index Rest Exercise Intensity pre post pre post Redwood et al. TP 4300 3521 Submax WL 1972 4300 4885 Angina start Frick, Katila TTI 2519 2941 5161 4382 Submax WL 1968 RPP 103 107 262 242 Submax WL Clausen et al. TTI 2470 2380 3943 3393 Submax WL 1973 RPP — — 204 166 Submax WL Hellerstein RPP 248 193 Submax WL et al., 1967 Detry, et al., RPP 81 64 116 94 45% of pre-1971 V02max 166 137 75% of pre-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: Triple Product (HR x SBP X Ejection Time) TTI: Tension-Time Index (area under systolic pressure curve x HR) RPP: Rate Pressure Product (HR x SBP X 10 z) Adapted From: Haskell, W., 1977, p. 352 181 Sanne in 1973, utilized a large control and exercise group in the experimental design, and found the classic responses to exercise training (reduced HR 10 to 24 bpm, reduced SBP at submaximal workloads, and increased work capacity). The interesting aspect of this study is not only the inclusion 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 application of varying levels of intensity, frequency and duration in the exercise prescription, as shall be discussed in further sections, might be the limiting factor in the potential physiological adaptations which can occur in this popuation. Although the ability for CAD and post-MI patients to show improvements in functional capacity (and indirect benefits to the myocardium) after exercise training of varying lengths and intensities can be demonstrated, the exact cause of these adaptations has become an important research and clinical issue. In most of the earlier literature, peripheral mechanisms have been primarily implicated, with some or questionable involvement of central or cardiac function. Detry et al., (1971) implied that peripheral adaptations were responsible for the 23% increases in VC^max, reductions in RPP and HR at given absolute workloads. However, the 182 bradycardia at rest and exercise was compensated for not by increases in SV, as would be found in normal populations, but increases oxygen extraction at the tissues (A-VO2 difference). The authors thus concluded that increased capacity for exercise after training was a result of primarily increased arterial 02 content (increased Hb and blood volume) and peripheral 02 extraction. Their patients trained 3 times per week for 3 months, 45 min/session. Sim and Neill (1974), utilizing a similar training protocol with their 9 patients found increases in maximal RPP, TTI, and anginal threshold, with parallel decreases in indirect indicies of myocardial 02 consumption during submaximal work. Although MV02 was reduced at rest, this change was non-significant, as were changes in coronary A-V02 difference and some cardiac volumes. When cardiac pacing was performed however, there was no change in RPP, which the authors concluded, pointed to no intrinsic changes in cardiac function or blood supply due to exercise training. This was reinforced by Detry and Bruce (1971) in a study with 11 patients who trained for 3 months, 3 days/week. Although V02max increased 21%, and complementary changes in submaximal RPP and ST-segments, ST-segment depression still occurred at the same HR, (and presumably the same MV02) after training. This finding prompted the authors to conclude that submaximal changes are a function of 183 peripherally altered hemodynamics and increased O2 extraction, and the failure to increase the threshold for ST-changes indicated that myocardial circulation or function does not change with exercise training. This same conclusion was proposed by other investigators (Raffo et al., 1980, Myers et al., 1984), who found submaximal changes in ST-segment depression, but no changes in maximal HR ST-segment depression which would have supported actual increases in myocardial O2 consumption (and hence, cardiac circulation) after training. It is worthy of mention however, that these two studies were characterized by low training intensities (approximately 60% of HR reserve, using Karvonen's (1956) method). The evidence for the predominant nature of the peripheral training effect was further supported by a study by Ogawa et al. (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 in post-exercise hyperemia and limb blood flow during hand and ankle exercise. VC^max increased significantly (9.4 to 12.4 METs), and resting and exercise calf blood flow decreased significantly in the trained legs, but not in the arms, as did other parameters ("flow debt", peak and total active hyperemic blood flow). This study demonstrated the importance of peripheral (biochemical and 184 capillarization) effects of training, in addition to the specificity concept. Although these studies have implied peripheral changes in the dominance of the training effects in the CAD and post-MI patient, none had actually demonstrated histological and biochemical alterations in the trained muscle. Only one study to date has verified the peripheral effects with muscle biopsy techniques in the CAD patient. Ferguson and Taylor (1982) studied 26 MI/CAD patients after 6 months of training at an intensity equivalent to their anginal threshold, one hour, 3 sessions/week. The patients increased VC^max by 41%, and demonstrated the expected changes in submaximal HR, RPP and catecholamines. Muscle biopsy data revealed significant increases in succinate dehydrogenase activity (1.75 to 3.31 IU) and percentage of type I fibres (43.6 to 54.3%). The authors also demonstrated small but suggestive changes in cardiac indicies. These included an 8% increase in coronary sinus blood flow and MVO2 (11%). These adaptations were not correlated with the muscle biochemical changes, but curiously, were similar in proportion to those observed in highly trained endurance athletes. The results of this study indicated still a preponderance of the periphery as the mediator of the training effect, but with some indication of central involvement. 185 Maximal Oxygen Consumption and Alternate Variables to Measure Functional Capacity in CAD Patients It is clear from the literature that the "gold standard" in the measurement of maximal functional capacity has been the maximal oxygen consumption (V02n\ax) , either measured in 1. min-1, ml-kg-1-min-1 or METs (1 MET = 3.5 ml-kg-1-min-1) . Most patients cannot attain a true physiologically defined V02max because of failure to achieve the previously discussed physiological markers. One increasingly popular, as well as clinically and physiologically appealing alternative to relying solely upon V02max when interpreting the magnitude of cardiorespiratory fitness is the Ventilatory Threshold (VT), also referred to as the "anaerobic threshold" (Wasserman and Mcllroy, 1964, Wasserman et al., 1973, Sullivan et al., 1985, Skinner and McLellan, 1980). The VT is controversial because of its name, detection patterns and the underlying physiological mechanisms. Traditionally, the abrupt increase in minute ventilation (VE) with increasing VO2 has been ascribed to the HCO-^ buffering of increased H+ ion levels as the work rate exceeds that which can be accomplished entirely aerobically (Wasserman et al., 1973). The debate continues whether there is a point where muscle O2 supply is diminished, 186 leading to anaerobic metabolism and lactate output (Davis et al., 1976), versus the notion that 02 delivery is maximal at maximal exercise, lactate is present even at rest, and that lactate accumulation is simply a function of varying rates of lactate disapparance versus lactate formation (Donovan and Brooks, 1983). In any case, the parameter is a fairly reproducible physiological event, regardless of its mechanism, and can be used to modify exercise prescriptions based entirely on the "percentage of maximum" values, which can not entirely account for differences in effort (Katch et al., 1978). VT values are commonly reported as abrupt changes in several ventilatory parameters occurring at either percentages of VC^max or at specific VC^/HR/Workload values. Elite athletes have VT's of up to 85% of VC^max, indicating very high sustainable steady-state exercise capacities (Kinderman et al., 1979). Symptomatic cardiac patients, even with low fitness levels have VT's at high percentages (65 to 80%) of VC^max, (Roberts et al., 1984) and high percentages of HRmax. This is because chronotropic medications can shift the relationship of HR to workload. In addition, due to premature termination of the test, the VT can occur at a "high" percentage of maximum. The VT has been shown to shift to the right with increases in training in athletes and healthly normals (Kinderman et al., 1979, Davis et al., 1979), even if only slight changes in VC^max have occurred. 187 Only one study has compared the change in the VT with training in CAD patients. As part of a much larger trial, Sullivan et al., (1985) followed a control and exercise group (1 year training at 60 to 85% peak workload). Although there was no increase in VT (using the VE/V02 ventilatory equivalent for O2 parameter), there was as small correlation between the change in V02max and change in VT. This study however, included patients who demonstrated poor compliance and hence, a limited training effect. 188 Cardiac Adaptation and Exercise Training in Cardiac Patients It has"been demonstrated in previous chapters that cardiac morphologic and functional changes can be expected after a period of chronic endurance training in the healthy adult. Whether this can be demonstrated in cardiac patients is still under debate. The most compelling evidence for cardiac adaptations with exercise superimposed upon cardiac disease seems to come from the animal literature, and some early anecdotal human observations, namely relating 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 in the early part of the century, and examined his coronary anatomy after his death from cancer. The diameter of his main coronary branches were more than twice that of a typical non-trained male. Conclusions were put forth that it was this habitual training that resulted in the large coronary lumen, which must have provided greater coronary flow and resultant cardiac output. However, as we realize now, his coronary size could have been simply inherited, and the sample size was ineffective in generalizing to the population. An equally alluring study by Eckstein (1957) gave rise to 189 the concept of collateralization resulting from chronic ischemia. His animals were sacrificed after artificial coronary ligation, and casts of the coronary tree revealed increased coronary collateral proliferation. Unfortunately, there was no control group in the study design, and the separation of collateralization due to ischemia alone or ischemia plus exercise could not be evaluated. Caryle et al., (1981) found that there was an exercise-induced reduction of rat myocardial infarction size after artificially occluding the coronary arteries. The exercised rats had significantly increased capillary/fibre ratios compared to the control animals, and the MI size after the training period (60 minutes swimming, 5 days/week for 5 weeks) was 30% less than in the control rats. One problem in the study is that the suddenly induced coronary occlusion in these animals might in fact differ from the slowly developing atherosclerotic process in the human model. Nevertheless, it provided a model for the protective effects of exercise on the heart. A later study by Cohen et al., (1982) reproduced Eckstein's original study, but this time with more experimental controls, and , with the inclusion of an exercise intervention. The results demonstrated similar trends towards improved intrinsic cardiac function and vascularity after exercise training. 190 In a 5 year study, the components of diet and exercise were separated in an attempt to uncover the atherosclerotic process in the coronary arteries (Kramsch et al., 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 effects of a subsequently high fat diet (experimentally inducing atherosclerosis) resulted in coronary occlusion. The authors thus concluded that relying upon dietary changes without exercise would be less effective in attempting to control the coronary occlusive process. The benefits of using primates in the experimental design was that they more closely patterned the human biological and physiological model than rodents or canines. The work in this area of animal research is extensive, and beyond the scope of this short summary, and thus the reader is referred to two excellent review articles which comprehensively cover this aspect of exercise and the heart in animal research (Cohen, 1983, Dowell, 1983). Mention of some of the more outstanding papers in this area however, is important in understanding the related work in 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 directly from autopsy, but only estimated in humans. Furthermore, the exercise intensities administered to animals represents impossible equivalent work for humans to accomplish. This probably has enhanced the collateralization effect found in animals, and is possibly responsible for the equivocal findings in the human cardiac population, where the exercise stimulus is much reduced. Furthermore, confounding factors such as environment, diet, and behaviour can be effectively eliminated in animal research. Nevertheless, there is a growing body of literature, which has attempted to demonstrate an intrinsic . cardiac adaptation resulting from exercise training in the MI and CAD patient, independant from the previously demonstrated peripheral effects. Even before exercise training is initiated (approximately 6-8 weeks after the uncomplicated recovery from MI) , the myocardium undergoes a spontaneous improvement in function. Wohl (et al., 1977) indicated that left ventricular function improved gradually and then stabilized over the ensuing months as the myocardium heals. Obviously then, research attempting to document changes in LV function as a result of exercise training should begin only after this process is completed. Studies that fail to take this spontaneous 192 recovery effect into account could erroneously suggest improvements in LV function. The importance of improving the functional capacity by central, in addition to peripheral mechanisms, is not only important to determine for scientific curiosity purposes, but it also holds important prognostic implications for CAD and post-MI patients. White et al., (1984) in a study following 605 post-MI patients found that cardiac function indicies (LVESV, LVEDV, LVEF) were reliable and valid 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 relationship between cardiac performance and overall prognosis. The key question which needs to be addressed scientifically, is, whether after a MI the viable remaining human myocardium can demonstrate biochemical changes similar to that found in skeletal muscle when it is trained. Obviously, in the human model these changes can be only demonstrated non-invasively (radionuclide angiograms), or implied from indirect measures, such as symptomatology and ECG changes at peak or submaximal exercise loads. If in fact the heart muscle can develop increased activity 193 of aerobic enzymes and/or increased vascularity, this would theoretically reduce myocardial ischemia, probably not by recanalization of the existing atherosclerotic lesion, but by increasing the myocardial oxygen uptake in the viable remaining myocardium, this would effectively reduce the effect of the existing fixed narrowing. The "Bassler Hypothesis", first boldly put forth by pathologist Thomas Bassler in the mid- 1970's (Bassler, 1977) implied that marathoning (ie., the training neccessary to complete a marathon) would provide immunity to CAD. This hypothesis has been challenged now, even by pro-exercise cardiologists and physiologists, because of the many fit marathoners who have gone on to develop CAD or die suddenly from MI. Nevertheless, the cardiac hypothesis, particularly the collateralization theory has many applications for the training cardiac patient and the apparently healthy middle aged male. Figure 7.5 (above) summarizes the effects of chronic endurance training on the anginal threshold in cardiac patients. Froelicher lists some of the postulated cardiac mechanisms which could account for any benefit and reduced morbidity and mortality from CAD/MI in Table 7.4. 194 Table 7.4 Factors Affecting Cardiac Morbidity and Mortality Postulated Cardiac Mechanisms 1. Myocardial hypertrophy 2. Myocardial Histologic changes 3. Increased Coronary Artery Size 4. Coronary Collateral Circulatory Effects 5. Effects on Cardiac Performance (Peripherally Mediated) 6. Changes in Mitochondrial Enzymes 7. Effects of Fibrinolytic Alterations in Cardiac Function (From Froelicher, 1977) 195 The literature documenting cardiac effects of exercise training in CAD patients is varied in its methodologies, findings, and conclusions. Depending upon the sample size, training intensities, duration of training, and method of determining cardiac function, different conclusions can be made. In 1973, Rousseau et al., attempted to separate the contributions of central and peripheral adaptations in 14 post-MI patients. Although the trained group of patients had higher A-V02 differences (16.1 vs. 14.4 ml/100 ml), indicating a peripheral effect, SV decreased in both groups after 65% of VC^max. Stroke volume was not different at rest or exercise between the trained and untrained group, leading the investigators to determine that increased VC^max was a result of a widening of the A-VO2 difference, and that training effects were a manifestation of greater O2 extraction by the working muscles, and a more efficient redistribution of the CO. Two studies in 1976 were notable in that they utilized invasive catheterization to attempt to demonstrated changes in collateralization with exercise training. Due to the nature of the methodology, the sample sizes were small, and both failed to detect any collateralization effect or reduction in the size and involvement of atherosclerosis, 196 thus conflicting with the favorable reports in the animal literature (Conner et al., 1976, Kennedy et al., 1976). The training intensities utilized in the study were the standard 70% of VC^max, 3 days/week for 6 to 9 months. Although another direct catheterization study also yielded dissapointing results (increased workload by 17%, decreased RPP at submaximal work levels by 16%, but no change in LVEF from 45% to 44%) , the authors conceeded that the training stimulus might have been inadequate to induce cardiac adaptations (Letac et al., 1978). Ferguson et al., (1978) also discounted cardiac effects by measuring coronary sinus blood flows (CSBF) after 6 months of training in 10 Post-MI patients. Despite expected peripheral changes, CSBF and MV02 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 in MVO2 and CSBF were due to the peripherally-mediated effects. Nolewajka and Kostuk in 197 9 using the first reported application of nuclear medicine techniques (albumen-labeled Tc99ni) ^n cardiac rehabilitation research demonstrated no evidence for collateral development after injecting the tracer into the right and left coronary arteries. The advantages of this relatively non-invasive method of 197 investigation can be applied to the circulation, studies of generalized myocardial perfusion, or dynamic cardiac function. Consequently, it is not surprising that the earlier studies utilizing 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 yield more positive findings. Paterson et al., (1979) used the CO2 re-breathing Fick principle to determine cardiac changes after 6 and then 12 months of exercise training as part of the Ontario Collaborative Heart Study. The study design utilized a high and low intensity group (HIE and LIE, respectively). Athough the HIE group improved V02max from 2 6 to 30.3 ml-kg-1•min-1, there was no change in SV up to the 6 month period. After 6 months however, there was only a modest 10% increase in SV, leading the investigators to side with the peripheral effects and lowered sympathetic drive as the major determinants of the training effect. A later report (Oldridge et al., 1985) followed the Collaborative Heart Study patients for 4 additional years and did demonstrate a 16% increase in SV, but only at submaximal work loads. Two initially well quoted studies appeared in the same year using Thallium-201 and gated blood pool imaging techniques to uncover central training effects. The study by Froelicher (et al., 1980) utilized an interval program and trained the 198 arms and legs for 6 months. The training intensity was "60 -85% VC^max". Peak ejection fraction improved a modest 6%. Jensen et al., (1980) in a similar study converted the training from the interval scheme above to continuous walking/jogging at month 3. Resting LVEF increased significantly from 55 to 59%, but there was no change in peak LVEF. Their patients were able to increase peak RPP, but without changes in submaximal RPP. The authors found some subtle changes in Thallium scores, but the data is probably too subjective in nature to determine if increased vascularity had occurred. In contrast to these early suggestive results, Verani (et al., 1981) found no changes in LV function at submaximal loads despite an increased resting EF after 3 months of training and a 17% increase in VC^max. Ejection fractions were determined by the sometimes variable first-pass method. Similarly, Cobb (et al., 1982) found no changes in LVEF at rest, submaximal or maximal work rates after a 3 day/week, 6 month program. These patients trained at an intensity of 75 to 85% of symptom-limited VC^max. Hung et al., (1984) included a control group in the design, and the training group conducted the exercise program at home, which was monitored by telephone calls. Although the trained group increased MET's, and demonstrated the usual submaximal training adaptations, LVEF and Thallium scores were unchanged. The control group actually demonstrated the 199 greatest absolute changes in cardiac parameters, causing the investigators to conclude that home programs effectively improve functional capacity, but that this is due to mainly peripheral effects. Foster et al., (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 levels. Both the control and exercise groups increased their functional capacities. There were also no changes in LVEF with the training program for any level of metabolic stress. Other methods of determining cardiac alterations in function and structure from exercise have been applied to the cardiac patient with generally less conclusive results. Ditchey et al., (1981) using echocardiography, found no improvements in LV wall thickness or chamber dimensions, but the authors reported only a 21% gain in aerobic capacity. Vanhees et al., (1984) however used 2-d echocardiography also to assess cardiac changes in 20 combined CAD/Post-MI patients. They trained for only 3 months, 75 min/session 3 days/week, and utilized the upper and lower extremities. The authors state that the training intensity range was between 70 - 90% of functional capacity. Peak VO2 increased from 1.67 to 2.30 l-min-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 contractility. There was however no significant increase in LV internal diameter in systole, indicating no changes in preload. There was a significant correlation between the change in LV wall thickness and VC^max, which led to the conclusion that myocardial hypertrophy did occur, and was related to afterload. Unfortunately, other indicies of afterload were not accounted for in this study. A study by Williams et al., (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 in submaximal LVEF at workloads equal to the pretraining maximal workload (50 to 54%) , but there were no changes in resting or maximal LVEF. One significant finding however was an inverse relationship between submaximal HR and LVEF; as the HR is reduced at any given level of work post-training, LVEF is increased. In the case of other volumes, there were no significant changes• in both LVEDV and LVESV, although these variables displayed indications of change. Hindman and Wallace (1981) presented some impressive data which would indicate a definite cardiac effect of endurance training in CAD patients. All parameters were significantly increased; LVEDV: 177 to 194 ml, SV: 93 to 100 ml at 201 submaximal levels exercise. The data should be viewed with caution however, due - to the small sample size, and the failure to compare these variables to those which could artificially change them, namely changes in 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 al. (1984). One-hundred and forty-six males were randomized to two levels of training intensity. The higher intensity 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 controlled the statistical aspects of the study by utilizing analysis of covariance, and retaining drop-outs from the exercise group for analysis. Results indicated that indicies of aerobic fitness had improved; increases in V02max of 18% versus -3% for control patients, decreases in submaximal RPP and increased maximal RPP. Thallium scores improved only in patients with angina, but not in 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 rely less on the 202 Frank-Starling mechanism. This was suggested by less change (tendency to increase) in LVEDV. This study was interesting in that the study design and statisical controls should not have biased the results. However, there were a few weaknesses which could have limited the potential change for cardiac alterations. Firstly, all RNA measurements were made in the supine position, which would have attenuated increases in SV and possibly LVEF more than if they were measured in the erect position. Secondly, the training intensity might have been too low for cardiac changes, despite the study period consisting of one year. Thirdly, although this is overtly stated in . the results, inclusion of drop-outs from the trained group would have seriously contributed to type II errors. It is clear from the preceeding literature that although attempts to demonstrate a. clear cardiac effect from endurance training have been undertaken utilizing various interventions, the physical position of the patient during testing, the appropriate controls for systemic resistance, and the actual intensity stimulis of exercise (normally attenuated traditionally for the sake of safety) have not been addressed sufficiently to make conclusive statements regarding the presence or absence of adaptations. Table 7.5 203 lists some of the reasons investigators might have failed to uncover these changes after exercise training. 204 Table 7.5 Reasons for Failure to Identify Intrinic Cardiac Adaptations after Exercise Training 1. Insensitivity of standard radiopaque dye techniques to identify collateral proliferation in humans 2. Failure to identify specific changes in collaterization using radionuclide imaging techniques in humans 3. Insufficient exercise training frequency 4. Insufficient exercise training intensity (or exercise training occurring at low percent of true maximum due to symptom-limited maximum) 5. Insufficient exercise training duration 6. Failure to differentiate between vascular and biochemical myocardial cellular adaptations 7. The rate and extent of peripheral adaptations outstrip or mitigate possible central changes 8. Technical and statistical problems associated with human experimentation 9. The confounding effects of simultaneous pharmacological interventions affecting training 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 controlled for these deficiencies, altering the assumptions of training stimuli which Post-MI patients can tolerate, with impressive results. Siconolfi et al., (1984) found a large increase in VC^max after training in 14 patients, but the expected drop in total peripheral resistance was not correlated to improvements in VC^max (r = -.23), which indicated that peripheral effects are not always the important variable the other studies have shown, and that some proportion of cardiac involvement must take place in the average medically stable patient. In a landmark study, which was followed by a series of progressive studies, Ehsani et al., (1981) instituted a departure from the traditionally conservative training programs of other workers (excepting work by Blessey et al., 1981, and Kavanagh et al., 1974), who trained post-MI marathoners, with impressive results). The authors exercised the patients at the usually recommended intensities of 60 to 75% of maximal VO2 or 75 to 85% of HRmax for the first three months (Fardy, 1977, Fox et al., 1972, Pollock, 1973, and Zohman, 1970). From the 4th to the 12th month however, the training 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 effect of this training was to increase RPPmax from 24.9 to 29.8 and VC^max 38%. The patients increased their ischemic threshold from 119 to 138 bpm, and systolic blood pressure from 164 to 173 mmHg. The level of ST-segment depression was significantly altered both at maximal exercise and at submaximal levels, indicating that the myocardial 02 comsumption had increased. Obviously, the departure from the other studies which did not display such clear adaptation was that both prolonged and intense r training was employed. The authors also demonstrated concommitant changes in echocardiographic LV mass and LVEDV index. Although Laslett et al., (1985) also demonstrated similar changes in 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 if the above initial changes in echocardiographic indicies of 'myocardial adaptation were incorrectly implied by changes in systemic resistance. They compared the velocity of circumferential fibre shortening against various arm 207 isometric voluntary contractions at graded percentages of maximum (MVC). In this group of patients, the increase in VC^max was 42%, and the patients trained similarly to the previous study. In the trained group, the slowing of fibre shortening was not attenuated after training even at high percentages of MVC, with the control group demonstrating a progressive erosion of fibre shortening velocity as systemic resistance from the isometric contractions increased. A subsequent study from the same centre (Hagberg et al., 1983) measured CO and SV with CO2 re-breathing methods in a group of selected post-MI patients after the same intense training program. V02max increased 39% and resting 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 in stroke volume had occurred (16% increase). In addition, mean arterial pressure remained unchanged, leading to the conclusion that increases in SV were actually a result of improved cardiac contractility, 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 al., 1979). Additional research from this team, utilizing again the same intense exercise protocol has also demonstrated significantly increased systolic time intervals (Martin et 208 al., 1984), and greatly attenuated catecholamine response at submaxinal exercise (epinepherine from 209 to 132 pg/ml), and augmented levels at peak exercise (norepinepherine from 2049 to 3408 pg/ml) post-training. This effect acts, as the authors concluded, to lower the myocardial 02 requirements, and might even reduce the myocardium's irritability and hence tendency towards arrhythmias at high exertion levels. The most recent and perhaps most exciting research from this group is that which has utilized the combination of this intense exercise stimulis with radionuclide techniques (Ehsani et al., 1986). The same study design as before was applied to 25 post-MI patients for one year, yielding a 37% improvement in VC^max. Although no changes in resting EF were found, at exercise, there was an upward and left shift in the relationship between systolic blood pressure - and ESV and LVEF vs. RPP, indicating evidence for intrinsic cardiac contractile function. The authors were also able to demonstrate however, an additional but small contribution of the Frank Starling mechanism to the overall adaptation by the upward and right shift of the relationship of LV stroke work versus LVEDV during the transition from rest to exercise. These findings were in addition to expected increases in the parameters which would indicate that peripheral changes had resulted 209 (reduced HR and RPP at equivalent submaximal workloads after training). This confirmation of the intrinsic 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 al., 1987). The intense training program in this study resulted in a 41% increase in VC^max, with associated peripheral adaptations. These patients were able to increase their peak SBP from 162 to 174 mmHg after training at a higher HR (132 to 157 bpm). Peak EF increased from 52.4 to 56.2% despite this 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 in TPR at peak exercise, but the authors conclude that this inevitable decrease in systemic resistance was minimal compared to the increase in the overall increases in afterload. This last series of studies can be summarized appropriately by stating that in addition to the uncontested peripheral adaptations which probably still account for the predominance of the training effect in this population, under conditions of high exercise volumes and intensities, 210 significant alterations in cardiac contractility and function can be demonstrated in selected patients. The application of extreme exercise intensities however is controversial. Data from Hossack and Hartwig (1982) tentatively indicates that patients who exceed the 85% intensity level experience a greater rate of cardiac events during exercise than those who maintain themselves within the "training range". We have however, already discussed the possible myth of the relative percent concept and the utilization of the ventilatory threshold to individually prescribe exercise intensity. Obviously, this question has to yet be adequately answered. The additional argument which can be advanced with regard to the intense training and the impressive results is that the generalizability to the average cardiac patient is limited. 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 histological mechanisms responsible for these effects has not been uncovered, and probably will not be until better technologies are available to non-invasively determine cardiac biochemistry and vascularity. Promising areas include digital subtraction coronary angiography and nuclear magnetic resonance cardiac spectra analysis. 211 Upper Extremity Exercise Training in Cardiac Rehabilitation Traditionally, the mode of training 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 its af fordability, ease of learning, convenience, and favorable acute and chronic physiological effects (Kavanagh et al., 1973). It was generally accepted at the time that upper extremity exercise would raise systemic resistance and increase myocardial O2 demand, especially in tasks with large isometric components. However as early as the mid-nineteen seventies, investigators were already questioning the avoidance of arm exercise in the complete rehabilitation of the CAD patient. Hellerstein (1977) pointed out that although walking/jogging provides a beneficial generalized training effect, accomplishing the sought after physiological and metabolic adaptations, it has limited value in the rehabilitation of patients for a majority of occupations which rely on upper extremity fitness; because of the high degree of the specificity of fitness, the training effect of lowering MVO2 for a given amount of leg work would not be transfered to the arms, provoking ischemia during arm efforts in a "trained" patient (Fardy et al., 1977). Studies undertaken to actually measure the isometric 212 component of upper extremity exercise have found less isometric and cardiac 02 costs associated with these activities than previously thought (DeBusk et al., 1978). Magder et al., (1981) tested 8 post-MI patients with both cycle and swim-tethered maximal graded tests without significant differences in ischemic responses. Maximal HR for the swim test reached 87 to 89% of the cycle test. Kelemen et al., (1986) compared the physiological responses of 10 weeks of circuit weight training in an exercise group to a control group of patients receiving only volleyball and light walking and jogging. Both maximal single repetition strength as well as treadmill time was improved in the circuit group, which indicated not only a strength gain, but an unexpected gain in aerobic capacity due to circuit weight training. The authors concluded that this form of exercise rehabilitation is not only safer than previously thought, but might be more specific to certain patients than endurance training alone. The efficacy of the aerobic circuit training method, which utilizes several linked "stations" of endurance activities (rowing, cycle and arm ergometry, ball throwing, walking/jogging, and arm pulleys) was assessed by LaFontaine et al., (1987). Maximal 02 uptake was estimated by the Bruce test in 31 CABG patients after 12 weeks of training which consisted of various activities for 25 to 60 minutes per 213 session, 3 days/week. The authors found improvements in aerobic capacity equal to more traditional single mode programs; resting HR was reduced from 67 to 61.5 bpm, and aerobic capacity increased from 7.3 to 12.2 MET's. Wrisley et al., (1983) followed 13 patients for 6 weeks, with training consisting of 5 sessions/week of 30 minutes at 60 to 80% of VC^max. Both upper and lower extremity training modes were incorporated in the training program. Patients were able to increase cycle VC^max by 11%, and arm crank VC^max 13%, leading the authors to conclude that this form of multi-mode circuit training was as effective in producing favourable physiological training effects as leg training alone. Thus the programs which balance the exercise training over the whole musculature have been tentatively found to result in favourable physiological adaptations similar to that found with other single modes of endurance training. In addition, other advantages of reducing the emphasis of lower extremity exercise training not usually mentioned, relate to the patient with lower extremity musculoskeletal problems which would normally contraindicate training (diabetic ulcerations, arthritis, severe obesity, biomechanical limitations, and overuse injuries incurred from weight-bearing training) (American College of Sports Medicine, 1986). The latter example is well illustrated by elite 214 athletes who use alternate training modes to maintain endurance fitness during the recovery from lower extremity injuries, and the popularity recently of "cross-training" and triathlon participation. The Acute Physiological Effects of Upper Extremity Exercise Although the previous section has demonstrated the efficacy and safety of upper extremity exercise training for the CAD and post-MI patient, the physiology of upper extremity exercise does differ from larger muscle groups of the lower extremities, and should be reviewed. Studies in healthy individuals have demonstrated that arm exercise results in greater increases in systolic blood pressure, HR, RPP, VE, VO2, RER, and lactate at any given absolute work rate compared to leg exercise (Astrand et al., 1965). However, SV and anaerobic thresholds were lower at the same workloads than for leg work. The authors also found that the absolute levels of VC^max were lower for arm work (reaching 64 to 80% of leg VC^max) . Maximal HR was comparable or just slightly lower than for the leg, as was RPP and systolic BP. Franklin (1985) has demonstrated that arm fitness correlates poorly with leg fitness (r = .42 for arm max workload versus leg max workload and r = .32 for arm VC^max versus leg VC^max), illustrating the specificity concept. However, the 215 regression of HRmax to relative VC^max is the same for arm and leg exercise (ie., 57 - 78% VC^max is equivalent to 70 -85% HRmax for both arm and leg exercise). This is fortunate in that the same prescription methods can be utilized for' both arm and leg training, provided both sets of limbs are assessed separately. Nevertheless, Franklin has estimated that a workload equivillent to 50% of the leg workload can be applied to arm training, if arm testing has not been performed. Baldy et al., (1985) sought to examine the value of arm exercise testing in the detection of CAD. Thirty patients were assessed by either arm ergometery or Bruce treadmill tests. The arm test consisted of the application of 25 W every 3 minutes, starting at 35 W. VC^max was 13 METs for arm testing and 18 MET's for treadmill tests. Maximal HR for arm ergometry was significantly lower than for treadmill (109 vs. 101 bpm.) but ST-segment depression occurred at a higher percentage of maximum (62%) than treadmill testing (35%) . Coplan et al., (1987) also compared the responses of arm and leg exercise at 85% predicted maximal HR in middle-aged subjects to determine the appropriateness of arm testing to screen for CAD. They found that BP and HR increased at different rates for arm vs. leg tests, and that BP was higher in arm exercise at low work rates. However, the 216 situation reversed itself 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-min-1, and 187 bpm, respectively, and treadmill values were 30 mmHg/HR x 10-3, 2.7 l-min-1, and 174 bpm, respectively. The authors concluded that because of the variability in responses, testing with arms only would lead to an increase in false-negative test results, because the maximal physiological stress is less at maximal arm work rates compared to standard treadmill tests. The difficulty in assessing systolic blood pressure during arm exercise was overcome by Schwade et al., (1977) by the use of automated blood pressure units. Upon testing 33 male CAD patients, peak workload was found to be only 41% of the legs, but at the same absolute work rates, arm HR, systolic BP, and RPP were twice that of the legs. As suggested in the Coplan et al. study however, physiological measures became identical at maximal loads for both modes. Exercise Specificity and Transfer Effects in Arm and Leg Exercise. The possibility that training specificity is not 100% operative, and that there is perhaps some degree of generalizability which would allow a "transfer" of fitness to a group of untrained limbs, has been an alluring topic of interest for some time. Clausen et al., (1970, 1973) first demonstrated that after training of the legs, there was a 217 slight reduction in post-training submaximal heart rate for the untrained limbs. Arm VC>2max increased 10% (non-significantly) after training the legs via cycle ergometery, and the authors concluded that although the predominance of the training effect was therefore central, some transfer of fitness due to increased limb blood flow (due to increased cardiac performance) was responsible for the effect (Figure 7.6). 218 Figure 7.6 Exercise Specificity and Transfer Effect of Training _180r c 'E 1160 XD Arm training (arm) / (\eqyy' ro 1 120 / -* a 100 *' i i • • i i _180 c jE 1" 160 ca £^ w ro I 120 Leg training f: • / (arm)/ ('^X X* * -b 10C 200 400 600 800 1000 1200 Workload (kpm/min) Group mean heart rate and workload response to arm and leg exercise before ( ) and after (----.) training, (a) Arm training markedly reduced the heart rate response to arm exercise; however, the heart rate response to leg exercise decreased only slightly after arm training, (b) Leg training markedly reduced the heart rate response to leg exercise; however, the heart' rate response to arm exercise decreased only slightly after leg training. From Franklin, B. 1985, p. 108. Adapted from Clausen, et al., 1970. 219 Saltin et al., (1976) noted the same effect for the untrained limb after one-legged cycle training, and demonstrated unchanged mitochondrial enzyme adaptations in that limb. The authors speculated that in the absence of central cardiac factors being responsible for this effect, improved fitness in the untrained limb could have resulted from a greater efficiency of the heart, liver, kidney and the ability of slow-twich muscles to oxidize lactate. One aspect of the transfer effect was highlighted by McKenzie et al., (1976), and relates to the magnitude of the cross-over effect according to the size of muscle groups trained. There was a larger effect of transferring fitness (as measured by HR response only) to the untrained arms when the legs were trained than the reverse situation. This agreed with the Clausen et al., (1973) observations. The initial level of fitness is another factor which determines the potential transfer effect. Magel et al., (1978) found that subjects with initially high levels of aerobic fitness had no improvement in treadmill VT^max after arm training. A study by Lewis et al., (1980) reproduced these results; bicycle training resulted in a 15% increase in leg VC^max and a 9% increase in arm VT^max, but the subjects with an initially low VC^max benefited more from any potential transfer effects that the subjects with higher endurance fitness levels. 220 Rosier and co-workers (1985) hypothesized that the untrained muscles actually undergo ultrastructural adaptations due to an independent central cardiovascular training effect. This was tested in 10 subjects who trained on cycle ergometers for 8 weeks, 5 days/week. They trained at a high intensity equivalent to 90 to 95% of VC^max. Muscle biopsies were obtained from the deltoid and vastus lateralis for analysis before and after training. 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 level equal to 4 mM*l-1 increased 27% for the legs, but not for the arms, however. Histological examination revealed increased leg muscle mitochondrial densities, and capillary/fibre ratios, where as these changes were absent in the arm. Clearly, increased capillarization due to increased cardiac output and muscle blood flows did not occur, and led the authors to conclude that this was not the reason for the increased capacity for arm work after leg training. They speculated rather, that because the post-training arm VC^max was lower than pre testing leg VC^max, even before training, the cardiovascular capacity was already sufficient to support the increased arm V02max. Consequently, they concluded that during arm exercise, the trained but now inactive leg muscles, in addition to the liver, metabolized lactate, resulting in a 221 greater capacity for arm oxidative processes, and hence higher external work output. Thompson et al., (1981a) subjected healthly young adults to 11 weeks of either leg or arm training, and compared the cardiac responses during testing of the untrained and trained limbs. In contrast with the study by Rosier et al. (1985), cardiac changes were observed during testing of the untrained arms, and characterized by increases in LV ejection time (presumably contractility) using echocardiography. Transfer Effect From Training in Cardiac Rehabilitation Surprisingly few studies have been conducted by applying the exercise specificity model utilized in healthy populations to uncover the role of central vs. peripheral training adaptations in CAD/ post-MI patients. Thompson et al. (1981b) randomly assigned patients to either arm, leg or control exercise training settings for 8 weeks. The training groups exercised at or near their anginal thresholds for 40 minutes, 3 days/week. After training, 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 in the HR at which angina occurred for the trained and untrained limbs, and this 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 intrinsic cardiac training effect had occurred, because decreases in sympathetic tone and circulating catecholamines and reductions in TPR could cause these effects. It was. thus speculated that approximately half the training effects were peripheral and the other half central. Unfortunately, the sample size in this study was small, the training stimulis mild, and no direct measurements of cardiac function were performed to verify the above speculation. A more recent study also designed to detect a central training component by testing a set of untrained limbs was undertaken recently by Ben-Ari et al., (1987). Two groups, differing only by the training intensity (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 results demonstrated that although the magnitude of the training adaptations did not differ across training intensities, there was some indication of transfer effect from the legs to the arms as quantified by reductions in submaximal HR and RPP, and increases in the anginal threshold HR. Again, the authors concluded that a component of intrinsic myocardial adaptations could have occurred, but these were not directly measured in the study. 223 Appendix II Nuclear Medicine Calculations and Processing Samples 1. First Pass Cardiac Output Processing em o v;W;/v *r'W^~-: s^-vsestjv...... Forward CO. = BV X AE 224 Gated Blood Pool Angiography Processing 225 Appendix III Ventilatory Threshold Sample Plots 1. End-Tidal PC02 vs. End-Tidal P02 2. Minute Ventilation (VE) vs. V02 226 Appendix IV Sample of Consent Form Cardiac Rehabilitation and Exercise specificity study INFORMED CONSENT FORM Investigators: L.S. Goodman, D.C. McKenzie, W. Schamberger, M.B Walters, W. Aaman, J. Fleetham. The purpose of this study is to 1., evaluate and compare the extent of the adaptations of the heart to endurance training for whole-body vs. legs-only training groups of post-myocardial Infarction patients, and 2., to determine if central (heart) or peripheral (muscles of the limbs that were trained) are the main factors in bringing about the physiological adaptations in training cardiac patients. You will be asked to undergo two two-day series of exercise tests; one session before you start exercising, and the second after 6 months on the exercise program. These will consist of: Day 1. A maximal test with the arras on an arm-crank machine, 2 hours rest, and then a maximum test with the legs on a bicycle ergometer. Both tests will start out at easy loads, and then progress in difficulty as the pedalling tension is increased. You will be breathing into a mouthpiece so that your expired air can be analyzed for content of oxygen and carbon dioxide. These tests will be' medically supervised, and act as a test that your cardiologist would routinely perform in your clinical work up. Day 2. The next day, or within one week, you will undergo another series of arm and leg ergometery tests in the Department of Nuclear Medicine to evaluate cardiac function while you are exercising. A small amount of low-level radiocative tracer will be injected into a forearm vein, and a scanner will be placed over the chest to take pictures of-the left ventricle contracting while exercising, first with the arms, followed by a 2 hour rest, then with the legs at 3 two-minute workloads, and then at maximum exercise. The amount of radioactivity is minimal and does not represent a health hazard. Your heart rate and ECG will be continually monitored throughout the tests.. The risks of the arm and leg ergometry tests are minimal, but if any problems do arise , the laboratory does have all the necessary medical equipment for treatment of emergencies. Based on the results of the maximum tests, you will train ln either the YMCA or Shaughnessey Hospital cardiac rehabilitation programs, as previously decided for 6 months. The final 3 months training will be more intensive than your non-participating peers, and you will be montiored closely to maintain a safe level of exercise. You will be required to follow the exercise prescriptions explicitly, especially with regard to the special instructions for YMCA participants regarding the avoidance of arm exercise. All data will be treated in confidence. In reporting the results, names of the subjects will not be used. We will be happy to answer any inquiries concerning the procedures for the study in general. I consent to participate in this research project, and I understand that I may withdraw from the study at any time without predudice to further care. (Signature) (Witness) (Date) 227 Appendix V Subjects' Raw Group Mean Data Description of Variables on SAS Output Variable Description Suffix: PRE = pre-testing PST = post-testing ID identification (not applicable) HT subject's height in meters WT body weight in kg BMI body mass index SOS sum of 5 skinfolds in mm WHR Waist-Hip ratio SOTS Sum of trunk skinfolds in mm FPCO First-pass cardiac output in 1/min. FPCI First-pass cardiac index in ml/kg PFSV First-pass stroke volume in ml AVO Arm maximum oxygen uptake in 1/min ARER Arm respiratory exchange ratio AWL Arm maximal workload in Watts AVTRHR Arm ventilatory threshold as % of maximal heart rate- pre-testing suffix: PR, post-testing suffix: PT. AVTVOR Arm ventilatory threshold as % of maximal oxygen uptake- pre-testing suffix: PR, post-testing suffix: PT. LVO Leg (cycle) maximum oxygen uptake in 1/min. LRER Leg respiratory exhange ratio LWL Leg maximal workload in Watts LVTHRR Leg ventilatory threshold as % of maximal heart rate- pre-testing LVTVOR Leg ventilatory 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 in mm LHRM Leg maximal heart rate, bpm LPHRM Leg % age-predicted maximal heart rate LSB Leg maximum systolic blood pressure, mmHg LST Leg ST segment depression at maximal exercise in mm HDL High density lipoprotein cholesterol, mg/lOOml LDL Low density lipoprotein cholesterol, mg/lOOml CHOL Total serum Cholesterol, mg/lOOml TG Triglyceride, mg/lOOml SBP Systolic Blood Pressure, mmHg 228 DBP HR EDV EF Diastolic Blood Pressure, mmHg Heart rate, bpm End-diastolic volume, ml Left ventricular ejection fraction, % Pre-Testing Workload Suffixes: R = Resting, 1 = WL-30, 2 = WL-50, 3 = WL-70, 4 = WL-90. 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'.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 OEVUTIOH UIM1MUU VALUE MAXIMUU VALUE STD ERROR OP U£AN 0HPPST3 HPPST3 EDVPST3 EFPST3 SBPPST4 oep°STd HRPSTJ EDVPST4 EFPST4 SBPPST5 DBPPST5 HRPST5 EDVPSTS EFPST5 SBPPST6 DBPPSTS HRP5T5 EDVPST6 EFPST5 SBPPSTP DEPPSTP HRPSTP EDVPSTP EFPS7P ERPSTP ERPST4 EP.PSTP FRPS7F FRPST4 FHPSTP LRPPMPPE tRPP'JPST RATIOFPE RATIOrS T RPPPPc.P RpppOCi RPPPDC2 HPPPpcT RPPPRE4 SVPPER SVPR=i SVPRE2 SVPPE: SVPRE4 COPPER COPPE1 CCPPE2 COPPE3 COPSE* ESVPOE 1 ESVPPE2 ESVPREi ESVP°Ed UAPPR£3 MAPPRE I MAFPREc UiPPPE3 HflPDRc-1 TPRPRHP TPRonci TPRPRE2 TPRPBEi pvprpcp pvcpoc l PVRPocj PVRPRE3 PVPOcc^ LVSWPse I LVSfcP" LVSWPS LVSVIPe AVCFP E -LVOPPE30 LVCPRESO LVOP°E70 LVOPRE50 AVOPPE1 AVDPFE2 AVDP=E3 AVOPCE-l RPPFSTB RPPPST1 RPPPST2 RPPPS'3 RPPPST a RPPPST 5 RPDPSI5 RPPPSTP SVPSTR SVPST 1 SVPS72 SVPST3 SVPST4 SVPST 5 SVPSTS SVPSTP CCPSTP CCPST . CCPST£ COPST3 CCPST4 CCPST5 COPST5 •"E3 13 13 13 13 ' 13 13 13 12 12 12 12 12 12 13 13 12 12 12 12 12 12 13 13 13 62 100 2C5. 123 169 0 189 B5. 120. 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 U615 . 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 22.50169140 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 2.515C005I 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. .32221937 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. . 12772889 85. 50000000 153. 0 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. .05505046' 104 . 50000000 134 . 70000000 8. . 75233302 94. 29000000 267 . 62000000 50. 061 15393 0. 59000000 0. 32000000 0. .0721QS03 lie. 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. . 16537534 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. .074721ii 0 . 48106359 1 .20743055 0, 05392553 0 . 233 195 1 7 I ,02162344 0 .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 7979* 19 93 . 52508925 203 .44 150432 10 .03 3 13GS5 5 .55321125 1 1 . 5B942534 0. . 44225 = 70 .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 , 734"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 1 .54959352 10 .11470765 20 .37551532 3 -2*642535 1070 .0000000 24 .730759 1303. ,600000 257 .502554 26 7 7 . 1300000 3623 .637505 8 .0000000 0 .006244 2259 .0000000 623 . 102554 IDS; . 0000000 24 3 1C2S5 1482 ,6000000 360 .877532 2573. . 7300000 4364 , 507241 8. .5600000 0 .011847 2006 .OOGOOOD 556 .654545 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 .033275 44 . 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 = "11 = 1436 .36244 17 1650. 723927 '632 . .5372540 805. 75 1489 IB? 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 32, .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. MO 17,443 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 OEVUrrON vat.L'E VALUE OF M£AN COPSTP ESVPSTR ESVPST1 ESVPST 2 ESV»ST3 ESVPST4 ESVPST5 ESVPSTS ESVPSTo MAPPSIR MIP^ST1 MAPPST2 UAPPST3 M4PPS7 • MAPPST5 UAPPST5 MAPPSTP TPRDS" TF=F£~ i TFPPS7Z TPf!PSr3 TPRPST4 TPRPST5 rpPPSTB TPPP3TP PVRPS f» p,.'RPST ! °vpr-s' 2 PVPFST3 PVRP5T4 PVPPS75 PVRPC 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 105 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 3 533"4Sd 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 no 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 '.40 1 3030000 3 5 157 7J02 1052 7349000 1202 0204 30 *2 30580000 g 925590J3 91 i 4455000 1280 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 U63 6600000 I 1 3 95204 1 139 60000000 3 4 133 1 705 1298 4300000 123 C5416C 13 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 0505354l 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 01 7962 0 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 3J£ 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 5U6 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 6804ig 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 U08 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 30j-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 MAXIMUM VALUE OF MEAN ID HT AGE WTPRE 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 SE»PRE4 0BPPRE4 HRPRE4 EDVPRE4 EFPRE4 ERPRER ERPRE4 FRPRER FRPRE4 WTPST 8MIPST SOSPST WHRPST SOTSPST FPCCPST FPCIDST 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 S30DS Tl DBPPST1 HRPSTI EDVPST1 EFPST1 SBPPST2 DBPPST2 HRPST2 EDVPST2 EFPST2 SBPP5T3 5.OOOOOCOO 17:.2896959^ 55 33333333 78.611111]) 26.07333333 6S .55555555 0 . 9927 7 7 78 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 48 1333 2'7 10000C00 127 62222:22 1 U . 44444444 75.55555555 72.60000000 138.gg444444 0,44444444 131 44444444 ?e . 33333333 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 160.77777773 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 .5656655 7 77 . 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 T810P41i 3 . 4934 7505 22 . 30M272E 0.C90 1 7729 U 73«3P55 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 '(1531993 2 4 27 . 5"3£57R 77 120^0796 10 341CZ29T 7.24750497 1!.03741530 44 93424922 0 10736749 10 22S4B650 5.OOOOOOOO 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 . oooooooo irr.aouoooco 35 OOOOOOOO 54 .7DD00OO0 21 . 1D00G00O 39 . 500OUUOC 0 70000000 1 7 . OOOOOOOO 4 . 3BGCG00G Z 07000000 53.40000000 0.83900000 0,98000000 12.50000000 78 90000000 49.50000000 1 0330OOQO 0.33000000 65.40000000 71.60000000 53 50000000 73.00000000 45 OOOOOOOO 0.oooooooo B5.OOOOOOOO 4g oooooooo 134.OOOOOOOO 0.OOOOOOOO 28.OOOOOOOO I 1 • CQGOOCCO 18G UDOQCOCO 33 £0000000 96 OOOOOOOO 60.00000000 59 .60000000 92. 170000GO 0. 21000000 122 aaoooooo 7o.ooaooooo 74.00000000 89 5Q0D000U 0 33DO00O0 122.00000000 70.00000000 74.30000000 87.79000000 0.30000000 130 OOOOOOOO 7B .OOOOOOOO 79.20000000 98.01000000 0.330D0000 130 aooooooo 75.0OOOOCOQ 83,20000000 96.6000DOOO 0. 31000000 0 99000000 2.00000000 0 96000000 ! .3 7000000 58 . 30000000 22,50000000 45.50000000 0. 72000000 25 . OOOOOOOO 4 .7 1000000 2 45000000 56 10000000 0. 90800000 a.39oaocco i8.eoooooao 64 90000000 59 60000000 1 . 10000CCO 0.86000000 65 40000000 82.2aaooooo 56.50000000 94.00000000 55.00000000 0 OOOOOOOO 95,00000000 55.00000000 140,00000000 0.00000000 32 OOOOOOOO B6 60000000 193 70000000 44.00000000 90.OOOOOOOO 70.00000000 57.50000000 139.6 3000000 0 .23000000 10'J DOOOOOOO 70 OOOOOOOO 70 9000GCC0 15?.90000000 0,29000000 125 OOOOOOOO 70.00000000 7 3.30000000 159 03000000 0 35000000 134 OOOOOOOO 9.OOOOOCOO 17$ 400GCGCG 58.OOOOOOO? 95 . 400000CC 31 laooccoo 112. 50000C3C 0 96500C00 59 .0009000? 7 . 970CUCGC 3.8400GUCO 102.20000000 2.267000CO 1 .07000000 50.00000000 92 COOOOOOO BO OOOOOCOO 2.B8D00000 1.10000000 179 70000000 92 4000000C 80.60000000 173.00000000 97.OOOOCCCO 1.OOODOOCG 200 OOOOOOOO 113. DOOOOOOO 207.OOOOOOOO 4.50000aC3 53,00000000 193 COOCGCCC 257 OOOOOCOO 240.DOOOOOOO 13G.ODOO0CCO 83.0D0O0C3C 90. 10000GCG 236 35000O0G 0.59000000 150.00000000 85 OOOOOOOO 123.60UUUUOQ 261.42O00U00 0.62CQ00G0 162.00000000 90.00000000 136.20O00OC0 263.83000000 0.63000000 193.00000000 95.00000000 160.00000000 320.54000000 0. 7 1000000 210.00000000 95 .OOOOOOOO 172,00000000 288.92000000 0.69000000 2. 17000000 4.06000000 1 .6 7000000 4.33000000 93.70000000 31 , 100G00C0 B9 OOOOOOCO 0.9700COOO 51 . 50000000 7 .91000000 4.12000000 1 16.30000000 2.48000000 1 . 10OOOOOO 68.80000000 91 .5D000000 84.20000000 3.0S0CC000 1.15000000 212 400C0000 99.OOOOOOOO 91.80000000 169.DOOOOOOO 95.OOOOOOOO 0.OOOOOOOO 18 3.OOOOOOOO 103.00000033 215.00000000 1.50000000 SB OOOOOOOO 208 . OOOOOOOO 284.00000000 240.00000000 140.OOOOOOOO 82.00000000 100.70000000 267 42000000 O.5600C000 152.COOOOOOO 85.0COOOOGO 124.COOOCGGQ 256- 13000000 0-61000000 180.00000000 go.oooooooo 135.00000000 284 520COOOO 0 G4000000 185.OOOOOOOO 0.91297093 2 01*35435 S.2C1730S7 4 . 25035137 1 . 1644g?02 7 43370909 0.030059 10 4.9132 1295 0.33772335 0.17033232 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 599525 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 0.24913300 0.03070234 17 16664349 3.6927 1472 3.45547517 8.41625412 4.20684334 0.OOOOOOOO 1 1 . 29523435 5 67312217 10.5515-1248 0 20030340 2 66391061 12 . 35B49286 9.BB 3 t 38 15 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 '559.5C000C0 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 . 5000000 13JS.5CCDCOC 1953 3000000 1 148 .5000000 103D.OOOOOOO 63D.OOOOOOO 553 . 4000000 1250.950GOOQ 4.OOOOOOO 1 183.GOOOOOO 705.aoooooo 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 1175 OOOOCOO 701 OOCCOOD 765.9000000 172 1.2600000 4.4200000 1279 OOOOOOO 7 16 OOOOOOO 856 .6000000 1850.2200000 4 . 8200000 1368 OOOOOOO 7.5000CG 36.5 186 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 022.34CC00 '57 730000 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 45 5 I 224.61Q00G 6D.O275G0 76.985944 0.495533 0.00754 1 2363.045714 122.725278 107 462776 637 500000 159.277778 a.ocoooo 1020.333286 257.929571 907 .54295' 0.35 11 11 53 86777? 1374.591111 879.OB7773 4417.127500 24G.CGGOOO 24 777773 163.229444 1535 385553 0 .00^694 405.000000 33. min 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 . BSC '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 19 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 BUG 154 52^ 19 . HP 23.84* 13.C7C 51 . 6 6 3 14 163 5.565 IE.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 DBPD5T 4 5 82 HPP3T4 a 1 15 EDVPST4 8 195 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 PVRPPE1 9 1 PVBFRE2 9 1 PVRFPP 3 9 2 PVPpFr.''. 9 2 LVSWFPER 9 72 UVSrtP=E' 9 109 LVSWPOE2 g 1 15 LVSVIPPE3 9 134 LVS*ac=J g 13G A'.'DrFSP. 9 6 LV0PPE20 9 0 LV0PPE50 9 0 LVGPFE70 1 I.VOPPE90 9 1 AVDPRE 1 9 B AVCPP-2 9 12 AVPPFE3 9 1 4 AVDPF=4 9 9 RPPPSTP Q 7 RPPFST1 9 10 RPPPST? Q 13 RPFPST3 9 16 BPPPCTJ 2 19 RPPPST 5 5 24 RPP°ST5 1 26 RPPPSTP 9 21 SVPSTP 0 77 SVPST 1 g 94 S V P 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 . 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33804635 45 :7320000 175 '5140000 13 27934878 797 5660000 42 56598008 4 7 7230000 184 7 2300000 14 22199336 753 7 520000 40 4SS3J594 A3 12440000 152 9S7BOOOO 13 4SB1I531 764 4519000 32 79991088 49 25600000 137 94460000 10 93330350 757 5621000 8 09638259 72 54000000 9B 51000000 2 89879420 795 5000000 4 735B1302 88 •5000000 106 4 5000000 1 57350434 862 7400000 9 18042634 97 15000000 110 4 1000000 3 05014211 907 6100000 10 96585083 96 50000000 127 34000000 3 5552835! 959 8200000 12 99943142 93 31000000 123 63000000 4 33281047 989 3900000 0 29343815 0 =50IS647 1 66886938 0 09AA793S 11 1462092 0 41405469 0 50177033 1 S004 1132 0 13B01B23 7 5476157 0 39074579 0 '•7375329 1 77981742 0 13024860 7 1671482 0 26073552 0 •717J351 1 290901 19 0 OB691184 6 1854142 0 33594483 0 3'307332 1 50435578 0 11 198IB1 6 I06646A 0 47580327 0 5=912544 2 25178659 0 15893442 14 8541105 0 65420581 0 71337764 2 S8743850 0 21806860 15 4962972 0 70130023 0 71455346 3 08222161 0 23376676 17 4529351 0 89435913 0 93739740 3 45507575 0 29811971 19 0143621 1 03154516 0 3535432B 3 85939312 0 34334839 20 2416114 25 98158057 33 53325805 114 07045478 8 66056022 655 5533808 42 94505224 54 07360432 181 036793B6 1A 31535075 983 2069409 49 281S225! 53 3320998! 202 83845770 16 42-27417 1039 2307608 74 C9012539 54 13577472 294 30473510 24 596 70896 120S 4050E02 7 1 598 '06 13 54 :2"r472 26 7 S7552325 23 85956938 1227 3759629 1 67377942 4 324 10356 9 5108/638 0 55792647 56 3197198 0 1E6S1799 0 30590DOO 0 "6400000 0 05550600 5 1792000 0 27802999 0 51650000 1 44000000 0 09267666 8 6320000 0 38924198 0 72310000 2 01800000 0 12974733 12 0848000 0 50045398 0 32970000 2 5920CO0O 0 16681799 15 5378000 3 39780874 5 45107227 15 24938550 1 13250291 74 8308551 5 52148815 7 31910890 24 24775753 1 BA049505 114 7644825 5 59 32'7G2 3 045!: '939 24 95C0B962 1 86440587 132 5705295 8 24 2 7 1 dj 2 7 77=71255 35 42237467 2 74757147 163 4977469 1 97545793 5 29920000 11 07700000 0 62548599 67 8308000 1 91061063 8 98COOOOO 14 83000000 0 53587023 98 9860000 2 24851732 9 33240000 16 57500000 0 74950577 120 5305000 3 27435731 10 526 20000 20 10000000 1 09145250 144 B749000 4 39758351 1 1 50600000 24 46600000 1 72e02172 158 39B8GOO 6 04653995 4 55000000 30 989COCOO 2 70409487 120 7158000 25 3 4240000 26 34240000 26 2A24Q0O 6 53744707 11 5050COOO 30 26900000 2 27914902 19 1 2034000 IB 39262535 44 134 30000 105 0725COOO 6 29420845 699 5019000 30 46230551 53 0265C300 145 31420000 10 !54 10184 354 3S93OO0 31 6992352e 63 3 3 3C00G0 170 7120C000 10 53309543 1002 1595CC0 39 53503090 5£ 35'50000 194 39530000 13 23203030 1010 1422000 49 02253573 JE '703COOO 20? '.'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 15 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 622110 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 22 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 7.278 21.078 22.095 19.40! 17.372 5.876 24.646 27 834 22.516 20.213 7.999 18.455 41.B72 15.454 20.471 6.408 23.579 30.923 I9.8B0 23.107 33.595 34 326 11.409 22.742 29.897 30.888 30.241 32.325 16.727 12.256 17.321 18. 162 25.BS0 29.443 31.697 39.739 37.268 43.920 41.944 24.954 35.104 34. 105 4 3.266 A5.874 52.616 44 955 50.944 47.868 38.967 9. 160 4.940 9. 103 10.265 11.324 22.966 49.373 49.067 37.938 49.512 28.889 37.995 36.164 42.332 45,865 35.553 39.312 42.579 55.'81 52.575 25.747 28.988 28.908 28.988 28.988 40 666 43.300 37.371 45.373 24.997 17.372 16.790 20 34' 24.685 25.045 234 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 54.6334igj5 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 406 . 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 12 2 . 33552500 0 . 1 1697337 13. .954595= 0. . 122 155 3. . 32452522 0. . 2 157540 16 . 68 55 3=0 0. .43071= 3. . 75 1 35716 0. 16  5948313 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 . 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1051C2E5 0 2r..5207J 2 IS6L10 0 0000062 9 S0122170 0 C0CCC030 [ 0GC00032 0 PS2S7S01 2 7. - 2 o 6 c 567217 0 C00002S £1 3S052272 0 00000066 2 00000050 1 26232275 0 627:2522 I 567217 0 OGOOOES £1 53052272 0 G0OG0O66 2 0G00CQ90 I 26252279 0 52712525 S65EEO 0 0000055 6 21222690 0 00000055 t 00000021 1 70062E9I 0 12532752 I 250900 0 0000022 C 69926EEO 0 00000029 0 00000052 0 65192690 0 55271297 0 7162CS 5717 0000092 £221 EE20E27E 72 00000005 022 0O0OOD72 67 50206917 79 27125996 15L 051975 527 OOOOOOO 022 75276962 2 OGGGGOOO 7£l OOOOOOOO 62 76022625 02 55271253 201 25/ r05 £2 ooooooo 235 07052672 c OOOOOOOO 56 OOOOOOOO 89 53292565 5 237.2562 23 occoor. 239 ooocooo 1 20! 60529228 5 DOOOOOOO 521 OODODDOO 001 698527E1 52 2-2000000 251 OOIEOO 0 C00005E I C5S71220 0 00000009 0 0000006E 0 792295SO 0 C20D005P C COL 126 29501 OOC0022 70S 07111 807 69 00000006 0E2 0000007E 67 22/58/63 201 CGCG0O6C 391 00005/ 91 7 onoooos 2i7£ /06E57L6 11 oooooooo 7£l OOOOOOOO 76 £6162297 02 51 1 ££££££ 991 ooooooo 372 92030199 2 oooooooo 56 oooooooo 69 235:2253 El 2-5 55355 28 OOOCOC IE ooooooo /OS S502S20S S oooooooo 521 OOOOOGOO 351 102EEEE3 5 7.2.2.0GGCO 59! 2L8SOO 0 0000063 2 52902CEO 0 OO0OOG29 0 OOOOQGOI' 0 UE5S290 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 El 35 259991 201 GGGGOCO £67 03227921 7 oooooooo 06 OOOOOOOO £9 OB2522C! 01 23555591 29 SiSeDO riSdOD E:Sd03 iiSaOD biSaOD ciSdAS SiSdAS SiSdAS 7iSs.*.S C.Sri\S SiSclAS .iSaAS diS-cda Si 3addd Si Sosdti EiSdadU Bi-Saadd i iZzadH dlSeodU ir^dQAT DJSadDAT CS 3 "3=0 AT bdsdCAV EHdo'.'.SAl d3adrV5AT rdadHAd EBddaAd 2==aMAd .SaddAd aasdMAd Paadcdi tB^dtidX isaaadi iasoodi d2ddadi LsaddflH S3ddd*H t adadTH uadddvn PaodAS3 EaadASB 23ddftS3 1 aba.A S3 = = dd.*£3 faddCD £3UdOD S3dd03 . 3ddOD batidOO ratidAS catidAS H3ddAS .3tidA3 b3ddAS P3dddd« EBddddtl HBadddd !aSdddU ei3addd« iSdJliVH 3adOIiVa iadi'idddT andi'iadUl dl-SdHa rLSdbd diSdb3 nsdaa diSdd3 dlSad3 ciSdAQS diSdaH diSdoaO alCadBS aiSdda SiSdAQ3 SISriBH BlSdaaO 9iSddSS Sl5ad3 &iSdAG3 5iSaHH GiSddBO SlSdsSS ?i 5a 22:3 PiSdAGB PiSddH 7i=ca30 USc3 = £i.5dAG3 iliidaH S!i3a = aQ rVV3ft 40 UOUtia QlS 3mvA N0I1VIA3Q 9ZZ 237 57i>iCH"0 U1NIKUM DEVISIION 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 .24740504 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 20.19574 157 0.06245321 0.10410536 0.14574750 0.18738964 0.3B945557 0.B7044495 1.30129275 1 .47678635 19.07305:52 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 ventilatory threshold 1/min 02 VARIABLE N MEAN STANDARD STD ERROR DEVIATION OF MEAN GROUP=1 AVTVOPRE 13 0.829 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 0.816 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 2.110 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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