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The use of a radioiodinated fatty acid analogue in the study of myocardial ischemia and infarction Hudon, Marck P.J. 1988

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The Use of a Radioiodinated Fatty A c i d Analogue i n the Study of Myocardial Ischemia and I n f a r c t i o n By Marck P . J . Hudon B.Sc. (Zoology), U n i v e r s i t y of B r i t i s h Columbia, 1985  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE  in  THE FACULTY OF GRADUATE STUDIES  Department of Academic Pathology i n a f f i l i a t i o n with Department of Radiology, D i v i s i o n of Nuclear Medicine and Department of Surgery, D i v i s i o n of Cardiovascular and Thoracic Surgery We accept t h i s thesis as conforming to the required standard  The U n i v e r s i t y of B r i t i s h Columbia December, 1988 © Marck P . J . Hudon, 1988  In presenting degree  at the  this thesis  in partial fulfilment  of the  requirements  for an advanced  University of British Columbia, I agree that the Library shall make it  freely available for reference and study. 1 further agree that permission for extensive copying of this thesis for scholarly purposes department  or  by  his  or  her  representatives.  may be granted It  is  by the head of my  understood  that  copying  or  publication of this thesis for financial gain shall not be allowed without my written permission.  Department of  P^-WaVc^w  The University of British Columbia Vancouver, Canada  D  ^e  DE-6 (2/88)  \ ft / 1 a t / Q - 9 -  ABSTRACT  The purpose of this study was decanoic acid ( acid (B  123  123  to u t i l i z e 15-p-  123  I-phenylpenta-  123  IPPA) and 15-p- I-/3-methyl iodophenylpentadecanoic  IPPA) i n the assessment of myocardial metabolism and  following ischemia and  perfusion  infarction.  Canine models of global ischemia, regional ischemia and i n f a r c t i o n were used.  Time-activity curve analysis was  using 15-p-  123  I-iodophenylpentadecanoic acid to determine changes i n  metabolic status of the myocardium. SD.  B  123  performed on the f i r s t two models  IPPA, 201x1  Reported are the h a l f - l i f e values +  and a histochemical method (tetrazolium staining)  were used i n the l a t t e r model to assess perfusion defects, including ischemic r i s k zone.  S i g n i f i c a n t differences i n the elimination rate (mins) of  123  IPPA  metabolic by-products for the early and late phases of the t i m e - a c t i v i t y curves of the global ischemia model i n the l a t e r a l wall (early and late phase) and a p i c a l wall (late phase) were observed with Iso-osmolar (Tyers) solution.  There were no s i g n i f i c a n t differences for either the Iso-osmolar  + superoxide dismutase (SOD)  or Iso-osmolar + a l l o p u r i n o l .  Also there  no s i g n i f i c a n t difference i n th values between the three areas of the  was left  v e n t r i c l e (apex, septal wall and l a t e r a l wall) within the control group.  Results with the regional ischemia model indicate an increase i n early phase th values representing  123  IPPA washout, between control and 14 days ii  post-operative  animals i n both the l a t e r a l w a l l (22+10 to 60+107 min -  p>0.05) and the a p i c a l w a l l (23+10 to 37±33 min - p>0.05) and a decrease i n washout i n the septal w a l l (22±14 to 14+7 min - p>0.05).  I23IPPA  An  increase i n th between c o n t r o l and 14 days was seen i n the l a t e phase post-operatively i n the l a t e r a l w a l l (34+12 to 71+50 min - p>0.05), the apex (44+8 to 115+104 min - p>0.05) and the septal w a l l (34+2 to 626+1325 min p>0.05).  The r e s u l t s of the myocardial i n f a r c t i o n model i n d i c a t e d a greater degree of c o r r e l a t i o n between the s i z e of perfusion defects estimated by a histochemical method (TTZ s t a i n i n g ) v s . B vs.  2 o i i T  (  r  =  123  I P P A ( r = 0.65, p<0.005), than  o.49, p<0.005).  The f o l l o w i n g conclusions  can be made on the basis of the r e s u l t s  obtained. ' The u t i l i z a t i o n of iodinated free f a t t y acids w i t h i n each area of the l e f t v e n t r i c l e ( l a t e r a l w a l l , a p i c a l w a l l and septal w a l l ) demonstrate s i m i l a r rates of  123  I P P A washout. The e f f e c t of r e v e r s i b l e g l o b a l  ischemia on myocardial washout of 15-  123  IPPA may be modified by the  a d d i t i o n of SOD or a l l o p u r i n o l to the c o n t r o l iso-osmolar c a r d i o p l e g i c solution.  The imaging agent  123  I P P A may be a u s e f u l i n d i c a t o r of  metabolic status of the myocardium, revealing changes i n washout rates during the period of developing regional ischemia. of B  123  L a s t l y , the u t i l i z a t i o n  I P P A does not appear to be e f f e c t i v e i n determining the s i z e of  perfusion d e f e c t s , or i n i d e n t i f y i n g the ischemic r i s k zone because of border demarcation problems.  iii  TABLE OF CONTENTS  Abstract  ii  Table of Contents  iv  List  of Tables  ix  List  of Figures  xi  List  of Appendices  xv  Abbreviations  and Formulae  xvi  Acknowledgments  xix  I  Introduction  1  II  Literature  7  (1)  (2)  Review  Myocardial Metabolism  7  a)  Fatty Acids  7  i)  membrane t r a n s p o r t  7  ii)  a c t i v a t i o n and t r a n s f e r  8  iii)  /3-oxidation  8  b)  Glucose  c)  Fatty Acids  Myocardial  .  10 and Energy P r o d u c t i o n  I s c h e m i a and I n f a r c t i o n  10  11  a)  Cytoskeletal Alterations  11  b)  Electrophysiological  12  c)  Functional Alterations  13  i)  echocardiography  13  ii)  hemodynamics  13  Alterations  d)  Metabolic Alterations  e)  Experimental Models o f  13 Ischemia  iv  15  (3)  Radiopharmaceuticals i n the C l i n i c a l  Diagnosis  of Ischemia and I n f a r c t i o n a)  b)  c)  18  m  Technetium ( " T c )  .  i)  pyrophosphate  18  ii)  isonitriles  21  Thallium - 201  25  i)  H i s t o r i c a l perspectives  25  ii)  R a d i o n u c l i d i c properties  26  i i i ) C l i n i c a l A p p l i c a t i o n s and Experimental Evaluation  26  Iodine - 123, 131  28  i)  H i s t o r i c a l Perspectives of Iodinated Fatty A c i d s .  28  ii)  i23Iodine  31  (i23i) 1 2 3  1.  Production of  I  2.  Fatty A c i d I o d i n a t i o n Procedures  31 33  i i i ) A p p l i c a t i o n s : C l i n i c a l and Experimental  (4)  18  39  1.  Iodinated Decenoic a c i d  2.  Iodinated Decanoic a c i d  42  3.  Iodinated Pentadecanoic a c i d  46  4.  Miscellaneous Fatty Acids  52  Ischemia and Cardioplegia  .-  39  61  III  Purpose  64  IV  Experimental M a t e r i a l s and Methods  65  (1)  Global Ischemia  65  a)  Experimental Model of Cardioplegia  65  b)  Protocol  65  c)  Preparation of 15-pacid ( i 2 3 )  123  I-iodophenylpentadecanoic 67  I P P A  i) ii)  Radipiodine Production of  67 123  IPPA  i i i ) Hexane E x t r a c t i o n  v  67 67  iv)  d)  v)  Preparation of  vi)  Q u a l i t y Control  68 123  IPPA for Injection  68 68  E l e c t r o n Microscopy  68  i)  Tissue C o l l e c t i o n  68  ii)  Processing  69  i i i ) Sectioning  69  e)  L i g h t Microscopy  69  f)  Data A c q u i s i t i o n  70  i)  Imaging  70  ii)  Blood-Gas Analysis  70  g)  Data Analysis 123  i) ii) (2)  Purification  71  I P P A Image A n a l y s i s  S t a t i s t i c a l Analysis  71 71  Regional Ischemia  72  a)  Experimental Model of Regional Ischemia  72  b)  Metabolic Assessment  73  c)  Preparation of 15-pacid ( i) ii)  d)  123  123  I-iodophenylpentadecanoic  IPPA)  74  Radioiodine  74 23  Production of * IPPA  74  i i i ) Hexane E x t r a c t i o n  74  iv)  74  Purification  v)  Preparation of  vi)  Q u a l i t y Control  123  IPPA for Injection  74 74  Data A c q u i s i t i o n  74  i)  Imaging  74  ii)  Blood Gas Analysis  74  vi  e)  E l e c t r o n Microscopy  75  i)  Tissue C o l l e c t i o n  75  ii)  Processing  75  i i i ) Sectioning  75  f)  L i g h t Microscopy  75  g)  Data Analysis  75  123  i) ii) (3)  I P P A Image A n a l y s i s  75  S t a t i s t i c a l Analysis  75  Myocardial I n f a r c t i o n  76  a)  Experimental Model of Myocardial I n f a r c t i o n  76  b)  Metabolic Assessments  77  c)  Preparation of 15-p-Beta-Methyl-  123  iodophenylpentadecanoic a c i d ( B d)  e)  V  IPPA)  77  Data A c q u i s i t i o n  78  i)  Imaging  78  ii)  Histochemical Assessment  80  i i i ) Autoradiography  82  iv)  84  Histology  Data Analysis 123  84  i)  B  I P P A Image Analysis  ii)  S t a t i s t i c a l Analysis  Results (1)  I-  123  84 85 86  Global Ischemia  86 123  a)  Analysis of  I P P A curves  b)  Hemodynamics  93  c)  Histology  93  i)  E l e c t r o n Microscopy  93  ii)  Light Microscopy  95  vii  86  (2)  (3)  Regional Ischemia a)  A n a l y s i s of i I P P A Curves  b)  Metabolic Assessments  102  c)  Hemodynamic Assessments  102  d)  Histology  106  i)  E l e c t r o n Microscopy  108  ii)  Light Microscopy  108 I l l  a)  Metabolic Analysis  I l l  b)  Analysis of Perfusion Defect Assessments 123  i)  B  ii)  2oiTi  IPPA  113 113 113  i i i ) Histochemical  113  Autoradiography - Assessment of Ischemic Risk Zone ....  120  i) ii)  VII  97  Myocardial I n f a r c t i o n  c)  VI  97 23  B 2  123  IPPA  120  oiTl  120  d)  Histology - L i g h t Microscopy  122  e)  Inter-observer and Intra-observer Variance  122  Discussion  124  (1)  Global Ischemia  124  (2)  Regional Ischemia  130  (3)  Myocardial I n f a r c t i o n  136  Summary and Conclusions  143  V I I I Bibliography  145  IX  168  Appendices  viii  L i s t of Tables  Table 1  -  Imaging properties of the i d e a l 5  radiopharmaceutical  Table 2  -  Imaging properties of  2 0 1  T1,  123  IFFA  and  physical c h a r a c t e r i s t i c s of an i d e a l 6  radiopharmaceutical  Table 3  -  Physical properties of and  Table 4  -  1 2 3  2  I , i &I 30  " i i  Washout rate (th operatively and  i n minutes + SD) of  123  IPPA pre-  post-operatively.  Myocardial regions examined by time-activity  (T-A)  curve analysis included the a p i c a l w a l l , 89  septal wall and l a t e r a l wall Table 5  -  Measured and calculated parameters of cardiac hemodynamic status.  Parameters were assessed  at 2 time intervals including pre-cardiopulmonary bypass (as a control assessment) and post-CPB (as a post-operative  Table 6  -  123  92  assessment)  IPPA washout for both early and late phases  of the T-A  curves over 14 days of developing  ischemia.  Areas examined were the l a t e r a l ,  apical and septal walls of the l e f t v e n t r i c l e  Table 7  -  Hemodynamic and Metabolic Assessments.  99  Hemodynamic  and blood analysis at various time periods during progressive  coronary artery occlusion over 14 105  days  ix  Table 8  -  Perfusion defect size calculated as % of t o t a l s l i c e size f o r each of the three methods - histochemical (TTZ staining) B  Table 9  -  123  IPPA and  115  20iTi  Autoradiographic and scintigraphic assessment of ischemic r i s k zone calculated as % of t o t a l s l i c e size  121  x  L i s t of Figures  Figure 1  -  Schematic from WHO showing causes of mortality i n developed countries  Figure 2  (1986)  2  (A)-  Various sizes of ameroid constrictors available  17  (B)-  Ameroid constrictor i n place on LAD coronary artery - Heart has been excised following 14 days of gradual coronary occlusion to demonstrate  collateral  circulation  17  Figure 3  -  Catabolic pathways of  Figure 4  -  Aromatic e l e c t r o p h i l i c and nucleophilic  Figure 5  -  Figure 6  (A)-  1 2 3  I P P A and  1 2 3  IHA  34  substitution  reaction  38  Metabolic trapping scheme  55  2 0 1  T h a l l i u m SPECT-scan i n dog (anterior projection  at 6 hours p o s t - i n f a r c t i o n ) . (B)-  Figure 7  -  Figure 8  (A)-  B  123  I P P A SPECT-scan i n same dog as above  (anterior  projection at 6 hours post-infarction)  79  Heart showing l i g a t i o n and section cutting technique...  81  Autoradiographic assessment of perfusion i n s l i c e s of myocardium from one experiment with s l i c e tracings of myocardial s l i c e s overlaid onto the autoradiograph showing borders of the s l i c e s and i n f a r c t s .  (B)-  The clear acetate paper overlaid onto autoradiograph showing demarcation of the i n f a r c t i o n and the r i s k zone  ischemic 83  xi  Figure  9  -  Time-Activity curves f o r  123  IPPA washout  from the myocardium (normalized to 2 min peak counts) (A) pre-operatively and (B) post-operatively, following 2 hrs of global ischemia  Figure 10  -  87  Washout rate (th i n min) of  123  IPPA f o r the  (A) early phase and (B) late phase of the T-A curve  Figure 11  -  88  Washout rate (th i n min) assessed pre-operatively for the (A) early phase;  and (B) late phase of  the T-A curves  Figure 12  -  91  Electron microscopic evidence of ischemic changes at the u l t r a s t r u c t u r a l l e v e l : (A) normal tissue (B) ( i ) (ii)  Iso-osmolar (Tyers') solution 10 + SOD  ( i i i ) 10 + A l l o p u r i n o l  Figure 13 (A)-  94  Control specimen showing macroscopic anatomy of the myocardium.  (B)-  Ischemic specimen showing gross changes at the cellular level: (i)  Iso-osmolar (Tyers') solution  (ii)  10 + SOD  ( i i i ) 10 + A l l o p u r i n o l  Figure 14 (A)-  Regional myocardial washout rate of  96 123  IPPA (th i n  min) f o r the early phase of the T-A curve. (B)-  Regional myocardial washout rate of  123  IPPA (th i n  min) f o r the late phase of the T-A curve  xii  98  Figure 15 (A)-  Control scintigram i n dog i n j e c t e d with 15-p-  123  I-iodophenyl pentadecanoic a c i d  ( a n t e r i o r view) with T-A curve and  th values (Cl) (B)-  Post-operative scintigram i n dog i n j e c t e d w i t h 15-p-  123  I-iodophenyl pentadecanoic a c i d  (anterior view) at 14 days with T-A curve and th values (Tl) Figure 16 (A)-  101  Lactate dehydrogenase and creatine kinase l e v e l s pre- and p o s t - o p e r a t i v e l y .  (B)-  CK-MB% assessed at pre-operative and post-operative time i n t e r v a l s  Figure 17  -  103  Lactate assessed at pre- and post-operative time i n t e r v a l s  Figure 18 (A)-  104  Microscopic assessment of LAD coronary a r t e r y showing normal diameter with no c o n s t r i c t i o n .  (B) -  Assessment of LAD coronary a r t e r y i n one experiment at 14 days of c o n s t r i c t i o n .  (C) -  D i f f e r e n t degree of closure i n another animal i n the study.  (D) -  Microscopic assessment of LAD coronary a r t e r y showing complete closures of v e s s e l from animal which collapsed from myocardial i n f a r c t i o n .  (E) -  Ameroid c o n s t r i c t o r s - at 0 days and a f t e r 14 days in situ  Figure 19  -  107  E l e c t r o n microscopic assessment of normal myocardial t i s s u e , (A) Dog 1;  (C) Dog 2.  U l t r a s t r u c t u r a l changes of myocardial t i s s u e showing evidence of ischemia, (B) Dog 1; (D) Dog 2  109 xiii  Figure 20  -  L i g h t microscopic changes produced by ischemia at 14 days i n two d i f f e r e n t animals (A) Dog 1, and (B) Dog 2  Figure 21  -  110  Venous concentrations of l a c t a t e dehydrogenase, creatine kinase and creatine kinase-MB isoenzyme at pre- and post-operative i n t e r v a l s  Figure 22  -  112  S t a i n i n g of a myocardial i n f a r c t using a s t a i n combining n i t r o b l u e t e t r a z o l i u m and t r i p h e n y l tetrazolium.  The s t a i n i n g of formazans w i t h i n  v i a b l e t i s s u e can be seen as dark t i s s u e , while the i n f a r c t e d region remains pale Figure 23  -  114  Relationship between estimates of i n f a r c t s i z e by the histochemical method (TTZ s t a i n i n g ) versus (A)  Figure 24  -  B  123  I P P A and (B)  Graph of B  123  20iTi  118  2  I P P A versus °iTl showing the  r e l a t i o n s h i p between the estimations of p e r f u s i o n defect s i z e by these two imaging agents Figure 25 (A)-  119  L i g h t microscopic assessment of normal canine myocardium.  (B)-  Gross c e l l u l a r changes f o l l o w i n g acute myocardial i n f a r c t i o n  123  xiv  L i s t of Appendices  Appendix I  - Histochemical assessment (TTZ s t a i n i n g ) of perfusion defect s i z e using p l a n i m e t r i c quantification  Appendix I I  -  S c i n t i g r a p h i c assessment of p e r f u s i o n defect using  Appendix I I I  167  B  1 2  3IPPA  and a o i T i  171  12  - B 3 i p p A / 2 0 i x i r a t i o s f o r each experiment and corresponding a r e a - o f - i n t e r e s t  Appendix IV  -  180  I n f a r c t e d t i s s u e as percent of the e n t i r e s l i c e expressed f o r each of the three techniques of perfusion defect assessment, i n c l u d i n g histochemistry (TTZ s t a i n i n g ) , B  123  I P P A and  201TI  Appendix V  .  184  - Autoradiographic assessment of the ischemic r i s k zone f o r dogs 8 and 9 using p l a n i m e t r i c quantitation  188  xv  Abbreviations and Formulae  ANOVA  - Analysis of Variance  gi23ippA.  - Beta-methyl-iodophenylpentadecanoic acid  BMIPP  - Beta-methyl iodinated pentadecanoic acid  CAD  - Coronary Artery Disease  CI  - Cardiac Index  CK-MB%  - The % of Creatine kinase i n the form of the MB iso-enzyme  J1  CPA  -  11  Carbon-palmitic acid  CVD  - Cardiovascular Disease  Cs  - Cesium  CPI  -  m  " T c - h e x a k i s (carbomethoxyisopropyl-isonitrile) technetium (I)  Cl  -  DMIPP  - Dimethyl iodinated pentadecanoic acid  dp/dt  - F i r s t Derivative of Left Ventricular Pressure  DMIVN  - Dimethyl-  DCM  - Dilated  ECG  - Electrocardiography  EF  - Ejection Fraction  FFA  -  7  - Gamma  HCM  - Hypertrophic cardiomyopathy  HR  - Heart Rate  HDA  - Hexadecanoic  HSA  - Human serum albumin  IPP 1 2 3  123  ,  1 3 1  I  IPPA  Chlorine  125  I-18-nonadecanoic  acid  cardiomyopathy  Free Fatty Acids  acid  Iodinated phenylpentadecanoic acid  - Iodine -  Iodinated phenylpentadecanoic acid  IPI  -  " T c - h e x a k i s ( i s o p r o p y l - i s o n i t r i l e ) technetium (I)  IHD  -  Ischemic Heart Disease  IHA  - Hexadecanoic  KI  - Potassium iodide  KeV  - Kiloelectron volts  m  acid  xvi  LVP  -  Left Ventricular Systolic Pressure  LAD  -  Left Anterior Descending Coronary Artery  LCX  -  Left Circumflex Coronary Artery  MVO2  -  Oxygen extraction  MUGA  -  Multiuser gated angiography  MIBI  -  " T c - h e x a k i s (2-methoxyisobutyl-isonitrile)  m  technetium (I) mCi  -  Millicuries  M.W.  -  Molecular Weight  PCTA  -  Percutaneous transluminal  PP  -  Pyrophosphate  Rf  -  Regional front  RP-30  -  " Tc-methoxy-isobutyl-isonitrile  RMBF  -  Regional Myocardial Blood Flow  SI  -  Stroke Index  SWI  -  Stroke Work Index  SBP  -  Systolic Blood Pressure  SVR  -  Systemic Vascular  SPECT  -  Single Photon Emission Computed Tomography  Sb  -  Antimony  T-A  -  Time-Activity  TBI  -  " T c - h e x a k i s - ( t - b u t y l - i s o n i t r i l e ) technetium (I)  " Tc  -  Technetium  201TI  -  Thallium  th  -  Half-lives  Te  -  Tellurium  TTZ  -  Tetrazolium  TPT  -  Triphenyltetrazolium  WHO  -  World Health  Xe  -  Xenon  m  angioplasty  m  Resistance  m  Organization  xvii  (i)  Body Surface Area  2  2  3  BSA (m ) = K f w O 4 / 10  (Constant) K  =  wt = weight  11.2 (dog)  ( i i ) Cardiac Index  CI =  MCO BSA  (iii)Stroke Index  SI =  CI  2  (L/min/m )  (1000') HR  MCO = Mean Cardiac Output  2  (mL/beat/m ) HR = Heart rate  ( i v ) Systemic SVR = Vascular Resistance  (MBP - RAP) ( MCO )  80  5  (dynes . sec/cm ) MBP = Mean Blood Pressure RAP = Right A t r i a l Pressure  (v)  Ejection Fraction  EF  =  SV EDV  x 100 SV = Stroke volume EDV = E n d - d i a s t o l i c volume  xviii  Acknowledgments  I thank Dr. D.M.  Lyster, Dr. W.R.E. Jamleson and Dr. A.K. Qayumi for  their assistance and guidance i n the completion of t h i s study. I wish to express sincere thanks to Dr. David V. Godin for h i s guidance and support during t h i s thesis preparation. I thank the members of my committee for t h e i r comments and suggestions. I would l i k e to thank Mr. Tom Wells, Dr. R.R. M i l l e r , Dr. D.A. Owen, Mrs. Maureen Day and Mrs. Eva Chung, i n the Department of Anatomic Pathology and Laboratories for their assistance i n many aspects of t h i s study. I thank Diane Minshall, Bruce Gregg and Dr. Maria Kiess for their assistance and for the use of their computer f a c i l i t i e s at St. Paul's Hospital. I wish to thank Dr. M. Shulzer and Ms. Eva Germman f o r t h e i r assistance with the s t a t i s t i c a l analysis for the study. I thank Mr. Craig Sartori and Hayes Dougan f o r t h e i r guidance with iodinated free f a t t y acid preparation. I express my gratitude to Dr. D.A. Jackson for h i s assistance and time he devoted to the discussion of various aspects of this t h e s i s . I wish to thank Miss Cathy Legg, Mr. Greg Funk, Miss Donna MacKenzie, Mr. Trevor Neufeld and Mr. Darryl Barber for their encouragement and support throughout t h i s thesis preparation. In addition, I would l i k e to thank Mrs. Christine Kirkham for the typing of the t h e s i s . I dedicate this thesis to my family, especially to my father.  xix  TO MY  FATHER BROTHER  "There  is  "You  no  wealth  cannot  find  but  Life".  a medicine  AND  MOTHER  AND  SISTER  John Ruskin:  Unto t h i s Last, 1862.  for  once  Chrysippus:  xx  life  when  550 B.C.  man  is  dead".  - 1 INTRODUCTION Myocardial ischemia continues to plague many people i n most developed countries of the world (WHO  s t a t i s t i c s , 1986).  was the primary cause of death i n Canada i n 1986 1986).  Cardiovascular disease (Figure 1, WHO  (CVD)  statistics,  I t has been reported that 4.3 b i l l i o n d o l l a r s i s l o s t by the  Canadian economy per year as a r e s u l t of cardiovascular disease (B.C. Heart Foundation Fact L e t t e r , 1987). addressed.  C l e a r l y , CVD i s a major problem that must be  A major c l i n i c a l goal i n CVD i s i t s i d e n t i f i c a t i o n p r i o r to i t s  presentation as myocardial i n f a r c t i o n , or i r r e v e r s i b l e myocardial damage. C u r r e n t l y , diagnosis of myocardial ischemia i s based on electrocardiography, elevations of s p e c i f i c serum enzymes, angiography and p a t i e n t h i s t o r y (angina p e c t o r i s ) (Braunwald, 1982).  However, the diagnosis remains  i n c o n c l u s i v e w i t h these f a c t o r s , only becoming conclusive subsequent to myocardial damage. C a l i f f et a l . (1988) have developed an angina score based on the cause of angina, frequency of angina and ECG changes to grade the s e v e r i t y of CAD.  The score also incorporates the p a t i e n t ' s age, sex,  coronary anatomy and l e f t v e n t r i c u l a r f u n c t i o n as independent v a r i a b l e s . However, c a l c u l a t i o n of the angina score, which can range from 0 to >9, w i l l only i d e n t i f y those p a t i e n t s who may require aggressive therapy and w i l l not i d e n t i f y those p a t i e n t s before angina appears.  E a r l y diagnosis may  prevent  some of the deaths associated w i t h myocardial ischemia. Since the diagnosis of myocardial Ischemia remains i n c o n c l u s i v e , development of a l t e r n a t i v e diagnostic m o d a l i t i e s , which w i l l i d e n t i f y myocardial ischemia e a r l y i n i t s pathogenesis, are needed. may serve t h i s need.  Nuclear medicine  However, no radiopharmaceutical e x i s t s at present  which possesses a l l of the desired c h a r a c t e r i s t i c s necessary f o r optimal  - 2 -  Figure 1  -  Schematic from WHO, showing causes of death i n developed countries (1986). I.H.D.  -  Ischemic Heart Disease  C.V.D.  -  Cerebro-Vascular Disease  Diseases of the circulatory system A - I.H.D. B - C.V.D. C - Other diseases of C S . Neoplasms Other and ill—defined causes Respiratory diseases  - 3 myocardial imaging. Thallium-201, having been considered the most s u i t a b l e radiopharmaceutical f o r c l i n i c a l a p p l i c a t i o n , i s u t i l i z e d i n cardiac centres as an accepted non-invasive t e s t to evaluate myocardial p e r f u s i o n . 201  T1  However,  does have some drawbacks, i n c l u d i n g 7 energy, which f a l l s below the  optimal range of commercially a v a i l a b l e imaging systems, a long p h y s i c a l h a l f - l i f e and a high t o t a l body r a d i a t i o n exposure to the p a t i e n t (Zaret, 1977).  A l t e r n a t i v e imaging agents are presently being developed and  evaluated f o r optimum assessment of myocardial ischemia and i n f a r c t i o n .  Two  such groups of compounds are r a d i o l a b e l e d free f a t t y acids and i s o n i t r i l e s .  The use of r a d i o a c t i v e tracers to study the cardiovascular system dates back to the 1920's (Blumgart and Weiss, 1927).  The use of r a d i o i o d i n a t e d  f a t t y acids as myocardial imaging agents was f i r s t developed by Evans and colleagues i n 1965.  Evans u t i l i z e d  131  I - o l e i c a c i d to demonstrate the  p o s s i b i l i t y of photoscanning the hearts of mongrel dogs.  The authors chose  free f a t t y acids because they are an important energy substate f o r the myocardium (Bing et a l . . 1956).  However, a problem w i t h the  131  I-labeled  f a t t y acids was a 7 energy of 364 KeV f a l l i n g above the optimal range of the imaging systems of that time (decreasing diagnostic q u a l i t y of the images obtained).  Another problem associated with t h i s e a r l y work by Evans was the  double-bond s a t u r a t i o n technique used to iodinate the o l e i c a c i d .  The  products of t h i s procedure e x h i b i t e d a reduced myocardial e x t r a c t i o n e f f i c i e n c y and a lower rate of blood clearance, r e l a t i v e to the non-iodinated parent compound (Poe et a l . . 1973).  In order to a l l e v i a t e  t h i s problem, Poe et a l . (1975) developed a radioiodine exchange-type process, y i e l d i n g a t e r m i n a l l y - l a b e l e d product which retained the  - 4 -  characteristics  o f t h e p a r e n t compound.  ideal radiopharmaceutical proposed the use o f (Tables  1 &  suitable  for  izsj because of  In addressing the problem of gamma i m a g i n g Poe e t a l .  its  more i d e a l  of u s i n g these  iodinated fatty  i m a g i n g h a s b e e n e s t a b l i s h e d b y Poe a n d h i s technique  remains  (1976b)  properties  2).  The t e c h n i q u e  this  imaging  an  to diagnose myocardial  an a r e a o f a c t i v e  research.  acids  colleagues.  in  myocardial  The a p p l i c a t i o n  i s c h e m i a and i n f a r c t i o n ,  however,  of  - 5 -  Table 1.  Imaging Properties o f the "IDEAL" Radiopharmaceutical  Gamma Energy (KeV) E x t r a c t i o n E f f i c i e n c y (%)  100-200 100  P h y s i c a l H a l f - L i f e (min)  30-60  B i o l o g i c a l H a l f - L i f e (min)  short  T o t a l Body Exposure (mrad/Ci)  low  - 6-  Table 2.  Various p h y s i c a l c h a r a c t e r i s t i c s of and the i d e a l radiopharmaceutical  20  lfl  201  IDEAL  Gamma Energy (KeV)  80  100-200  E x t r a c t i o n E f f i c i e n c y (%)  87  100  Physical  Half-Life  72 hrs  Biological Half-Life  7 hrs  T o t a l Body Exposure(mrads)  210  30-60 min short low  123  -Thallium,  123  IFFA  I-FFA 159 78  13.3 hrs 0.5 h r s 30  - 7 -  II  LITERATURE  REVIEW  (1)  MYOCARDIAL METABOLISM In view of the c l i n i c a l use of these iodinated fatty acids, a b r i e f  review of myocardial metabolism i s necessary. a b i l i t y to maintain a v a r i e t y of energy stores.  Cardiac muscle has the However, i t has long been  appreciated that the myocardium p r e f e r e n t i a l l y u t i l i z e s above a l l others  free f a t t y  acids  (Bing, 1956).  (a) Fatty Acids  -  The metabolic process of fatty acid oxidation is  well-documented and may be divided into various steps including: i)  membrane transport;  ii)  a c t i v a t i o n and acyl transfer to c a r n i t i n e ;  iii)  beta-oxidation  (Idell-Wenger et a l . . 1978).  i)  Free Fatty acids are removed from the blood by the myocardium. two forms:  While i n the blood, the fatty acids may e x i s t i n as free fatty acids bound to albumin, or as  t r i g l y c e r i d e s (Lehninger, 1982).  The majority of serum fatty  acids are bound to albumin (Idell-Wenger et a l . . 1978 and Goodman, 1958).  Following release from albumin, the transport  of the FFA through the c e l l membrane occurs v i a passive d i f f u s i o n (Idell-Wenger et a l . . 1978).  - 8 An e q u i l i b r i u m , however, i s maintained between plasma and c e l l u l a r pools by an energy-dependent process (Opie, 1968).  This equilibrium-maintaining e x t r a c t i o n process i s c o n t r o l l e d by a number of f a c t o r s , i n c l u d i n g the albumin:FFA molar r a t i o , metabolic status of the t i s s u e , concentration of the substrate i n plasma, a v a i l a b i l i t y of a l t e r n a t i v e s u b s t r a t e s , mechanical a c t i v i t y of the h e a r t , rate of o x i d a t i v e r e s p i r a t i o n and plasma l e v e l s of c e r t a i n hormones (Neely, 1972).  The other form of the f a t t y a c i d w i t h i n the blood i s as a triglyceride.  The former i s composed of a g l y c e r o l backbone  with three f a t t y a c i d molecules attached to i t .  Triglycerides  are the major storage form of f a t t y acids i n c e l l s , but are not normally found i n membranes (Lehninger, 1982).  ii)  Following d i f f u s i o n through the c e l l membrane, FFA's are transformed i n t o f a t t y acyl-CoA esters (Lehninger, 1982). This step occurs on the outer mitochondrial membrane and i s enzymatically catalyzed (Idell-Wenger et a l . . 1978) and allows the f a t t y a c i d to continue through the three-step transport process, i n which f a t t y a c i d moves from the outer mitochondrial membrane into the mitochondrial m a t r i x .  i i i ) There are three known pathways of f a t t y a c i d o x i d a t i o n of which only beta-oxidation predominates i n the body (Antony and  - 9 Landau, 1968).  Beta-oxidation occurs w i t h i n the matrix of the  mitochondrion.  The sequence of beta-oxidation has been known  since the e a r l y 1900's. Knoop (1904) demonstrated the successive removal of 2-carbon fragments (as acetyl-CoA) from the long chain f a t t y a c i d .  Each successive removal of a c e t y l  CoA r e s u l t s i n the loss of hydrogen atoms from the f a t t y a c i d (through the a c t i o n of dehydrogenases), which subsequently enter the e l e c t r o n transport chain also located i n the mitochondria  (Lehninger, 1982).  The product i s the o r i g i n a l  f a t t y a c i d l e s s 2 carbon atoms, which can then re-enter the beta-oxidation sequence.  Fatty a c i d o x i d a t i o n i s not l i m i t e d to the  mitochondria,  having been shown to also occur i n peroxisomes (Christensen et a l . . 1986).  These authors used hepatocytes from f a s t e d r a t s  to show that peroxisomal f a t t y a c i d o x i d a t i o n plays an important r o l e i n chain-shortening of very long chain f a t t y a c i d s , i e . C22  and longer.  These f i n d i n g s have been  confirmed by Yamada et a l . (1987) who,  again using i s o l a t e d  r a t hepatocytes, showed that peroxisomal beta-oxidation i s involved i n the chain-shortening of omega-phenyl f a t t y a c i d s . The products of the peroxisomal beta-oxidation sequence, with fewer carbon atoms, were then able to enter the  mitochondria  and undergo mitochondrial beta-oxidation w i t h subsequent generation of ATP through coupled processes.  Several  important differences e x i s t between peroxisomal and  - 10 mitochondrial beta-oxidation including individual enzymes, cofactor requirements, coupling to energy production and specificity for fatty acids of different chain lengths (Wanders et a l . . 1987). Much of the work reported on peroxisomal beta-oxidation confirms the presence of these organelles within the l i v e r .  However, other studies have also  shown their existence in other tissues including the myocardium (Connock and Perry, 1983). Therefore, when examining beta-oxidation of free fatty acids within the myocardium, one must refer to both components, i e . a mitochondrial and a peroxisomal sequence.  (b) Glucose  -  It is known that the myocardium preferentially utilizes  fatty acids over glucose as a metabolic fuel (Bing, 1956;  Evans et  a l . . 1962). The glycolytic cycle must be inhibited in some way f o r this to occur.  Randle et a l . (1964), Neely et a l . (1969), and  Neely (1972) have demonstrated that glucose transport is inhibited by fatty acids or ketone bodies.  Opie (1972) has also reported on  the inhibition of glycolysis by free fatty acids.  (c) Fatty acids and energy production  - The end result of fatty acid  oxidation is the production of acetyl-CoA units.  The latter can  then enter the c i t r i c acid cycle via a condensation reaction with oxaloacetate to form citrate (Lehninger, 1982). The latter continues on through the c i t r i c acid cycle, producing reducing equivalents and C02.  The electrons from the reducing  - 11 equivalents are transferred to the e l e c t r o n transport chain w i t h i n the inner mitochondrial membrane, which transports  them to oxygen.  The energy l i b e r a t e d from these electrons cascading down t h i s chain i s coupled to the synthesis of ATP  from ADP  and phosphate i n a  process c a l l e d oxidative phosphorylation.  (2)  MYOCARDIAL ISCHEMIA AND  INFARCTION  Ischemia i s defined as a d e f i c i e n c y of blood due to f u n c t i o n a l c o n s t r i c t i o n or actual obstruction of a blood v e s s e l , leading to a reduction i n the d e l i v e r y of oxygen to that p a r t i c u l a r t i s s u e (Dorlands, 1988). P a t h o l o g i c a l myocardial ischemia e l i c i t s a s e r i e s of progressive s u b c e l l u l a r and c e l l u l a r changes which a f f e c t many of the c e l l ' s normal metabolic processes.  I t i s a dynamic process, which can have v a r y i n g e f f e c t s ,  including:  a)  cellular alterations;  b)  electrophysiological alterations;  c)  functional alterations;  d)  metabolic a l t e r a t i o n s .  a)  C e l l u l a r A l t e r a t i o n s - Ischemia i s a dynamic, heterogeneous process  characterized by a continuum of stages sometimes leading to i r r e v e r s i b l e i n j u r y (Trump, 1982).  Although the e f f e c t s of ischemia on c e l l homeostasis  are many, an increase i n c y t o s o l i c Ca  *T"~f"  i s very important.  The  latter  - 12 j j  leads to an increase i n Ca  -calmodulin complexes, which a l t e r s the c e l l ' s  cytoskeleton i n a number of ways, i n c l u d i n g c e l l shape, organelle o r i e n t a t i o n and a l t e r s p a r t i c l e s w i t h i n the membranes (Trump, 1982). increased number of Ca  The  -calmodulin complexes also a c t i v a t e s  phospholipases, which leads to h y d r o l y s i s of membrane phospholipids which, i n t u r n , w i l l cause c e l l membrane damage and mitochondrial membrane damage (Trump, 1982).  The l a t t e r may a f f e c t the transport of f a t t y acids and t h e i r  release. b)  E l e c t r o p h y s i o l o g i c a l - A l t e r a t i o n s - Under normal r e s t i n g  conditions,  heart rate may be w i t h i n a range of 60-80 beats/min (Guyton, 1986) . The P wave i s produced by e x c i t a t i o n of a t r i a l muscle, with the r i g h t a c t i v a t e d p r i o r to the l e f t atrium.  The i n t e r v a l between the P wave and the QRS  complex represents the time taken f o r the a c t i o n p o t e n t i a l to t r a v e l from the SAN ( s i n o a t r i a l node), through the AVN ( a t r i o v e n t r i c u l a r node) and the Purkinge system.  The QRS complex represents the e x c i t a t i o n of the  v e n t r i c l e s and the T wave i s the r e p o l a r i z a t i o n of the v e n t r i c l e s . E l e c t r o p h y s i o l o g i c a l evidence of ischemia i s l a c k i n g i n s p e c i f i c i t y , i e . one cannot diagnose ischemia based on ECG evidence alone.  I t has been  demonstrated on many occasions that S-T segment e l e v a t i o n often precedes coronary a r t e r y l i g a t i o n (Opie, 1972; Coraboeuf e t a l . . 1976).  Sampson et  a l . (1960) have a t t r i b u t e d t h i s e l e v a t i o n i n the S-T segment to a flow of current towards the ischemic area, which i s surrounded by normal t i s s u e . Therefore, the ECG w i l l be deflected i n the p o s i t i v e d i r e c t i o n during the S-T segment. controversial.  The exact mechanism of t h i s phenomenon i s s t i l l Other changes include T-Q depression (Fozzard and M a k i e l s k i ,  - 13 1985), shortening o f a c t i o n p o t e n t i a l d u r a t i o n , slowed intramyocardial conduction and d i s p e r s i o n o f r e f r a c t o r y currents (Corr and Sobel, 1979). The c e l l u l a r events underlying these e l e c t r o p h y s i o l o g i c a l changes remain o i n c o n c l u s i v e , but these are b e l i e v e d to be m u l t i f a c t o r i a l .  c)  Functional A l t e r a t i o n s  - The f u n c t i o n a l consequences o f ischemia  on the myocardium have been examined e x t e n s i v e l y . Vatner (1980) demonstrated that myocardial dysfunction i s c o r r e l a t e d with a reduction i n blood flow i n the conscious dog.  Echocardiographic  assessments demonstrated  that i n d i c e s of l e f t v e n t r i c u l a r f u n c t i o n , i n c l u d i n g r e g i o n a l w a l l t h i c k e n i n g , e j e c t i o n f r a c t i o n and e n d - s y s t o l i c pressure/area ( A k a i s h i e t a l . . 1985).  r a t i o decreased  These authors also demonstrated a f a l l i n cardiac  output, l e f t v e n t r i c u l a r stroke work and ^ / ^ t f o l l o w i n g severe stenosis of the myocardial v e s s e l s . controversial issue.  The cause o f t h i s dysfunction continues to be a  Some b e l i e v e that the f a l l i n t i s s u e ATP l e v e l s i s the  cause (Braunwald e t a l . . 1982; Swain et a l . . 1982), while others b e l i e v e that dysfunction associated with g l o b a l ischemia i s due to oxygen f r e e r a d i c a l s (Myers e t a l . . 1986).  Becker e t a l . . (1986) have demonstrated that  the ischemic myocardium possesses s i g n i f i c a n t f u n c t i o n a l capacity and therefore d e f i c i e n t l e v e l s o f ATP may not be the ultimate cause o f the dysfunction.  C u r r e n t l y , many authors b e l i e v e that oxygen free r a d i c a l s are  very important i n d i s c e r n i n g the underlying cause of any v e n t r i c u l a r dysfunction associated with  d)  ischemia.  Metabolic A l t e r a t i o n s  - Many studies have been performed  examining the e f f e c t s of ischemia on c e l l u l a r metabolic a c t i v i t y .  The  - 14 o x i d a t i o n of f a t t y acids i s one pathway which i s d r a m a t i c a l l y a f f e c t e d by an ischemic episode. Early work by Evans (1964) demonstrated that subsequent to an ischemic episode, f a t t y acids are d i v e r t e d away from beta-oxidation and converted to the storage form of f a t t y acids ( t r i g l y c e r i d e s ) , which are then deposited i n the l i v e r and adipose t i s s u e .  The e f f e c t s on mitochondria  and free f a t t y a c i d o x i d a t i o n w i l l a l s o be discussed under the radiopharmaceuticals s e c t i o n of t h i s t h e s i s . The metabolic consequences of ischemia r e s u l t from a f a l l i n oxygen tension.  Since the myocardium i s dependent upon aerobic metabolism, a f a l l  i n oxygen tension w i l l give r i s e to an increase i n anaerobic g l y c o l y s i s , i n an attempt to generate high energy phosphates.  Associated w i t h t h i s s h i f t  i n metabolism to the anaerobic state i s an accumulation of end-products of metabolism, such as l a c t a t e , hydrogen ion, leading to a f a l l i n myocardial pH.  purine bases and adenosine,  In response to a l i m i t e d supply of  energy, hormones are released which stimulate cAMP synthesis w i t h i n plasma membranes of adipocytes (Trump, 1984).  This induces a l i p o l y t i c cascade  which r e s u l t s i n a c t i v a t i o n of l i p a s e s which hydrolyze t r i g l y c e r i d e s to f a t t y acids and g l y c e r o l .  The l a t t e r i s released i n t o plasma f o r transport  to the l i v e r and subsequent use i n the formation of glucose (Lehninger, 1982) .  Shug et a l . (1973) reported that free f a t t y acids accumulate i n the  mitochondrial f r a c t i o n of myocardial c e l l s subjected to ischemia because of a reduced u t i l i z a t i o n .  Concomitant with t h i s increased concentration of  i n t r a c e l l u l a r free f a t t y a c i d i s an accumulation of long-chain acyl-CoA and long-chain a c y l c a r n i t i n e esters (Subramanian et a l . . 1987).  These esters  have been shown to i n h i b i t a number of enzyme systems i n c l u d i n g the mitochondrial adenine nucleotide t r a n s l o c a t o r , an enzyme involved i n the  - 15 t r a n s l o c a t i o n of ATP and ADP across the inner membrane of the mitochondria (Shug et a l . (1975), Paulson e t a l . (1984), Paulson e t a l . (1986), Shug e t a l . (1987)).  Thus, hearts exposed to t h i s increased concentration of free  f a t t y acids during ischemia may show enhanced d e t e r i o r a t i o n of metabolic f u n c t i o n w i t h subsequent l i m i t e d energy production. Also a f f e c t e d by ischemia are the processes of l i p i d and p r o t e i n metabolism Jennings, 1986).  (Reimer and  Thus, ischemia w i l l a l t e r many aspects of the c e l l ' s  normal metabolic machinery, along with f a t t y a c i d metabolism.  e)  Experimental Models of Ischemia  - There are a large number of  a v a i l a b l e parameters which can be u t i l i z e d to assess myocardial ischemia. In view of the many p h y s i o l o g i c a l changes associated w i t h ischemia, the proper choice of a representative system w i l l be dependent upon the purpose of the study.  i)  The experimental models used i n t h i s study include:  Global Ischemia i n s i t u - Global ischemia involves the  production of ischemia throughout the h e a r t . Animals are placed on cardiopulmonary bypass, w i t h oxygenator support, caval o c c l u s i o n and l e f t a t r i a l v e n t i n g . An a o r t i c cross-clamp i s p o s i t i o n e d e f f e c t i v e l y e l i m i n a t i n g coronary flow, producing g l o b a l ischemia.  Cardiac s u r g i c a l  procedures r e l y on t h i s technique to o b t a i n a quiescent, bloodless f i e l d i n which the surgeon can work. Many studies have been completed v a l i d a t i n g t h i s model i n the examination of the metabolic and f u n c t i o n a l consequences of temporary t o t a l ischemia (Conti e t a l . . 1984;  Rousou et a l . . 1986).  This approach can also be used to assess  the e f f e c t i v e n e s s of c a r d i o p l e g i c s o l u t i o n s i n myocardial p r o t e c t i o n ( C a t i n e l l a et a l . . 1984).  - 16 ii)  Regional Ischemia i n s i t u  - Regional ischemia d i f f e r s from  the f i r s t i n a number of ways (Schaper, 1979): (a)  collateral circulation;  (b)  mechanical s t r e s s of one p o r t i o n of myocardium (non-ischemic) compared to the ischemic p o r t i o n ;  (c)  l i p i d accumulation;  (d)  c e l l death accompanied by extravasation of blood c e l l s and p r o t e i n s .  The process of coronary a r t e r y disease involves the progressive closure of a coronary a r t e r y u s u a l l y by the development of an a t h e r o s c l e r o t i c plaque.  A r e l i a b l e experimental model, t h e r e f o r e ,  should produce a gradual coronary o c c l u s i o n over a known time p e r i o d , so that various ischemia-related parameters can be assessed.  One  method, developed i n the l a t e 1950's by L i t v a k and Vineberg, u t i l i z e s a casein p l a s t i c , Ameroid, which has been cured i n f o r m a l i n to harden i t (Figure 2A).  The ameroid c o n s t r i c t o r i s composed of the ameroid, which  i s sheathed by a metal j a c k e t .  There i s a c e n t r a l lumen, which  communicates w i t h the outer surface by a narrow arm (Figure 2B).  The  c o n s t r i c t o r can be placed onto the coronary a r t e r y by way of t h i s arm. The m a t e r i a l w i l l slowly engorge w i t h f l u i d and p r o g r e s s i v e l y s w e l l and pressure w i l l be d i r e c t e d towards the c e n t r a l lumen.  Thus, the  coronary a r t e r y w i l l be gradually stenosed, mimicking the progression of coronary a r t e r y disease. Vineberg and Mahonti (1960) demonstrated that t h i s technique i s an e x c e l l e n t model o f gradual coronary o c c l u s i o n w i t h death of the animals occurring when 50% or more of the lumen of the two l e f t coronary a r t e r i e s was blocked.  - 17 -  Figure 2 (A)  -  Various sizes of ameroid constrictors a v a i l a b l e .  (B)  -  Ameroid constrictor i n place on LAD  coronary artery  - Heart has been excised following 14 days of gradual coronary occlusion to demonstrate c o l l a t e r a l circulation.  - 18 i i i ) Myocardial I n f a r c t i o n i n s i t u  - Myocardial i n f a r c t i o n i s  an i n e v i t a b l e outcome of untreated coronary a r t e r y disease. Gradually, the l e s i o n from CAD w i l l grow inwards and r e s u l t i n complete blockage of that a r t e r y .  The i n f a r c t i o n i n t h i s study was produced f o l l o w i n g a  thoracotomy and d i s s e c t i o n of the coronary a r t e r y .  U t i l i z i n g a dexon  suture, the coronary a r t e r y was l i g a t e d , producing an acute loss of blood flow to the regional myocardial bed supplied by that a r t e r y . Myocardial i n f a r c t i o n ( i e . a heart attack) may vary i n i t s outcome. With small i n f a r c t s , the remaining v i a b l e myocardium can continue to f u n c t i o n , such that hemodynamic status i s r e l a t i v e l y w e l l maintained. However, i n many cases i t i s f a t a l (See Figure 1, p.2).  RADIOPHARMACEUTICALS IN THE CLINICAL DIAGNOSIS OF MYOCARDIAL INFARCTION AND ISCHEMIA.  (a)  "m Technetium ( Tc) "m (i) Tc-pyrophosphate One approach to imaging myocardial i n f a r c t i o n i s the use of 9 9m  i n f a r c t - a v i d agents, such as Tc pyrophosphate. "m "nL, "m -Technetium ( T c ) , as Tc stannous pyrophosphate, was f i r s t used to image acute i n f a r c t e d human myocardium by Parkey and "m his  coworkers i n 1974.  Of 23 p a t i e n t s , t h i r t e e n had p o s i t i v e  Tc  scans, f o l l o w i n g planar gamma imaging - eleven of these p a t i e n t s were scanned 3-5 days f o l l o w i n g i n f a r c t i o n and two, 7-10 days a f t e r "m infarction.  L o c a l i z a t i o n of i n f a r c t i o n by  correlated w e l l .  Tc scan and ECG  These authors b e l i e v e d that pyrophosphate was  -  incorporated  into  mitochondria  of  Since size  -  hydroxyapatite  irreversibly  this  myocardial  the  19  study,  a  damaged  number  infarctions  crystalline  of  under  structure  found  i n  attempted  to  the  myocardium. investigators  have  experimental conditions  using  9 9  "Tc this  PP  and  SPECT.  3-dimensional  Keyes  et  a l . (1978)  representation  of  the  were  the  f i r s t  myocardium  to  using  attempt 15  mCi  of  9 9m Tc LAD  pyrophosphate.  and  main  LCX  arteries  problems  attenuation  both  latter  and  volume  measured  a  by  high SPECT  myocardial of  l e f t  counts  image  by  Keyes  size  did exist. degree and  ventricle  of  which  normal  r  0.70.  tissue  from Kaul  et  good  2 0 1  minutes  of  correlation  between  the  staining) (r =  0.85),  study,  (r =  by  T1  was  infarct  though et  the  a l .  (1984)  i n vivo  well-counting volume  The  as  used  with  that  volume  to  of  this  assessments were  defect  of  standard deviations  two  i n order  even  between  defect more  SPECT  Caldwell  0.92)  or  these  and  the  later. to  correlations  needed  ligation  related  defined  I f  60-90  volume,  2  by  co-workers  similar  between  Although  b o r d e r s were  ischemic  The  below  myocardium.  volume  accurate  his  defect  f e l l  correlation  more  a  authors  the =  and  correlation  technique, was  performed  was  In  i n vitro The  produced  (tetrazolium  i n grams,  samples.  from  imaging  were  resolution.  infarct  problems  reported  and  reported  histochemical size,  Infarctions  deemed  of  defect  appropriate,  differentiate  infarcted  tissue.  a l . (1985)  addressed  this  issue,  u t i l i z i n g  99m  Tc-labeled  microspheres,  authors  concluded  area  risk,  at  average  that  assessments  i s d i f f i c u l t  correlation  on  SPECT  a  to  and of  macroautoradiography. perfusion  determine  slice-by-slice  i n the  defects, apical  comparison  was  These  including  region. r  =  0.88  the  The with  - 20 -  the basal s l i c e s showing the highest degree of c o r r e l a t i o n and the apical s l i c e s showing the worst.  I t must be noted that these studies  were performed i n excised hearts. With the evident success of t h i s i n f a r c t - a v i d agent i n the experimental s e t t i n g , Holman et a l . (1982) took i t to the next l e v e l the c l i n i c a l s e t t i n g .  In 20 patients with acute myocardial i n f a r c t i o n ,  99™  99™  Tc pyrophosphate and  xc-labeled RBC's were used to  quantitate i n f a r c t s i z e , both by planar imaging and SPECT.  Infarct  size assessments were then correlated with patient prognosis.  Results  showed that 85% of patients with i n f a r c t s of >40g had complications during the 17.8 month follow-up period.  Of the patients with i n f a r c t s  of <40g, only 29% had complications. This study also indicated that two-dimensional  imaging cannot be used to assess the size of perfusion  defects because of problems with edge detection and boundary overlap. Anatomical location of the i n f a r c t i o n also l i m i t s the usefulness of planar imaging with only anterior i n f a r c t s being seen.  SPECT imaging  proved to be more accurate with better delineation of borders and better able to detect both i n t e r i o r and anterior i n f a r c t s .  In a  s i m i l a r study, Corbett et a l . (1984) assessed i n f a r c t size v i a planar imaging and SPECT with and without blood pool overlay to determine i t s sensitivity.  Blood pool overlay refers to the a c t i v i t y within the  chambers of the heart.  I t was found that SPECT with blood pool overlay  was s i g n i f i c a n t l y better than SPECT or planar imaging, alone, at determining myocardial i n f a r c t s i t e and s i z e , e s p e c i a l l y s e n s i t i v i t y f o r detection of non-transmural  infarcts.  i n the  A number of  other studies have validated the use of SPECT as a tool f o r i n f a r c t  -  quantification (1984)  2 0 1  -  - Jansen  T1  Socher  and et  et  21  -  ^Ic-PP,  a l . (1985)  - Nohara  et a l .  SPECT.  a l . (1987)  have  demonstrated  a  net  retention  of  9 9m Tc-PP  approaching  zero  within  normal  myocardium  versus  >30%  i n  "m reperfused was  myocardium.  dependent  These  authors  assessment Although in  upon  of  suggested  to  nuclear  appeared  degree  myocardial  appearing  c l i n i c a l  the  further  of  It  be  extent  demonstrated  damage  optimal  medicine,  the  irreversibility and  tissue the  that  based  using  agent on  a  for  of  of a  Tc  uptake  myocardial more  dual  damage.  accurate  tracer  assessment  i t s radionuclidic  technique. of  perfusion  properties,  9 9™ Tc  has  yet  to  replace  2 0 1  T1  i n the  assessment  of  cardiac  9 9m ischemia. limiting "m (ii)  Tc-PP i t s  i s also  a  n o n - p h y s i o l o g i c a l agent,  thereby  potential.  Tc-Isonitriles "m  The  more  optimal  of  6  hours  and  imaging  agent  which  h a l f - l i f e for  an  gamma  energy  i t s ease i s  (140  of  taken  KeV)  of  g e n e r a t i o n has up  by  normal  Tc,  i t s  led  to  the  myocardium.  search One  9 9m possible great  Tc-based  deal  of  myocardial  attention  imaging  recently,  i s  agent,  the  which  labeled  has  received  isonitrile.  In  a 1981,  99™ Deutsch  and  coworkers  screened  complexes  for myocardial  complexes  investigated  uptake  were  a  large  number  i n dogs  divided  into  dimethylarsines,  diphenylarsino-ethanes,  ethylphosphines,  monothioglycerols  Of  only  these  groups,  one,  the  and  of  cationic  and  rats.  5  groups,  Tc  Nineteen  cationic  including  the  diphenylphosphino-  diphenylphosphinoethyl  dimethylarsines, exhibited  amines.  detectable  - 22 myocardial  uptake  upon  within  group,  variability  the  biological best  distribution.  images.  hydrofluoric compounds. 0.022 2 0 1  %  acid  with  appeared  The  the  Even  existed bromo  danger  and  and  revealed  the  uptake  was  dimethylarsine.  et  a l . (1984)  state  success  imaging  shown  of  i n  the  tremendous  an  alternative  t h a t none  (I) cations  latter,  the  i s o n i t r i l e  ligand  Deutsch  and  c o l l e a g u e s i t was  studies  i n mice  myocardial  post-injection. increased Although uptake  uptake The  normal  liver  lipophilicity  lipophilicity  being was  s t i l l  these  agents  was  involving  human  myocardium.  the  with  uptake  dose/g  of  for  were  of  good  derivative  a l . . 1983). agents,  thus  although these  far,  animal  authors  - hexakis  difference  being  while  of was  being  i n  the  muscle  the  injected  dose)  shown  with  imaged,  u n c l e a r and  to  work  the of  uptake at  affect  increased the  i n  Biodistribution  skeletal  also  (alkyl  that  and  associated  myocardium  of  the  complexes  bidentate ligand.  (1.22+0.12%  heart  chloro  et  these  i s monodentate,  marked  yielded  images  the  and  former  0.038%  Therefore,  x c  technetium  some  of  quality  m„  of  a  the  human m y o c a r d i u m ,  isonitrile)  revealed  with  species  working  average  (Ketring  promise.  class  of  of  studies,  halogens  9 9  developed  image  myocardial  later  Jones  any  best  compared  lower,  In  an  halogen  complexes  d i f f i c u l t y  studies  for dimethylarsine  4 of  fluoro  Distribution  the  have  i n terms  investigation  be  studies  the  further  to  shown  among  favors  Although  quality  have  However,  dose/g  T1.  imaging.  mins.  uptake  with  uptake.  mechanism  t h e r e were  5  and  no  of  the  studies  99 Holman isonitrile)  et  a l . (1984)  technetium  (I)  utilized (TBI)  for  " V c hexakis imaging  4  (t-butyl  normal  persons  and  2  -  patients  with  obtained  by  may  not  be  the  lung,  CAD.  both  low  planar  suitable which  post-injection uptake  agents,  Sands  the  neonatal uptake  suggested  that  wall  the  (30-60%)  as  understand  and by  human  that  had  shown  i n cultures  times  >  or  by  technetium  (I)  system. was  so  Sands  involved  et  a l .  was  the  of  these  and using  found  that  the  probably  (1986)  Maublant  myocardial cells  hour  a l . (1984).  (IPI),  i t was  i n  spleen  i n myocardial uptake  previously. of  that  and  et  TBI  I t was  uptake  problem  mechanism of  however,  f i r s t  liver  Holman  kinetics  KCl,  high  Another  images  agent,  i n the  1 hr,  uptake  the  This  image  image.  the  quality  of very  erythrocytes.  ouabain  l i p o p h i l i c i t y  the  reported  examined  good  scanning.  of  At  Na+/K+ATPase  the  a l . (1984)  demonstrated  quality  of  very  because  1986).  a l . (1986)  unaffected to  et  use,  (isopropylisonitrile)  unrelated  Jones  yield  r a t myocytes  was  tomographic  the  apical  -  demonstrated  for c l i n i c a l  to better et  xc-hexakis  and  (Gerundini,  radiochemical order  study  decreases  obscures  In  The  23  et  of  just  a l . (1988)  newborn  as  have  rats  9 9m Tc-hexakis-2-methoxyisobutylisonitrileTechnetium  (  insensitive  xc-MIBI) to  shows  slower  metabolic inhibitors,  uptake such  and  as  i s  relatively  cyanide,  iodoacetate  and  ouabain. 99™ ( changes  u?c)MIBI i n pH.  uptake  was  Piwnica-Worms  also et  found  to  be  a l . (1988)  insensitive  have  found  to  that  hexakis  99„ (carbomethoxy-isopropylisonitrile) technetium (I) ( T:c-CPI) uptake i s also insensitive to several metabolic i n h i b i t o r s , but  was  9 9™ temperature-sensitive. pyrophosphate,  i s a  Clearly,  this  agent,  like  non-physiological  tracer  and  Tc thus  would  be  useful  - 24 as  a  tracer  for  information.  tissue  I t was  perfusion  also  found  studies that  but  would  y i e l d  extracellular  no  metabolic  alkalinization  (pH  9 9m 8.5)  partially  changes clear,  had  no  data  questions  to  much  with  Tatum  et  stress  of  test  however,  was  ischemia.  means  of  and  The  myocardial  on  suffering  Therefore,  an  area  the  ischemic  not  some  myocardial  of  the  the of  and  areas  patient  underwent  a  scan  unlike the  activity,  patient  A  representing  borders  a  stress  but  no  a  myocardial  scans.  T l ,  study,  underwent  small  2 0 1  were  the  myocardial  post-exercise  around  and  acute  the  shown  c l i n i c a l  identify  o  decreased  post-exercise  were  thickening  recent  indicated  isonitriles,  ratios  uptake  or  endocardial  a  t  x l  from  day,  results  resting the  answer  wall  In  20i  and  following The  i s s t i l l  isonitrile,  Normal  RP-30.  RP-30  demonstrating  only  w i l l  excellent  TBI.  normal  T1,  seen  which  shown  post-infarction,  the  mechanism  pH  a l . . 1988).  over  days  identifying  infarction.  patient  on  uptake  intracellular  Background-to-target  Nine  both  et has  imaging  u s i n g RP-30.  seen  as  u t i l i z e d  i n a  the  while  T^c-methoxy-isobutyl  well  ischemia.  infarct,  of  as  planar  defect  which  f o r RP-30  a l . (1988)  2 0 1  (Zanelli  i s  uptake,  available  a l . . 1986).  motion  using  evidence  et  improved  infarction. test  remain  gated  perfusion  Although becoming  potential  (Maddahi  epicardial  T'c-CPI  isonitrile  RP-30  seen  s t i l l  which  imaging  be  effect.  are  Another and  inhibited  may of  defect, an  area  provide a  a  myocardial  -  -  (b)  Thallium  (i)  Historical  studies  of  Blumgart  -  the  and  Perspectives  Weiss,  circulation  i n man.  possibility  of  4 2  to  study  K  the  be  need et  would the  the  u t i l i z i n g  unsuitable  show  a  reduced  f e a s i b i l i t y was  and  It  was  not  a l . (1970)  be  a  demonstrated and  heart.  high In  of  4 5  K  C  pulmonary many  pathways  (Greenberg  and  of  of  K. 8 6  saw  and et  the  localize  al..  these  1938) agents  biodistribution  reported  carrier  i n  that  the  as  an  of  radioisotopic  now  turned  to  agent  which Thus,  studies  the  of  this,  myocardial infarction.  using  of  because  In view  Rb  use  i n  of  the  development  tracers.  with  the  realization  emissions which  the  Lebowitz  use et  of  the  of  a l . (1974)  species,  the  were  available  too  high,  ion, T l  demonstrated Studies  tracer  including  that  thallous  i n myocardial scanning.  other  1920's.  radium  the  trace  u t i l i z a t i o n  concentrations  many  the  myocardial circulation,  Attention  had  of  absorption  i n areas  1970,  to  radioisotopic  authors u t i l i z e d  injected  the  suggest  agent  to as  of  use  of  radioisotopes,  a l . (1954)  suitable  analogs  imaging.  useful  et  of  uptake  until  Kawana  may  pathways  for studying  more  isotopic  radionuclide  These  possibility  potassium et  agents  back  through  of  1939).  Love  the  flow  such  established.  refinement of  dates  advent  these  examined  u t i l i z a t i o n  described  the  amounts  a l . (1962)  system  elements,  al..  for large  myocardium and  With  systems.  The  of blood  predominant  organ  may  Carr  velocity  (Joseph et  various 4 2  i n 1927,  physiological  K  -  cardiovascular  the  and  -  201  determining  various  25  within  rabbits,  dogs  +  , for 2 0 1  that  using the  d i d  T1  goats  kidney, and  liver  mice,  no  - 26 adverse  reactions  characteristics 2 0 1  made  and good  o f having  Radionuclidic  thallium  lies  metallic  element,  atomic  +1  substitute al..  ranging  i i i ) as  f o r K  from  a  +  Much  IIIA  I t h a s a M.W. 1980).  isotopic  forms  u s e ,2  the problem  0 1  optimal  f o rc o m m e r c i a l l y  images,  Thallium  table,  a n d h a s two  with  kinase with  i s a an  stable  to potassium  o f pyruvate  andcan  (Strauss  atomic  found  th =  as a myocardial utilized imaging  et  masses  e t a l . . 1981) , a n d a l s o available  gamma  both  report  due t o a t t e n u a t i o n  by other  over  i t s energy imaging  resolution  tissues  T l g ^ ,  orbital  agent c e n t r e s as  t h e p a s t 10-15 Zaret  precludes any  importance.  on poor  by  cardiac  downfalls.  which  2 0 1  -  imaging  i n many  agent,  some  72 h r s ,  t o be o f considerable  (1979)  Evaluation  o f 73 h r s a n d d e c a y s  T 1 h a s shown  of a  (Maublant  Burdine  systems  o f patients  chemistry.  o f T l exist,  Although  imaging  and  imaging  on the chemistry o f  o f the periodic  and Experimental  and i s u t i l i z e d  o f c l i n i c a l  also  o f t h e work  I t i s similar  has a h a l f - l i f e  e t a l . . 1975).  was  gamma  1980).  o f 204.39  i n the activation  Application  capture  discussed  standard  of organometallic  standard myocardial perfusion  years  I t s physical  191 t o 210.  radioisotope,  (Lebowitz  with  et a l . .  -  i n group  (Kemp,  Twenty  Clinical  electron  the  o f 81.  a n d +3  1975).  Properties  found  found.  o f non-invasive testing  (Botvinick  i n the f i e l d  number  valences  IHD  were  resolution  T 1 a n a c c e p t a b l e means  suspected  ii)  to the tracer  (1977) sequential  o f 89 K e V was n o t  systems. Keyes  Attenuation  et a l .  of myocardial  (1978) planar  o f the thoraco-abdominal  -  cavity.  Another  area  non-physiological the  metabolic  fact  areas any  status  were  Another (Wackers recent  et  and  tissue.  during  which and  continues  was  over  time.  collateral  myocardial The  resolved  have  l  T l  use  2 0 1  T1  2 0 1  an  and  problem,  to  T1  was  information  In  view  of  on  the  ischemic blood  not  flow  able  these  i t s lack  T1  and  to  two  both  y i e l d  areas  2 0 1  this  T1  et  (cold  i s assessing  T1  associated  i n  c l i n i c a l  on  i n i t i a l  represent result  oxygen  of  scans  an  area  areas  after  3  to  significance  of  describe  a  of  increased  demand.  identify  study  a l . (1988)  myocardium  following  the  the  These  ischemic  may  myocardial  2 0 1  myocardial  a l . . 1980).  spots)  infarct as  of  problem  into  observation to  et  size  a l . (1977).  and  between  necrotized  a l . (1980),  time,  r e p e a t i n g the  Tatum  the  et  i n dogs et  and  major  Pohost  apparent over  A  specificity  distinguish  ischemic  (Beller  of  of  d i d not  determine  areas  decreased  however,  phenomenon.  and  between  or  Beller  i t s e l f  by  2 0 1  was  of  defect  u t i l i z e d  infarction,  redistribution  0  i n man.  circulation  a l . (1984)  2  occlusion  Thus,  l i t t l e  1978).  normal  investigated.  that  yield  a  a l . . 1980).  redistribution  tests  i s  myocardial  rates,  r e p o r t e d by  coronary  resolved  which  within  infarction  be  T1  (Gewirtz,  regional  of  of  f i r s t  demonstrated transient  would  i s redistribution  demonstrated  hours.  et  2 0 1  that  distinguish  The  to  studies,  et  would  Leppo  technique  ischemia,  T1  washout  u t i l i z a t i o n  exercise-stress  tissue 2 0 1  of  disadvantage  Redistribution authors  rates  a l . . 1980).  The  this  thus  old myocardial  infarction with  agent  the  similar  information 1978  was  u n a f f e c t e d by  exhibited  (Gewirtz,  of  -  concern  imaging  t h a t washout  myocardium  of  27  Massie of  acute  4 this  case-study  -  in  which  study  the  was  information  inaccurate,  28  obtained  defining  a  -  following lesion  2 0 1  a  much  T1  redistribution  larger  than  that  defined  99m by  (  vivo 2 0 1  Tc) and  T1  isonitrile.  i n vitro  from  the  (Table  into  1).  studies  infarcted  Clearly, research  Tatum  problems the  One  the  more for  fatty  acids.  of  i t s early  stages  (c)  Iodine-123,  (i)  Historical  of  has  et  a l .  to  (1963)  palmitic 1 4  assess  acid  C-labeled  extraction resulted  i n  and  This  an  optimal  an  2 0 1  T1  report  that  accelerated  called  ideal  both  i n  efflux  of  free  for  further  radiopharmaceutical  substances  myocardial  and  of  under  which  imaging  fatty  possess  are  acids,  experimental  Iodinated  aerobic  importance the  more  iodinated  however,  free  remains  assessment.  acid  by  rat  to  the  fatty  acids  and  labeled  to  allowed  acids  and  heart  storage  into  Acids  conditions  of  1950's as  fate  model.  accurately  Evans  radioisotope fatty  of  Fatty  since  extraction  isolated  isotope,  of  more  iodinated  triglyceride  attempts  incorporation  a  appreciated  examined  palmitic  gamma-emitting a,b).  been the  i n  with  promising  Perspectives  by  order  also  131  utilization  heart  of  c l i n i c a l  preferential the  (1988)  demonstrated  associated  characteristics use  a l .  myocardium.  ideal  in  have  development  of  The  et  free  the  i n  fatty  co-workers  to  u t i l i z e  both the  fatty  acid  myocardial  1956). pool,  inability  both  In Evans  1  3  metabolism 1  I ,  et  extraction form  of  myocardial  acid  (Evans  triglyceride  acids  C-labeled  involved  the  fatty  energy  1 4  The  assess  The  (Bing,  an  of  -  to  a  a l . . and be  1964  -  assessed. of  Evans  these  heart.  and  labeled  fatty  Problems  usefulness  as  radiation  dose  residual  a  to  Therefore,  (-193 work  the of  patient activity  was  needed  procedures  obtain  average  i n vivo  to use  greater  recognized  the 1  the  imaging  -  for  for  with  hrs  radionuclides to  acids  c l i n i c a l  -  co-authors  remained  exposure  h a l f - l i f e  his  29  purpose 3  1  and  These  of  the  because  l i f e  279  identify  of  label,  agent.  because  and  l  the  of  the  potential  photoscanning which  limited  included  a  (Myers,  i n  final  the  i t s  and  1974)  availability  the  large  i t s extremely  refinements  purity  diagnostic  /? e m i s s i o n s  of  hrs)  the  a  large  long (Table  of  suitable  labeling  products.  3).  Table  3  Physical 1974)  -  30  Properties  o f  - c l i n i c a l l y  -  1  used  Modes Beta 7  of  decay  Particles  energy  3  I ,1  1344 h r s .  EC  EC  none  none  I (Myers  keV  e ta l . ,  90.4%  27  192  363  keV  7  6.8%  KeV  average  &  keV)  none  Sowby,  193 h r s .  none  KeV  274-530  1  131 j  13 h r s .  7 - 3 %  3  1 25J  35 photons  1  1983. e d . F.D.  N.Y. , N . Y . )  158  I and  P u b l i c a t i o n 38,  ICRP  Pergammon  (X-rays  Other  S  (Radionuclide  Transformations, Press,  2  radioiodides.  123 J  Half-life  2  -  -1.6%  637  keV  723  keV  -  The next  decreased  decade  prompted  non-invasive 1 2 9  included 1 3  N-NH4  Cs  (Yano  1974).  Many  Landau,  1968).  1975 of  as  that  HDA  1 2 3  Poe  medicine one  (n,p), 29  X 1  1 2 3  of  early  (n,7)  which  of  1  2  3  8 1  use  C  label  earlier,  was  1 3 1  I  i n  that  also  acid  and  and  being  was  not  terminal  extraction  occurring  agents  a l . .  It  the  for  1971),  (Antony  perfusion.  naturally stearic  1 4  et  the  agents  These  a l . .  (Martin  the  u t i l i z e d found  Ru  imaging  system. et  over  actively until  position  percentages  compounds  61+7.8%  for  (77+11%  oleic  for  acids  I .  1985).  followed iodine  for  around  thyroid  produced  by  Sb  1 2 1  Iodine  A l l are  by  the  (He4,  and 1 2 3  on  2n)I  i n  I  has of  medical  scanning.  involve  including  et  use  reaction with  and  (n,7), Of  the  ideal  (Myers  The  i n  physical  an  i n vivo  used  (n,fission).  the  use  1 2 3  be  reactors  lastly,  medical  and  can  reactions,  requirements  i n vivo  uptake  which  produced  decay,  available,  studies  centered  of  neutron-induced  satisfies  c l i n i c a l  the  alternative  (Hurley  discussed  and  for  possible  radiopharmaceutical These  K  and  to  radioisotopes  (Mani,  radioisotopes  properties  4 3  myocardial  the  radionuclide  I )  29  five  (n,a),  with  a  C).  (  today  of  (HDA)  70+7.5%  exist  of  as  of  as  cardiovascular  1971),  co-workers  Production  There  any  to  the  continued  acid  iodine  a l . . 1970),  indicator  favourably  Iodine  of  Monahan,  and  over  -  development  Thallium,  an  with  1)  et  workers  compared  labeled  ii)  &  hexadecanoic  compared  the  assessment  (Hunter  explored  enthusiasm  31  1  a  a l . .  of 2  3  the  1962). 1 2 3  I  l  was  f i r s t  30  MeV  beam.  label  -  This The  difficulties  associated  with  method  necessitated the  of alternative  reactions,  including  and Blue,  (Sodd  et al..  decay  of  I  Wolf  1969),  Xe.  reaction  1  dose  utilized  examined  the  1  Te(p,2n)  1 2 7  I(p,5n)  energy  Xe  2  3  1  2  3  the  1  2  and an i n d i r e c t  much quick  1  2  2  5  3  f o r this  availability  of the research  1  2  3  2  3  1  I , Lambrecht 1 2 3  <0.2%  which  increased  o f an  i n 3.0 4  I .  >123  Xe  reported  2  Xe,  i o nby the  eliminated.  and no  1 2 3  I ,  I ,with  i t was  reaction  types  1 2 3  alternative  that These  authors  mCi/7*A/hr.  However, t h e  i s >50 MeV,  o f nuclear  which  i s not  1 2 4  Xe  and purity  will  (p,2n)  1 2 3  1  2  3  1 2 4  latter  1 2 3  Cs  Xe(p,2p)  >  1 2 3  l  >123I (25%)  method  was t h e  endeavour.  I i s necessary as the thrust  the development  yield  suitable f o r  e t a l . . 1986) and a  Xe  experimental  of  i s into  Xe  reaction  (p,pn)  This  f o r this  1 2 4  (Machulla  a direct  reactions  0+)123I(70MeV),  Xe(EC,  MeV),  reaction  k i t , which  1  of  resulting  and, l a s t l y ,  both  today  3  I .  cyclotrons.  I (25-40  I used  2  Te(4He,3n)  were  I impurity  B.C., C a n a d a ) . 3  (a,3n)  iodide  impurity,  i n which  reaction,  I(p,5n)  involving  Vancouver,  labeling  most  1 2 7  (75%)  The  1  I (25-40MeV)  (EC, £ + )  of  of this  1  —  yields 1 2 2  Te  l e d t o the development  a r e 4 main  sequence  preparation  Xe  required  there  I :  1 2 3  1 2 2  Xe  o f 99.8%  contaminants  0.1%  from  high  purity  The presence  final  (AECL,  a yield  1 2 3  this  carrier-free  the use o f the  e t a l . (1972),  available  preparing  1 2 3  I .  2n)  produced  to the patient,  Currently,  (/9+)  5  and only  beam  readily  2  3  Te( He,  to obtain  a l l radioactive  activity  proton  1 2 4  In order  by Fusco  virtually  of  which  generator and found  contaminating  1 2 2  1968) and  (1972)  radiation  4  from  (Sodd  and  2  7-rays  technical  1 2 3  1  i n contamination with high-energy  resulted  development  32 -  a pure  of a  product.  simple and  of  -  2)  Fatty Acid Early  addition the et  to a  terminal  iodinated within  et  double  acids.  a l .  was  across was  The  (1975)  established acids  that  removed  limiting  than  from  intensity  position,  carbon  l e n g t h was  within (Figure  the blood 3).  preparation vivo and  the highest  o f background  authors  stream  and Dutschka  u t i l i z e d  determined  (1980).  f a c i l i t a t i n g  increased by and Lee  images.  due  f i r s t  had  They  to free  also  fatty  the fatty  iodide  may  et a l .  acid noted  iodide  background  In their  aromatic  acid  of  (1978),  a very  when high  recirculating acids  the  (IPPA)  f o ri n  et a l .  (1980)  preparation  substitution  acid  be  occurred  problem,  described by Machulla  (1981b).  acid  scintigraphy.  beta-oxidation of the fatty this  fatty  concerns  Machulla fatty  Poe  iodination  gamma  of free  o f omega  units.  by  labeling  (1974)  recirculation  uptake  by  I t was  amount o f t h e f r e e  was  labeled  I-phenylpentadecanoic  nucleophilic  unsaturated  of terminally-iodinated  larger  to eliminate  s t u d i e s was  was  (Robinson  activity  a  carbon  1 2 3  from  at  terminally  of  acids  following  of iodinated-  metabolic Machulla  17  acids  that  levels  et a l .  replacement  o f fatty  radioactivity,  In order  discrepancy  o f myocardial  that  chain  that  studies  obtained  by Machulla  Robinson  the possibility the accuracy  a  the circulation  demonstrated  level  Thus,  these  i n higher  extraction  that  chain)-fatty  t o images  f o r such  bond.  image  the terminal  regarding  reason  from  resulted  compared  myocardial  the double  being  when  monochloride  e t a l . . 1965) o r i o d i d e  apparent  analogs  45% h i g h e r  involved iodine  i n omega-bromo-(long  and reconfirmed  Although at  acid  Procedures.  (Evans  I t became  fatty  -  at iodination  bond  position  the tissue  fatty  Iodination  attempts  a l . . 1974).  33  o f IPPA,  iodine  the  -  Figure  3  -  Catabolic  pathways  34  of  -  1 2 3  IPPA  and  1 2 3  IHA.  -  123 co—  I-Heptadecanoic  -  co- (p-  Acid CO OH  1 23i  34a  123  1 23  l-Phenyl)-Pentadecanoic  Acid COOH  I3-Oxidation  Acetyl-CoA  1 23,  Acetyl-CoA  / \ / C O O H COOH 1 23i  -  onto  the  phenyl  substituent High  and  pressure  purify  each  was  animals. the  number para,  30%  the  ortho  result  was  chromatography forms i n 4%  Machulla  chose  para  myocardium.  This  of  including  30%  ortho), para  the  the  the  end  of  the  In  an  attempt  nucleophilic and  iodine-isotope  and,  HSA  the  lastly,  to  alleviate  these  substitution  synthesis  of  exchange.  p-  The  1 2 3  then  radioiodinated  using by  conditions  minutes,  yielding  95%  and  yields  at  The  background  reduced  para  demonstrated  1 2 3  an  of  of  acid.  The  into  to  the  29%  from  mixture  procedures  of  1 2 3  test  uptake  suffer  isomeric  70%.  and  i t s greater  found  I  IPPA.  liver  isomer.  a  (70%  to  label  and  authors areas  uptake  pure,  with  a  102°C  then  at  the  of  latter and  (95%,  78%  by  of  isolation  hexane.  the  of  The  and  noting  170°C  reaction  50%  scintigrams  demonstrated  background  a  of  product  exchange.  Studies of  interest,  p-IPPA  preparation  subsequent  from  the  devised  unlabeled  temperature  examined  with  (1982)  highest radiochemical y i e l d  140°C  The  acid,  included  associated  involved  iodine-isotope  reaction  and  of  Eisenhut  recrystallization  The  IHA  loss  from  procedure  was  1 2 3  was  problems,  IPPA  derivative,  and  para  separate  fatty  because  method,  para  liver  to  c o m p l i c a t e d HPLC the  the  respectively).  70%  for administration  formation of  15-iodophenyl-pentadecanoic  decreasing  used  labeled  method  of  of  radiochemical yield  then  isomer  isomeric  temperatures  i n a  the  preparation  production  preparation.  aromatic  simple  the  requirement  form,  the  was  of  dissolved  problems,  -  substituent  isomeric  then  isolate  fast  The  liquid  of  para-IPPA  by  ring.  35  at  activity  at  170°C,  30  various with  yields, of  rabbit  differences  increased  for  between  heart  compared  heart,  to  uptake 1 2 3  IHA.  -  However,  this  36  p r e p a r a t i v e method  -  results  i n a  relatively  low  specific  activity. Therefore, including (Franke  triazene  replacement  represents  an  present  In  reagent  (Goodman  replacement  (Kulkarni  and  component  to acquire  was  McKillop  the para  position  on  due  to the steric  bulk  compounds  the  formation  the  C - T l bond.  develop  a  authors  found  aqueous  KI  resulted  t o be  used  f o r  was  Thus,  developed.  an  reported  These  early  reactions,  of the an  of aromatic  compounds  which  by  iodine  molecule.  later  was  The  this  the cleavage reagent  iodides.  simple  i n a  to  with  aromatic  few  synthesis of  of  These  intermediates  complete  be  thallated  the corresponding  t o be  to  intermediates f o r  through  used  also  preference  believed  These  effective  compounds  of  extremely  electrophilic  developed  thallium  i n the formation  techniques,  co-workers  synthesis of aryl  the aryl  labeling  electrophilicity  very  aromatic  one-step  1934).  ring  e t a l . (1969b)  treating  reaction  temperature. was  and  latter  procedures  the procedure.  the thallium  found  McKillop  high-yield,  The  of  were  into  the phenyl  of substituted  that  and  f o r the t h a l l a t i o n  for  iodides  The  of aromatic  the poor  specificity  room  1982).  efficient  and Abbott,  isomeric  iodides.  destannylation  e t a l . . 1981),  the iodination  and more  some  aromatic  Parkey, of  developed,  e t a l . . 1982), (Kabalka  component  i n use by  I n 1969(a),  reagent  a  (Gilman  limited  used.  faster  i n t r o d u c e d as  i n 1934  were  alternative induced  o f p r e p a r a t i o n were  study.  substitution however,  boron  important  order  thallation  means  decomposition  e t a l . . 1983),  thallium  the  alternative  minutes  aromatic  at  -  The of  15-p-  (Dougan  reaction 1 2 3  the  nature  of  a l . . 1971)  and  by  temperature  The  could  acid  incoming  the  base  latter alter  4  describes the  u t i l i z e d  i n this  preparation study  the  authors  the  the  T l  electrophile  aromatic  also  of  nuclear the  yield,  be  substituents  reaction  demonstrated  radioiodination  could  that which  mixture  (McKillop (Eisenhut,  the  concentration  was  maximal  with  of 0.1  NaOH.  Machulla to  of  by  1982).  M  i n Figure  a l . . 1986a,b).  orientation  influenced et  shown  -  I-iodophenylpentadecanoic  et  The  sequence  37  generate  Kulkarni  that  the  ortho yields  a l . (1981a,b)  IPPA  and  iodination  et  with  Parkey  resulted  steric  were  s t i l l  (1983)  Therefore,  efforts  efficient,  allowing  found  i n yields  while  low,  electrophilic  isomeric yields  hindrance  substitution,  used  of  of  that  70%  para  combining  aromatic and  para  and  associated  with  thallation  however,  continue  to  with  para  develop  a  greater radiochemical  1%  ortho.  between  labeling yields.  with  They  severely  substitution.  values  ortho.  thallation  99%  promoting  30%  substitution  50  reasoned limits  Radiochemical and  method  70%.  which  i s  more  -  Figure  4  -  Aromatic reaction.  electrophilic  38  and  -  nucleophilic  substitution  - 38a -  (CH ) 2  (V WC F ,  Nucleaphilic Aromatic Substitution  3  —C  \_..  + Tl ( C F C 3  3  OH  \  \ 3 Q  room temperature darkness 60 mins  Electrophillc Aromatic Substitution  2  14  0TI-C3K(CH ) -<  c  2  14  Kl(aq)  60 mins 68 -60°C N a l in 0.1 M NaOH 1 2 3  123, _// V(CHO ) -C^ OH 2  U  -  i i i )  Applications a)  mentioned  potential  X 1  by  in  of  a  and  carboxyl  technique  acid  and,  Canine  and  of  each  oleic  acid.  acids.  The  terminally  labeled  generation  s c i n t i l l a t i o n washout  similar  the such  to  the  In label,  which  was  of  the  metabolic extraction  to  33  view Poe  +  of  et  5.2%  the  a l .  parent  cascade  mean  age  of  60,  was  by  from  undergoing  cardiac  acids  the  and  linolenic  sodium-iodide Biphasic  an  authors  double free  reduced  bond  (77  oleic  study  Twenty-one  catheterization,  gamma  myocardial an  also  concluded  sterically  ±  i n  efficiency  fatty  characteristics c l i n i c a l  by  resulted  at  saturated  compounds  acid.  myocardium  with  C  linoleic  yielded  These  the the  labeled  fatty a  at  1 X  The  acids  double  examine  acids  oleic,  the  the  (IHA).  a  iodination  much  a  to  the  imaging.  fatty  by  substitution  collimator.  the  physical  long-chain addition  using  associated  acid  l  diagnostic  products.  compound.  undertook  1  re-emphasized  hexadecenoic  curves  iodinated  16.123i-iodo-9-hexadecenoic  I  included  e f f i c i e n c y was  (1977)  1 3 1  of  fatty  terminal  protruding  optimal  3  for  u t i l i z e d  The  flat-head  that  for  1  i n j e c t i o n of  extracted  iodine-label  that  and  acids  these  acid  time-activity  indicated  that  normal  compared  artery  detector  curves  end-product  that  of  were  of  technique  (1975)  evaluation  hearts  saturation  the  fatty  lastly,  bond  coronary  coworkers  position,  double  Direct  acid  iodinated  efficiencies  stearic  Poe  -  Experimental  comparative  the  position.  extraction were  C  saturation  terminal  earlier,  made  and  hexadecenoic  usefulness  authors  labeled bond  Clinical  Iodinated  As  These  -  39  acid 11%  alters  oxidation,  for  IHA  acid).  of  the  1 2 3  I  u t i l i z i n g patients were  with  imaged  a and  -  washout  rates  anterior  calculated.  oblique,  anterior  demonstrated  reduced  asymptomatic  angina  in  tracer  uptake  infarction reported  or  IHA  any  high  acid  (-70%)  and  believed  true  analog  of  myocardial 1977). 1 2 3  Van  der  i n 4  Wall  et  with  twelve  acute  tracer  MI  and  4  with  distribution  demonstrating studied  the  metabolism ischemic  a  of  canine  segments  been  found  that  good  correlation  1 3 1  as  2 0 1  IHA  et of  utilized  this  acid  These the  i n an  authors  presence  isolated  demonstrated or  absence  the  rat  of  of  control  this  agent  1 2 3  I  with heart  changes glucose.  In  label,  a  1 2 3  I  for  et  a l .  2 0 1  T1  the et  were It  similar  (1981)  longer  has  more a l .  i n  also  showed  a  optimal  (1984)  intracoronary  perfused  with  Kreb's  i n  acid  metabolism  fatty  8  myocardial  values  of  -  latter  Wall  Demaison  tag  revealed  the  of  authors  disease  values.  view  of  et a l . .  These  and  a  properties  artery  th  that  a l . . 1980).  characteristics  injection  normal  uptake  physical  fatty  to  Poe  imaging  der  of  Both  and  with  that  f e a s i b i l i t y  regional  found  and  reflected  results  Van  i n determining  compared  (1975)  the  The  activity.  They  Lee  acid.  the  IHA,  deficiencies  Robinson  coronary  1 2 3  i n  no  thallium-201.  and  myocardium  had  a l . . 1976a  angina.  T1  model.  (Westera  same  and  study  16-iodo-9-hexadecenoic  fatty  compared  unstable  myocardial  et  the  right  p a t i e n t s who  behaviour  documented  increased hepatic  value i n  (Poe  acid  between  of  of  and  The  Definite  demonstrated  (1980)  patients with  rest.  unsaturated  IHA  a l .  regions  efficiency  l e f t  assessed.  abnormalities.  studies  1 2 3  with  including  pectoris  i t s metabolic  I-16-iodo-9-hexadecenoic  studied  angina  extraction  c l i n i c a l  imaging  were  patients at  physiologic,  and  views,  i n various  regional wall  the  of  lateral,  uptake  on  experimental  and  seen  -  number  pectoris  were  a  A  40  solution. induced  by  -  Some chain  years  earlier,  l e n g t h and  uptake  by  the  extraction carbon  or  higher  of  mice  radioactivity chain  length  (1981). 12,  due on  15,  18,  lengths  of  n  while  >  19  longer  <  15  the  were  agents.  latter  effects  et  1 2 5  has  high  1  2  3  residence  found  than  and  was  The  I , showed time  suitable  for  for myocardial  within  the  fatty  substituted exist  a l . (1987) and  hypertension  and  used  by  Som  verapamil  et on  the  fatty  Otto  fatty  performed  et a l .  acids  chain  acid  (n  =  10,  length  r a t myocardium.  Chain  of beta-oxidation,  are  being  on  et  imaging  because  myocardial  acids  and  metabolic  have  demonstrated  acid  to  have  shown  ratios  examine  kinetics  i n  have  of  these uptake,  for  (DMIVN). the  of  that  greater heart  acid  as  retention  behavior  heart:blood  a l . (1988)  investigated  a l . (1987b,c)  i n the  fatty  15  of  of  perfusion  Ambrose  fatty  higher  from  level  by  of  myocardium.  acids  agents.  length  authors  effects  study  i t s  of  washout  within  I]iodo-3,3-dimethyl-18-nonadecenoic been  The  that  the  myocardial  that  examined  that  affect  chain  background  methyl-branching  release  a  length.  release.  with  would  that  s i x omega-halogenated  imaging of  readily  extraction  and  times  acid  acids with  similar  a  a l . demonstrated  found  accumulation  iodide  labeled  differences  myocardial  (E)-19-[  of  nonadecenoic  Goodman  fatty  et  fatty  authors  of  well-suited  iodovinyl  significant  acids  using  were  a  o c c u r r e d more  free  uptake  perfusion  terminally  slower  to  26),  Currently,  examined  These  demonstrating  residence  potential  of  myocardial  21, both  n  labeling  studies  Experiments  influences  of  fatty  kinetic  myocardium  Machulla  omega-halogenated  alpha-halogenated comparative  of  -  i n 1978,  myocardium.  of  atoms  site  41  The  effects  rats.  of  -  b)  Iodinated  The  influence  possible  use  of  myocardial 1 3  may  The  have  Freundlieb  Republic  of of  old  using  myocardial  scan  was  a  Infarcted  from zones  The  the were  as  HDA  excellent  an  having  differentiating  Many fatty  acid  various values  i n normal  Nuclear  1 2 3  1 2 3  20  Center,  prolonged  th  patients  minutes by  and  as  cold  values.  pathological  followed  hexadecanoic  abnormalities. volunteers,  this acid)  and  authors of  at  Federal  i n  20  patients  with  technique the  the  acid  acid  of  routine  myocardium  spots  The  was  curves. ischemic  regions  concluded  that  non-invasively  myocardium.  work  i n an  metabolic  Freundlieb  patients  3  following the  by  fatty  subtraction  radiopharmaceutical capable from  the  i n the  I)-hepta-decanoic  released  visible  of  (1979a,b)  assessed myocardial  disease  I  the  Thus,  addressed Vyska  Research  background  activity  studies  (iodinated  cardiac  Na  clearly  normal  c l i n i c a l  of  acid.  background-corrected time-activity  identified was  by  The  examined  value.  u t i l i z e d  authors  as  and  hexadecanoic  method  was  the  that myocardial uptake  was  These  bolus  acid  into  such  a l . (1981)  activity  infarctions.  300/*Ci  et  15),  background  coronary heart  employed.  determined  than  omega-halogenated-( 35  (n >  reported  lower  Medicine,  Germany.  Wall  scintigraphic  whose  Nuclear  persons,  injecting  40%  acids  examination  I-hexadecenoic  I t was  of high  (1978),  metabolism normal  was  1 2 6  der  acid  prompted  fatty  Van of  greater  problem  Institute  acid.  acid.  acid  length  chain  distribution  hexadecenoic latter  chain  longer  ^-hexadecanoic  -  hexa/heptadecanoic of  hexa/heptadecanoic  42  et  attempt  aberrations  a l . (1980)  suffering  to  from  CAD  identify i n  examined and,  th  lastly,  -  patients  with  identify  areas  uptake.  Examination  differences by  Dudczak  values than  of  one  congestive  7.7  et 30  a l .  rapid  week's  these  an  three Van  duration.  curves to  of  and  and  had  subendocardium,  and  u t i l i z a t i o n  FFA  associated with  metabolic  substrate  suffering  from  1 2 3  der  I-hexadecanoic  found  similar  (perfusion normally  d e f e c t s ) were  The  areas  examined  and  of  Washout  to  (Van  examined  rates  which  the  i n  washout  washout  the  rates  30  acid  of  et  1 2 3  to  myocardium to  compensate requirements washout  by  a  shift  i n  a l . . 1981b).  rates  when 29.1  of  pectoris  and  segments compared +  reported uptake,  formation.  +  patients  ischemic  were  fatty  rates  phenomenon  angina  with  with  prolonged  washout  prolonged  triglyceride  34.8  Wall  unstable  compared  diminishes  increases  myocardial  +4.8  der  less  compared  oxygen  i n  of  th  lower  explained  glucose  the  significantly  inflamed  The  reported  assessed  subepicardium  were  were  mono-exponential  this  increasing  ischemia  significantly (45.4  within  the  thus  pectoris  (1983)  prolonged  ischemia,  beta-oxidation  fluids  acids  3.5  attributed  i n patients with  results.  respectively).  (1982)  a l .  +  subepicardium.  fatty  angina  acid  perfused  myocardial  from  et  the  reversible  stable  Wall  by  revealed  tracer  infarction  from  to  significant  (1981a)  obtained  (16.8  authors  tissue  a l .  no  able  i n  findings  myocardial  regions  non-functional  Van  a  rates  i n contractility  of  revealed  et  Wall  were  reduction  der  non-infarcted areas  increase  a  Similar  Washout  of  authors  groups.  infarcted  outflow  by  however,  suffered  These  These  ischemia  for  rates  -  failure.  values,  (1982a).  respectively).  influx  and/or  th  of  p a t i e n t s who  compared  min,  infarction  between  time-activity values  of  heart  43  3.6 to  to  min, be  due  to  reduces  Freundlieb  I-hexadecanoic  et  acid  a l . i n  -  patients  before  grafting. values  after  R e s u l t s were  et  a l . (1986)  I-hepta-decanoic  grafting  compared  ventricular HDA.  to  found  of  following  normal  metabolism  u t i l i z e d  et  i n normal  myocardial cause  metabolism  (mins) To  reflected however, be 69% 7%  of  diabetic with  as  as  at  rest)  was  i n  infarction.  to  k i n e tics  rats.  Kuikka  et  washout  proposed the  of  1 2 3  of  u t i l i z e d  metabolism  the  assessed  metabolism  a l . (1985)  examine  bypass  also  for myocardial  examined  following  to  the  point,  process  of  patients Beckurts  of  fatty  a l . (1988)  acid  assessed  diabetes.  I-hepta-decanoic  i t s usefulness administration  validity  many  acid  of  measured  were  raised  investigators  beta-oxidation.  that  radioactivity  unchanged  et  study,  for of  monitoring  drugs  which  may  toxicity.  demonstrated  the  authors  50%  myocardial  the  washout  representing beta-oxidation, since of  >  th  of  non-insulin-dependent  hepta-decanoic  this  the  agent  s u b j e c t s and  myocardial  (1985).  and  a l . (1985)  Speculation rate  assess  this  i n patients  Villavecchia  to  similar  myocardial  (EF  Visser  a  aortocoronary  These  i t with  function  thrombolysis  i n normal  kinetics  acid  acid  In  following  artery  revascularization,  kinetics  patients.  correlated normal  after  tracer  i n patients  metabolism.  successful  a l . (1985)  HDA  and  coronary  unchanged.  the  non-grafted  for  i n that,  were  examined  that  iodo-hepta-decanoic  or  -  surgery  variable,  acid  function  I t was  indicative  et  cardiac  increased, decreased  Fridrich 1 2 3  and  44  fatty  was  acid.  present Thus,  as  Visser  Visser  of  that  and the  minutes  free  washout  by  believed  rates five  myocardial  his fatty  after  iodine,  r a t e s may  24%  elimination  et a l . washout  rates  colleagues, acid IV as  may  not  injection, l i p i d  represent  and  washout  - 45 -  of  free  iodide.  distinct tracer  patterns  may  following  allow various  demonstrated fatty  acid  The  that  validity  a n d what  Schon  et a l .  quantitative those  MV02,  et a l .  o f distribution  metabolic  i trepresents,  assessment 1 1  CPA.  Also,  i s opposite  phase  demonstrated  authors  subtraction  a  test  that  (mins)  o f  this  metabolism  et a l .  should  ratio  (1988)  have  oxidative  infarction,  Stoddart  f o r CAD  conclusions  and by Gavin  transluminal  were  before  this  reported  et a l .  (1987)  angioplasty.  a  differed  ratio  over  the size  metabolism  o f  direct  et a l .  (1987)  suffering scan  6 days  o f  i n imaging  a r e needed  The  a n HDA  concluded techniques  not a  increased  phase  i n patients  h a d undergone  improvements  with  o f myocardial  within  that  was  occur.  demonstrated  values  questioned.  the kinetics  o f the early  a n d MV02.  who  to be  prolonged  actually  authors  l-hepta-decanoic  o f HDA  since  indicator  o f th  1 2 3  user-gated-angiographic-EF)  Similar  percutaneous  this  o f  continues  w a s h o u t was  These  the v a r i a b i l i t y  myocardial (Multi  HDA  may b e a b e t t e r  between  rates  the half-time  on T-A curve)  e t a l . . 1986).  correlation  however,  t o what  the late  useful.  Luthy  of beta-oxidation,  of  The  rate  i s representative o f  washout  believed that  (y-intercept  scan  interventions.  o f myocardial  the size  acute  demonstrated  o f myocardial  d e - i o d i n a t i o n o f HDA  (1986)  o f  which  (Schon  however,  and elimination  i t s use i n the study  of  HDA  (1986),  metabolism.  acid,  from  Visser  from  and a  MUGA  infarction.  and background  information  by Railton  becomes  et a l .  as an assessment o f  (1987)  as  -  c)  Iodinated  The acid  problem  imaging  authors high  iodine  coworkers the  result  agents  adding  was  2  uptake  and  heart,  when  product which  a  that  20-30  was  4%  The  although  of  results 1 2 3  adequately  be  straight et  acid  carrier,  IPPA  was  1 2 3  I  from  IPPA  and  a  a  the  IPPA  the  can  of  1 4  C0  between by  the  Eckhardt  physiological  metabolism  of  fatty  higher  end  effectively  examined  the  the  agent  i t does  acids.  ratio  acid,  limited  the  authors  acid.  a l . (1984).  agent,  tissue  rabbit  This  by-products  et  a  was  catabolic  I-benzoic  two  i n  The  was  i t  iodobenzoic  also  1 2 3  as  (1909).  mice,  c i r c u l a t i o n and  and  IPPA)  demonstrated  The  physiological  2  and  bind,  i n the  acid.  a l . (1984b,c)  that  image/background  acid.  hippuric  1 2 3  Dakin  Langendorff r a t h e a r t model,  reported  the  1 2 3  i d e n t i f i e d as  like  et  i s not  (1982)  The  such  accumulated  Eisenhut with  (  In  the  iodo-hexadecanoic  coefficient were  release.  rabbits,  activity  production  reflect  In  and  iodine  radioactivity  20.  Reske  In  the  fatty  Machulla  acid  (1904)  which  chain  a l . (1980).  minimized.  radioiodide  excreted  1 2 3  acid.  correlation  Similar  of  residual  between  rates  fatty  Knoop  to  injected  to  t o be  activity.  measured  group,  metabolism  background  C-palmitic  by  post-injection.  any  1 4  of  ratio  eliminated  differences  would  work  background  IPPA  known  on  i n free  compared 1 2 3  of  Machulla  i n the  activity  phenyl  min  lower  of  addressed by  based  heart/blood at  m e t a b o l i c washout  alteration  decrease  demonstrated a  an  agent  substantial  with  was  acid  omega-p-123I-phenylpentadecanoic  chose  of  rapid  background  imaging  -  Phenylpentadecanoic  of  proposed  46  was  r  =  0.87.  Therefore,  appear  to  -  In (1981) The  order  to  u t i l i z e d  authors  maximal  mouse  also  incorporated myocardial  examine  IPPA  for  the  uptake  and  washout  17%  dose/g  of  The  similar; segments  that  two  carrier-mediated less  active  The  as  was  derivative uptake  uptake  was  followed  1 2 3  was  present  free  1 2 3  (1982) . the  IPPA. The  Langendorff  1983).  as  This major  Schmitz  by  metabolites removed  from  identified,  formed the  by a  the two  i n  examined A  iodo-hexadecanoic within  chain  - passive  hypothesized  that  product 1 2 3  with  acid  The  than  authors  diffusion  the  and  ischemic  analogue  latter  found  I-benzoic a  and  a  becomes  extract of  acid  and,  Fuchs  acid  et  Most  dose/g  the  Three  method the  et  outflow (Ercan  major  lastly,  to  a l .  of  present  the as  a l . perfusate  of  et a l . .  characterize  perfusate  omega-p-iodo-phenylpropionic  omega-p-iodo-phenylpropenoic  Reske  gas-liquid  analysis  heart.  by  i n  by  curve.  <1%  reported  u t i l i z e d  l i p i d rat  lipids  also  spectrometric the  reported  component washout  was  (1984)  perfused  including  was  minutes  uptake  existed  extraction.  (1982a)  a l . . 1983).  myocardium  myocardial  catabolic  chromatographic-mass  2  a l .  occurs.  finding  a l .  a l .  et  myocardium.  straight et  acid  et  at  Daus  effective  rat  both  the  (Westera  p r e p a r a t i o n was et  for  They  from  relative  mechanisms  diffusion.  (1982a) IPPA  greater  ischemia  maximal  the  of  IPPA,  fatty  occurred  uptake  however,  the  Reske  IPPA  tissue  absolute  of  pool.  1 2 3  of  1 2 3  of  demonstrated  portion  triglyceride  phenylated  believed  a  the  was  myocardial  that  and  into  uptake  -  pharmacokinetics  myocardium  showed  post-injection. 1 2 3  the  47  as  i t  metabolites  was were  acid,  p-iodobenzoic  acid.  the  -  Time-activity following disease  by  1 2 3  acid  and  that  25-30%  every  from  min, et  the  washout  of  rates  1 2 3  was  passage.  3  40-60  was  et  Kulkarni 4  to  40  after  peak  exercise  et  min  slopes  at  spike  i n  the  (1982a,d)  normally  a l .  (1985)  following  i n normal  CAD  et a l . .  th  1 2 3  of also  were  I-hippuric  reported  obtained  myocardium clear  injection  volunteers  were  post-injection  perfused  the  0-10  findings  minutes form  heart  at  exhibiting  Similar  1-5  IPPA,  (Reske  patients with  a l .  e x t r a c t e d by  from  vascular  min.  i n which  Reske  images  and  and  activity  acid.  IPPA  min  into  radioactivity  the  a  1 2 3  of  valvular  multicomponent washout  (1984a)  blood of  a  exhibited  divided  6-10  a l .  I-benzoic of  imaging,  c o u l d be  50-80%  blood  myocardial rest  Reske  that  gamma  curve  Analysis  revealed  derived  f o l l o w e d by  0.24-0.5  studied.  at  was  The  of  reported  at  planar  which  1982c,d). values  -  intracoronary administration i n patients with  using  seconds,  curves,  48  with  1 2 3  of no  IPPA  adverse  effects.  Following potential various et 1 2 3  a l .  of  (1982b)  that  Dudczak  They  IPPA  many  found  et  a l . with  work.  both  found  values para  th  isomer  ratio  1.96,  Machulla  was  th of  of  also  a l .  to  shown the  from 1 2 3  CAD,  I-HDA  In  min,  to  ortho  (1986),  washout  a  which  have  CAD a  i n  and curves  later  study,  were  i n  from  his  decreased  isomer  however,  the  Dudczak  biexponential  values. 69.3  examining  acid  for patients with  relative et  rates  exhibited  values  reported  fatty  suffering  washout  agents  performed,  i n  patients  prolonged  myocardial/background respectively).  changes  myocardial  that  (1983a)  The  In  anesthesia  the  s t u d i e s were  i n analyzing  assessed  halothane  accordance earlier  work,  pathological states.  IPPA.  and  1 2 3  this  (1.50  reported  vs.  -  decreased  myocardial uptake  have  demonstrated  long  retention  studies  have  patients and  et  this  43-150 acid  IPPA  (EF)  The  normal  have  in  et  i n the  al..  occlusion. occlusion 1 2 3  (n =  et  of  a l .  (1988) with  other  washout  a l . (1987),  normal septum  and  and  i n such  patients  rates  Davies  et  i n  a l .  (1987)  and  12%  as  patients  curves  had EF  (30  found  min)  t o be  1 2 3  examined  and  4  1 2 3  IPPA  1 2 3  Dudczak  I-HDA  coronary uptake  below wall.  IPPA  1 2 3  IPPA  artery  i n a  i n viable  with  et a l .  and  Langendorff swine preserved  50%  of  (n  fractions  posterolateral  above. for  (HCM)  extraction  rates  fatty  dilated  injected  were  of  normal  into  were  values  following  examined  rates  cardiomyopathy  i n the  described  patients  washout  subdivided  DCM  group,  rates  biexponential  a l . (1987)  patients  normal  washout  a l . (1988)  was  acid  m y o c a r d i a l washout  findings  uptake  from  HCM  below  min)/reperfusion  were  ergometry,  p r o l o n g e d washout  IPPA  et  hypertrophic  i n the  biexponential  et  Knapp  suffering  assessed  demonstrated  showing  fatty  i n cardiomyopathy  9)  been  cardiomyopathic  with  patients  also  a l . (1982b)  These  1983b).  assessing  similar  Reske (40  and  have  et  fasting  patients  studies  found  calves  Cardiac  (DCM)  The  produced  (1982b)  number  acid  Dudczak  activity,  cardiomyopathy  below  Animal  A  fatty  Kaiser  i n human m y o c a r d i u m  IPPA.  et  curves.  irregular  undergoing  IV.  10%  1 2 3  cardiomyopathy  values  washout  (Dudczak  While  p-  Vyska  from  myocardial extraction  11).  to  analysis.  acid  cardiomyopathy  1 2 3  of  gross,  subjects.  isomer.  i s retained  examining  including  suffering  type  min  IPPA  ortho  a l . (1987).  labeled-fatty exhibited  1 2 3  relative  p r o l o n g e d th  extremely  o-  -  f o r the  performed  CAD,  Patients using  times  been  with  Reske  that  49  coronary  heart  model.  tissue  =  -  following  reversible  myocardial  imaging  ischemia.  agent  50 -  1 2 3  Clearly,  capable  IPPA  shows  potential  o f assessing metabolism  as a  as w e l l  as  flow. Since  perfusion directly  relationship  between  be  (Reske  addressed  (RMBF)  was  found  cardiac uptake  order  t o determine  between  was RMBF  as  under  At  increased  found that  high  flow  IPPA  in the  level  reported  rates  uptake  coronary  uptake  such  limit  similar  i n a  (1987)  instrumented  1 2 3  =  seen  with  pacing,  uptake.  a t 150-170 i n  1 2 3  whether  1 2 3  dogs.  While  could  be used  noted and  uptake  treadmill were  injected  authors  that et  at higher  IPPA  the animals  well  Schoen  The authors  and the agents  IPPA  also  uptake.  determined  deposition during  In  ml/min/lOOg.  ml/min/lOOg  uptake  RMBF.  a  dose.  these  I t was  limited  accurately  with  and as  20-50  IPPA  flow  ( r = 0.94)  conditions  with  occluded  that  correlation  RMBF  IPPA  blood  must  correlation  where  f a l l  findings  and microsphere  found  1 2 3  existed  reflect  was  o f  the  IPPA  animals  t h e two,  control  as those  1 2 3  o f the injected  a close  ischemia  o f  myocardial  i n control  between  under  availability,  and uptake  o f 4.5-6.0%  I t revealed  increase  et a l .  artery  I t was  IPPA  resulted  could  6 chronically  atrium.  rates,  or upper  Caldwell  1 2 3  o f acute  a moderate  this  (1984)  rates.  1 2 3  flow  a plateau  exceeding al.  IPPA  conditions  only  o f  IPPA  Regional  the relationship  1 2 3  flow  90-120ml/min/100g  performed. and  blood  e t a l . . 1984d).  total  analysis  myocardial  t o be  1 2 3  influences  flow  at  compared exercise running,  into  the  to accurately  left  assess  RMBF.  An of  1 2 3  interesting  IPPA  1984).  or fatty  finding acid  with  major  metabolism  implications  by lactate  i s the  (Eckardt  inhibition  eta l . .  -  Reske  et  a l .  decreased  (1986)  fatty  hearts.  Duwel  infusion  before  th  patterns  group,  ie.  acid et  oxidation  under  conditions. anaerobic  work  of  quality  prolongation  of  animals  (202  +  attempt  was  Rellas uptake  and  permanent measured. exhibited  normal  and  uptake.  th 65  that  in  this  of  1 2 3  temporary  Infarcted reduced  myocardial  but  does  i t also  success  to  have  in  the  and a l .  ischemia (1988)  inhibit  does  under  so  effects  assessment  attempted  to  +  to  IPPA  under  coronary  In  uptake  min,  quantitate  a  et  FFA  normal  during  control  artery  as  temporary  was  only  slightly of  myocardial  i n  fixed  with  zones  areas  i n  and dogs  LAD  to  control No  infarction  which after  were  closure  occlusion decreased  infarction  of  marked  experiment  dogs  The  as  compared  conditions  with  (1982d)  respectively).  occlusion  segments  a l .  revealed  the  similar  myocardial  cardiac  infarcts  kinetics  7.1  of  assess  Reske  i n f a r c t e d dogs  conducted  segments.  et  Similar  lactate  profound  imaging.  41.5  study  uptake.  lactate  CAD.  group  rat  conditions.  myocardial  myocardial  only  particularly  within  (1983)  a l .  not  of  et  from  Duwel  Examination  volumes.  sodium  intervention  oxidation.  concentrations  Langendorff  of  suffering  myocardial  values  and  effects  visualizing  tissue  and  acid  SPECT  compared  washout  reperfusion,  have  ischemic  IPPA  patients  conditions,  images,  made  of  fatty  i n high  hearts  the  lactate  investigators  1 2 3  obtained  in  lactate  canine  examined  found  could  -  that  in  the  i t s apparent  some  IPPA  of  and  or  using  1 2 3  for  ischemic  geometry  terms  (1987)  shown  states  metabolism,  in  a l .  This  view  reduced  oxidation  inhibition this  reported  scintigraphy  were  continued  In  also  51  followed compared  estimated  by  by to  -  1 2 3  examining  IPPA  kinetics  infarction  demarcated  that  was  there  probably  due  a  to  rapid beta  between  myocardium  1 2 3  examined  the  myocardial uptake was  of  i n i t i a l  metabolic  F-deoxyglucose,  rates.  even  et  a l . (1987)  . I t was  the  a l . (1987) and  of  was  short an  though  of  noted,  et  also  a l .  increase  i n  however,  which  was  could  stunned,  periods  normal  of  myocardium  Schwaiger  demonstrated  123JPPA i s  more  reversible  abnormalities, but  coronary  d)  sensitive  artery  but  viable,  (1987)  (30  min)  the  of  relative  myocardial  blood  flow  Miscellaneous  been  shown  quality  to  over  Fatty  time.  time  perfusion  defects,  assessment patient  may  to  groups.  attempted  to  2-dimensional  was  i n  i n patients  the  with  detection  equivalent to  CAD,  of  thallium  for  detection  Acids acids  and  from  rapid  i n i t i a l  Thus, be  the  washout,  fatty  which  increasing  a p p r e c i a t e d when  an  attempt  and  myocardial  c l i n i c a l  myocardial  Conventional the  imaging  systems  3-dimensional  Keyes  et  image  a l . (1978)  and The  to  believed  an  influence u t i l i z a t i o n been  heart  that  assess  Such  (ie. planar the  image  myocardial  d e f e c t s has  of  have  decreases  infarction.  significance  perfusion  acids  i s made  therapeutic interventions.  assess  plane.  iodophenyl  of  important  compress  the  benefits  i n particular,  have  management  radionuclides many  can  thallium  fatty  suffer  residence  than  that,  stenosis.  Straight-chain  by  et  zones  reinstituted.  Pippin  of  from  infarction  outcome  with  staining.  Kiess  consequences The  closely  washout  of  washout  ischemia. 1 8  tetrazolium  areas  IPPA  -  correlated  oxidation.  differentiate by  by  52  to  attempted  imaging) onto  of  have  a  accurately  -  quantify display  these  perfusion  3-dimensional  the location  planes  and z ) .  advantages  over  quantitate  perfusion  One ago  trapping, for  tellurium  This  defects  group  o f SPECT  imaging  a i d i n perfusion  by  washout  Goodman onto  also  2  By  A  similar  deiodination  (Goodman  rates.  carbon  6  rapid  study  One  the tellurium  towards  perfusion  within  attempt The  usefulness  studies  a  Livni  fatty  the myocardium  acid by  acid  Gallagher  atom  showed  at metabolic  a  trapping  o f  a  problems  of a  residence  uptake  was  retention  acid  time.  and low i n v i v o  performed  times  with  i n dogs  toxicity  o f oxygen  has  fatty  and  and  e t a l . . 1986).  tellurium  showing cats  stability  dramatically Efforts  acid  are  analogue  e t a l . . 1987).  e t a l . (1982) that  fluorine  new  (Machulla  (Srivastava  a  years  metabolic  introduction  myocardial  i n the presence  the development  Alternatively, straight-chain  However,  heteroatom  i t s c l i n i c a l  continuing for  was  34  o f 15-p-iodophenylpentadecanoic  using  and prolonged  e t a l . . 1985).  to  (proposed  imaging,  o f deoxyglucose,  tellurium-iodinated-phenylpentadecanoic minimal  distinct  attempting  substituting  e t a l . (1982).  demonstrated  i n a l l three  offered  when  would  work  infarction  b e t a - o x i d a t i o n and increased the myocardial  agent  limited  their  which  ( C a l d w e l l e t a l . . 1984).  at carbon  heteroatom  deiodination.  of  required  from  of the myocardial  The u t i l i z a t i o n  would  i n tissue  performed  blocked  Results  ( G a l l a g h e r e t a l . . 1978).  reduction  was  o f radiopharmaceutical development,  which  a hydroxyl  was  a method  conventional planar  method  i n 1954),  defects,  -  information.  demonstrated (x, y  53  hypothesized  i s partially  introducing  that  metabolized  a methyl  group  a  labeled  and  trapped  at the beta  carbon  -  may  offer  an  beta-methyl[  ideal 1 1  corresponding  perfusion imaging  C]-heptadecanoic  beta-oxidation  54  sequence  being  beta-keto-acyl  acid  -  agent. was  (Figure  their  u t i l i z e d  halted prior CoA  In  to  5).  the  with  scheme, the  formation  of  the  -  Figure  5  -  Metabolic  trapping  55  -  scheme  - 55a -  Straight-Chain  Fatty  Acid  RCH 2 CH 2 C00H  Beta-Methyl  Fatty  Acid  RCHCH 2 C00H CH-  RCH 2 CH 2 C0SCoA Dehydrogenase RCH =  CHCOSCoA Hydratase  RCH — CH,C0SCoA 2 ) OH Dehydrogenase RCCH o C0SCoA  II  2  RCHCH-COSCoA 2  I  CH 3 Dehydrogena se RC =  I  CHCOSCoA  CH 3 Hydratase OH RCCH 2 COSCoA  0  HSCoA RCOSCoA + CH3COSC0A  CH. Dehydrogenase^  -  The  radioactivity of  l i t t l e  decrease  dose/g  tissue  metabolism  over  at  60  halted The  to  be  and/or  et  a l . . 1984  steric  1 1  u t i l i z e d  fractions  were  zones)  and  normal  zones,  marginal  MV02,  i t was  <1%  decreased  glucose  and  lactate  i n FFA usage  myocardial  within  the  label  acid and  the  u t i l i z a t i o n  (Wijns  et  retention  of  myocardium,  and  45  an  18%  a l . . 1985). fatty  thereby  acids  i n  was  thickening  ischemic  oxidized  i n  Blocking  dysfunction, (Wijns  et a l . .  decreased  increase  i n  The  latter  and  increase  improving  also  Extraction  zones.  including  and  (Goodman  dogs  ventricular  wall  suggested  group  15%  agent  but  the  a l . (1984)  +  ischemic  i n minor  ensued,  also  et  2.7%  within  was  very  extracted  methyl  extracted  within  systolic  was  to  reperfusion.  of  also  acid  the  showed  minutes  i n open-chest  5%  %  dogs  remaining  from  i n normal  results  5  retention  5%  oxidized  and  fatty  +  alterations  decrease  the  was  at  and  Abendschein  occlusion  (25  that  LVSP  60%  spent  a l . . 1985).  sequence  a  time  the  inhibition  rats  tissue  myocardial  branch  noted  while  Metabolic  increase  Thus,  of  calculated  beta-oxidation  1985).  et  dose/g  radioactive  chemical  Livni  i n both  C-beta-methyl-heptadecanoic LCX  including  minutes). the  -  agent  (2.3%  mechanism  and  following  the  time  with  myocardium.  this  56  image  would their  quality  when  scanning.  Since  Goodman  et  phenylpentadecanoic  a l . (1982)  acid  with  extended  this  work.  Miller  activity  i n a  normal  zone  ischemic  zones  and  scanning  of  of  canine  f i r s t  beta-methylation,  et  a l . (1985)  (posterior myocardium  closed' chest  suggested  dogs.  wall)  some  examined and  following The  the  metabolic  value  investigators  the  border LAD  potential  of  have  metabolic and  central  occlusion/reperfusion behaviour  of  normal,  -  border  ischemic  differed. normal  The  zones,  significantly compared that  to  methyl  half-lives min;  and  central  latter  two  th  with  86.5  +  3  areas  fasted  within to  (1987),  myocardial  In  i n a  order  patterns  of  showed an  13.4  1.7%  et  Knapp  l i t t l e  and  a l . (1987a) The  accumulation  8.3  Otto +  et  1.1%  and  accumulation,  over  ±  0.2%  time.  IPPA  i n patients  urine  major  samples,  metabolic  In  et  order  investigators  to  determine compared  these  mitochondria  and  the  CAD  hippuric  using  the  assessed  the  and  acids  higher  IPPA.  myocardial  and  38%),  (18%  while  and  15%).  accumulation and  showed  MI.  et  found  metabolic  were  Grado-  to  of  microsomes, 13.7  retention  acute  min;  distribution  organelles  with  De  i n  (34%  however,  report  5-10  demonstrated  r e p o r t e d an  analogue,  30-45  hrs.  was  microsomes  29  (IPP),  compared  analogue  within  from  acid  (BMIPP),  model,  +  myocardial  subcellular  respectively,  suffering  byproducts  have  IPP  a l . (1986)  benzoic  and  being  a l . (1986a,b)  the  6-7  from  (115.6  differences  examined  within  beta-methyl  Dudczak  these  a l . (1985a)  of  The  3.7  acid  (DMIPP),  dimethyl  mitochondria  study,  et  increased  rat heart  understand  agents.  i n the  zones zones  f o r beta-methyl-IPPA  respectively.  and  control  acid  isolated  times  further  these  earlier +  to  Ambrose  predominantly IPP  working  retention  retention,  1 2 3  the  beta-methyl-iodophenylpentadecanoic  al.  B  ischemic  zones  different  iodophenylpentadecanoic  dimethyl-iodophenylpentadecanoic  In  the  considerably  rats:  infarcted)  significantly  respectively).  substitution i n  (partially  were  relative  min,  -  ischemic  values  prolonged  57  ±  of  0.3%  activity  behavior  From  of  plasma  identified  as  the  TLC.  c l i n i c a l  usefulness  currently  used  of  such  perfusion  an  agent,  imaging  agent,  -  2 0 1  T1  with  uptake  the  and  myocytes  ATP  2-deoxyglucose it  d i d not  of  B  was  1 2 5  affect  with  embryo.  after  The  latter  0.89  (p<0.05).  with  an  advantage  of  r  of  =  being  had  B  1 2 S  0.53  an  i n  no  B  compared  1 2 5  with  on  indicator  Thus, of  cyanide  uptake  uptake  2  of  o i  fatty  both  T  1  or  t  (CN)  or  although release  intracellular  correlation  (pNS).  to  by  IPPA  effect  measured  cultured  inhibition  IPPA  The  a l . (1987)  T1  were  decreased  CN  r  poor  values  et  2 0 1  and  metabolic  correlation  =  Okano  IPPA  These  The  distinct  [ATP] [ATP],  o  acids  myocardial  offer  the  metabolism  perfusion.  In acids  canine  the  2 0 1  and  suitable  the  with  zones  after of  fatty  infarction,  of  2 0 1  of  perfusion,  acid  c l i n i c a l  as  T1.  LAD  fatty  taken  studies with  that up  seem  thallium  studies  were  acid  by  to  as  These  authors  the  of  within the  size  examined imaging  7  found  that  i n  occurred  i n 7  of  decreased  RMBF,  myocardium.  imaging to  areas  are  another  thallium  accumulation  fatty  agents  activity  a l . (1988)  and  within  needed  both  overestimated  et  indicate  for  that  quoted  acid  i n dogs.  i t appears be  was  Fischmann fatty  beta-methyl  decreased  consistently  combined  ligation  animal  (seen  T1  of  reported  Redistribution  of  to  differences  a l . (1988)  2 0 1  The  use  continue  the  infarction  Therefore,  Although combining  the  decreased  acids  et  defect.  benefits  acute  animals.  fatty  Kairento  tissue).  perfusion  possible  days  examining  detecting  infarcted the  studies  T1,  for  inaccuracy  7  1 2 5  IPPA,  i t s release.  was  of  1 2 5  content  however,  and  B  (2-DG).  IPPA.  high  of  mouse  intracellular  -  beta-methyl-fatty acid.  release  from  58  the  usefulness  of  myocardial  optimise  of  i t s usefulness.  -  Patients angina  suffering  (n  =2)  from  and  severe  acute  MI,  transluminal  percutaneous  thallium  fatty  and  v a r i a b i l i t y stenosis. with  totally  flow  but  with  and  T l  the  agents  Knapp  2 0 1  normal  With  i n  the  able  used  to  the High the  heart/blood 4,4-DMIPP  heart/blood also  been  Investigations imaging  agent.  heptadecanoic with  within  the  longest were to  These have  (n  minimal  rest  (n  supply  studies,  severe  stenosis  6);  FFA  =  flow;  and  FFA  marked =  using  coronary  i n  =  unstable  with  these  of  » T 1  -  imaged  From  4).  more  T l  i n <  residual  Thus,  T l  FFA  than  i f  i n  et  a l .  fasted  c o n s i d e r a b l e washout  of  (Machulla  retention  and  longest  i n an  times  within for  the  vary,  attempt  to  i n  (1988)  injected  1-[  rats.  The  showed  activity  agent  from  the  for with  rats. however,  and  best  3,3-DMIPP  has  rats.  identify 1 X  of  agents;  since  time  1986;  reported  uptake  however,  be  a l . .  myocardium  heart  retention  may  analogues,  a l l three  highest  et  were  dimethylated-IPPA  times  the  mono-methylated  analogues  the  ideal  C]-3,3-dimethylmoderate  myocardium  over  i n  stenosis  both  information  of  dimethylated  myocardium  findings  the  degradation  reported  have  continue  Jones acid  at  that  Myocardial  shown  to  uptake  vessels with  metabolic  postulated  the  ratio.  shown  of  ratios  was  were  degree  circulation  indeed  monomethylated  showing  10))  the  stenosis with  pts  singly.  a l . . 1986b).  latter  FFA  distribution  remain  non-methylated,  (n =  on  (12  thrombolysis  a l . . 1987).  based  s u p p l i e d by  discovery i t was  et  collateral  may  ischemia  underwent  emerged:  severe  T1  who  noted  combination  are  acids,  et  or  myocardial  (Strauss  was  good  myocardium  used  better  or  -  angioplasty  patterns  occluded  reperfused  fatty  i n uptake Three  some  acid  59  uptake the  -  i n i t i a l again that to  30  low  minute with  dimethyl  (1988), directly that are  into  relatively  investigated al.. of  16-(  1 2 3  the  coronary  an  1987b,c; ideal  for  oxidation  are  the  Som  imaging  the  within  In  a  the  canine  lung.  beta-position  uptake  and  artery  and  may  be  retention.  studying  cellular  rates.  Other long  a l . . 1988).  agent.  isolated  rat  di-beta-methylated  iodo-vinyl  et  of  study,  These  I)-iodo-3,3-methylhexadecanoic  di-alpha  agents  low  at  i n myocardial  mono-beta, suitable  localization  substitution  using  -  post-injection period.  major  deficiencies  60  uptake  data  suggest  inadequate,  Demaison acid  et  hearts,  fatty  because  of  perfusion  imaging  agents  However,  there  acids, is  a l .  demonstrated  iodinated  fatty  due  injected  uptake  chain  was  acids  their being  (Ambrose  currently  a  et lack  -  (4)  ISCHEMIA  AND  (Jamieson with  changes  dysfunction  et  are  mitochondrial  activity,  In  rely  conservation of  of  order  metabolic  and  been  implicated  associated  with  coronary  to  rate  cellular  The  diverse,  1982). on  have  a l . . 1983).  ischemia  -  CARDIOPLEGIA  Ischemia-induced ventricular  61  subcellular  affecting  ATP  high  these  (hypothermia) of  and  cellular  changes,  stores  (rapid  combatting  ischemia  through  disease changes  ion  oxidative  diverse  energy  artery  transmembrane  p r o d u c t i o n and  mitigate  consequences  and  i n the p o s t - o p e r a t i v e  the  associated  balance,  metabolism  (Trump,  cardioplegic  diastolic  the  (CAD)  arrest),  deleterious use  of  techniques slowing  subcellular  protective  additives. There  are  extracellular  two ion  concentrations  basic  cardioplegic  concentrations;  (Hearse  et  solution  or  Na+  + +  intracellular  Each  Ca  type  of  considered by  the  (Shen  a  injury.  Jennings, on  the  Two of  Ca  1972;  explosive  of  them  myocardial  c r i t i c a l  and  of  former  the  be  choice  no  of  protection involved  1980).  , on  which  either  Na+  or  which  which i n  Shen  be  the  solution  the  latter free  and  reperfusion  contain  must  must be  oxygen  ion  C a ^ .  with  which  mimic  crystalloid  solutions  Experience  generation of  Ca  those  intracellular  can  contain  i s made.  Guarnieri,  uptake  with  disadvantages  factors  the  1)  extracellular  and  determine  and  those  The  Most  advantages  usually  aspect  accumulation  reported  has  2)  solutions  choice between  w i l l  important  and  blood-based.  solution  when  reperfusion the  The  surgeon  An  is  .  and  a l . . 1986).  potassium and  formulations:  solution i s  used.  addressed  i s  phenomenon  radicals  Jennings  following  have 40  -  mins. Ca  + +  o f ischemia, levels.  large  Indeed,  influx  addition  cells.  the  tissue  excitation  be  have  such  degree  o f success.  Therefore,  Ca  this  ions  calcium  nifedipine These  of this  altering + +  tissue  reperfusion by the  t h e amount  since  normal  to control  as verapamil,  beneficial,  dangerous,  above  attempted  following  limiting  appearing  and contraction.  (1980)  damage  proposed  and free  of  oxygen  Ca  or  agents  block  i o n which  enters  movements  within  mediate  entry  hydroxy  free  membrane  blockers  are not  membrane  mitochondrial  include  (Subramanian  e t a l . . 1987), (Guarnieri,  and increased  believed  i s produced  superoxide  They an  cause  myocardial  hydrogen  The  effects  release  edema b e c a u s e  e t a l . . 1980),  cellular  that  alterations  increased  permeability  was  by  anion,  e t a l . . 1987).  peroxidation, causing  permeability  activity  I t i s now  are widespread.  (Subramanian,  of reperfusion injury  reperfusion injury which  radical  radicals by  the etiology  o f the myocardium.  o f oxygen,  phospholipids  malondialdehyde  that  associated with  metabolites  peroxide  enhanced  thus  to re-oxygenation  cytotoxic  membrane  blockers,  increase  risks.  myocardial  these  the tissues  some  -  10-fold  researchers  achieved  sites,  also  Guarnieri related  many  entry  Although may  an almost  into  and have  receptor  the  without  o f Ca  of calcium  diltiazem, calcium  with  62  i n of of  decreased (Fox, e t a l . .  1985). Cardioplegia can  counteract  solution f i r s t of  some  u t i l i z e d  prepared  hypothermic  provides  by  a vehicle  o f these  i n this Tyers  ischemic  through  changes,  study  was  c a n be  which  administered  iso-osmolar  et a l .  (1974).  arrest  using  I n 10  coronary  protective  Tyers  canine  agents,  which  and assessed.  solution,  which  experiments,  perfusion with  60  The  was minutes  iso-osmolar  -  solution  resulted  in  histopathological Tyers is  et  the  a l .  and  of  (McCord,  allopurinol  (which of  superoxide  anion)  minimize  the  (1987),  Das  A  deal  great  functional available  the  et of  consequences examine  Regitz  The  of  f i e l d  being  of  Ledingham  et  the  (Greenfield rate  and  (Rousou  et  These  of  a l . .  of  1988).  et  the  of  a  include  blood  vs.  one  with  et  benefits a l . .  additives a  number  solution,  and  of as  of  (1988),  crystalloid  as  a l . .  a l . .  global  (1986)).  ischemia,  (Paulson  However,  the  et  a l .  precise  unknown.  many  controversies  oxygenated de  Wit  et  vs. a l . .  (Khuri  potential  procedural  to  primary  solutions  their  well  et  derivatives  dynamic  et  of  down  are  following  s t i l l  the  breaks  studies  the  are  result  the  acids,  effects  interest  examines  fatty  (1988)).  a  attempt  Mvers  of  a l .  as  (Ambrosio  number  L-carnitine et  an  which  by  oxygen  (which  i n  on  utilizing  A  myocardium,  recent  radicals  (1986),  available  free  Ferrari  is  radicals  ischemia. of  H202)  edema  c l i n i c a l l y  Of  performed  dismutase  a l . .  used  cytotoxic  hydroxyl  free  fate  of  of  oxygen  various  delivery  been  reduces  global  and  have  f i r s t  block  (which  (Tabayashi  (1988)),  or  superoxide  benefits  a l . . 1988),  method  protection.  currently  cardioplegia  provision et  moderate  Godin  of  perivascular  only  cardioprotective  solutions  a l . .  the  is  (1987).  debated.  non-oxygenated  of  substates  et_al.  these  by  mild was  generation  (1987a,b),  literature  only  solution  scavenge  catalase  induced  a l . .  which  mechanism  1988),  and  and  Studies  the  -  The  oxidase),  cardioprotective  (1986),  s t i l l  blocks  damage  to  1985).  xanthine  energy-generating and  showed  enzymes  metabolites  inhibition  function  assessments.  (1977)  inclusion  normal  63  et  a l . .  benefits  questions,  the  (1988),  optimal  such  as  temperature  - 64 III  PURPOSE  As  has  been  illustrated,  today's  society necessitates  and  improvement  the  evaluation aimed  at  of  medicine,  lack  acids  satisfy  myocardial  to  2)  ideal the  on  are  the  (both  objectives  effect  myocardial  of  longitudinal  the  of  tests  diagnostic  i n c l i n i c a l 1 2 3  Iodinated  (  the  imaging  ideal  diagnostic  I )  tool  thesis  are  reversible  global  ischemia  15-p-(  1 2 3  rates and  tests, nuclear  free  fatty  agent  and  this  of  i n  mortality  diagnostic  Current  for a  of  disease  for  method  of  three-fold:  i n  a  canine  I)-iodophenyl-  IPPA);  myocardial  effect  of  progressive  metabolism  of  1 2 3  IPPA  i n  regional a  canine  and  u t i l i z e  2 0 1  assessing  identify  (  1 2 3  to  for  Both  infarction  as  metabolism  acid  to  and  cardiovascular reduction  required.  requirements  pentadecanoic  model;  the  techniques.  infarction  the  on  of  radiopharmaceutical.  and  assess  into  ischemia  optimal  evaluate  ischemia  3)  techniques  Therefore,  model  research  myocardial  ischemia  evaluation):  1)  an  prevalence  assessment  current  assessing  may  of  the  the  Thallium  and  perfusion ischemic  Beta-methyl-  defects  risk  zone  and i n a  to  1 2 3  IPPA  (B  determine  canine  1 2 3  IPPA)  their  model.  a b i l i t y  to  -  IV  EXPERIMENTAL  (1)  Global  (a)  given  Experimental  as necessary  placed  into  monitor  were  A  standard  atrial  oxygenator  on a  were  A  caval  donor  dog  the left  prior  with  on cardiopulmonary atrial  to initiation  rate  catheter  and  to pressures  digital John  Fortin  monitored  bypass  venting.  o f CPB.  atrium  attached  were  was  pressure.  England;  temperatures  and  Bird  and right  were  with was  catheter  concurrent  (SE Laboratories,  and myocardial  A  -  thermodilution  T h e ECG, h e a r t  oscilloscope  intubated  blood  atrium  The catheters  occlusion and l e f t  0.5 mg/kg h e p a r i n  to monitor  artery.  placed  were  was p e r f o r m e d .  artery  pressure.  pentobarbital  Respirator  Swan-Ganz  capabilities  were  The dogs  7-French  twelve-channel  Rectal  and anaesthetized  sodium  (Mark-7  sternotomy  inserted into  to monitor  The animals  support,  with  (CPB),  The  dogs  T h e CPB pump  was  blood.  Protocol Following  recorded.  Supplemental  mammary  the pulmonary  Canada).  continuously.  (b)  overnight  the procedure.  internal  and recording  Ltd.,  primed  fasted  IV.  median  pressures.  transducers  received  kg) were  ( 2 5 mg/kg)  catheters  displayed  readout Mfg.  (17-28  o f Cardioplegia  throughout  inserted into  standard  Model  the right  Polyethylene  was  METHODS  on a pressure-limited ventilator  Corporation).  to  dogs  pentobarbital  maintained  AND  Ischemia  Adult sodium  MATERIALS  65 -  These  cardiac  included  cannulation,  heart  rate,  c o n t r o l measurements  arterial  blood  pressure,  were pulmonary  with  -  artery  pressure  measured right  using  a  atrium.  myocardial  2  was  groups  and Na  u t i l i z e d  +  without  solution  were  25 meq/L,  Mg  +2  B  (n =  7) , s u p e r o x i d e  One  third  of cardioplegia the f i r s t  (Wellcome  with  systemically  IV and the remainder  and infused  five  was dose  minutes Ltd.,  the majority  an a o r t i c  was  +2  (110-182  was  mg)  dose  -  mg/kg.  added  I n Group  to  dose)  temperature  C  (n  was being  to the final  connected  (SOD  administered  England)  dose)  was  dismutase a t 6.5  (95% o f t o t a l  cannula  Ca  administered  London,  solution  initiated  solution  of reperfusion.  (5% o f t o t a l  Cardioplegic  through  iso-osmolar  and the remaining  Foundation  a t 40 mg/kg  solution.  Denmark)  o f the total  a  range.  3 meq/L,  I n Group  Copenhagen,  at  Systemic  Cardioplegia  additions.  administered  8-10°C  +  the  administered  analysis.  5)  IV during  at  K  into  unit.  performed.  ( 3 1 0 mOsm/L,  were  arrest  at the desired  blood-gas  t h e CPB  was  (n =  delivery  cardioplegic  by  o f ischemic  solution  temperature  outputs  injections  A  the  of  t o two h o u r s  by periodic  a t 30°C  saline  I n Group  i n saline.  allopurinol  and c o l d  Cardiac  144 meq/L).  dissolved  =7)  pressures.  Cardioplegic  myocardial  o f experiments  Biotechnology,  systemically  computer  subjected  assessed  -  a t r i a l  o f 15-19°C.  Carlsberg  final  was  maintained  iso-osmolar  meq/L  output  to maintain  s t a t u s was  Three with  cardiac  temperature  temperature  and right  The h e a r t  intermittently Acid-base  and l e f t  66  was  to a  added  infusion maintained  CPB  circuit  pump. The prior  final  infusion  t o removal  rewarming  was  of cardioplegia  of the aortic  also  initiated  solution.  Following removal  occlusion,  the heart  was  was  cross-clamp  at the f i n a l o f the aortic  defibrillated  administered  twenty  and reperfusion. infusion  of  cross-clamp  i fnecessary.  minutes  Systemic  cardioplegic and release  of caval  Throughout the  -  cross-clamp  period,  infusion  cardioplegic solution  of  blood-gas  a n a l y s i s was  bicarbonate performed  was  1 2 3  1 2 3  Xe  2  *  3  l  1 2 4  Xe  B.C.)  calibration  in  a  to  1.0  (  1 2 3  I)NaI  This  was  of  for  two  rate  the  of  mmHg  period  Hemodynamic  from  60  through  lOOmL/kg/min.  post-CPB  and  the  Periodic  sodium  assessments  were  CPB.  I-iodophenylpentadecanoic  Radioiodine  (26MeV)  direct  (  1 2 3  I)NaI  acid  was  r e a c t i o n and  (Atomic  radionuclide purity  allowed  mixture  to  The  forming  0.75  mg.  To  the  i n  Energy greater  1 2 3  one  and  225  was  of  obtained  1 2 4  Xe  Canada  than  (p,pn) Ltd.,  99.9%  situ (6  produced  Thallation 3.0  /*L  allowed  hour  at  mg.  at  a  was  to  thallium  proceed  i n  at  58-60°C  and  out  tris acid  room  complex  d i s t i l l e d  method  carried  trifluoroacetic  parathallium mg/ml  by  was  added  H20).  resulted  i n  IPPA.  Extraction  into  ml.  1  IPPA  (1982).  i n  solution  for  1 2 3  PPA  was  Hexane  procedure  vacutainers.  Parkey  mixture  3/iL K I  react  -  dissolved  hour.  and  IPPA  and  using  hexane/extraction). the  1 2 3  [T1(TFA)3]  (lOmCi)  throughout  1 2 3  reaction  Kulkarni  one  ( i i i )  (lml  a  reactivial  iodo-dethallation  reaction  during  r  I  indirect  a l . . 1983).  temperature  1 2 3  Production  that  ml.  et  flow  above  time.  trifluoroacetate (Chien  15-p-  (p,2p)  with  (ii) similar  a  weaning  Radioiodine.  (26MeV)  Vancouver,  at  maintained  i f required.  after  of  was  -  IPPA)  (i) the  performed  minutes  Preparation (  pressure  administered,  thirty  (c)  through  aortic  67  of  The with  -  hexane activity the  The and was  majority  1 2 3  IPPA  washed  was  serially  measured (>80%)  extracted  i n  a  three  from more  the times  well-counter  occurring  i n  the  i n i t i a l  -  (iv) using  a  small  elution were  Purification  with  Si0  dissolved human  serum  f i l t e r  Preparation  albumin.  t o remove  (vi) on  s i l i c a  chloride Ten  nls  subsequently with  solvent (at  front.  solvent  (d)  taken  Electron  (overnight).  2  cacodylate  several  years.  1 2 3  Thin  3  with  was  completed  and  IPPA  fractions  with  was  was  IPPA  a  0.22/im  prior  2.5% m e t h a n o l with  applied  injection.  was  impurity  encountered  out  methanol.  to the origin f o r  carried  i n methylene  10-20/ils  value  and any  was  millipore  to  chromatography  The  were  1 2 3  s o n i c a t i o n i n 3 m i s . 6.0%  using  spotted  then  Following  the  matter  layer  1B2-F)  -  stream,  f i l t e r e d  developed.  1  IPPA  1 2 3  IPPA  and i s 0.6  travelling  included  with  benzoic  the acid  I (R^ = 0 . 0 ) .  Microscopy  Collection  evidence  The  -  impurities which  Tissue  placed  was  at the origin  and free  The  f o r Injection  particulate  control) were  1 2 3  PIN 51900)  chloride.  and suspended  origin  f o r electron microscopic  immediately  Sep-Pak  2  a nitrogen  flex  The  remaining  front)  ultrastructural  0.1M  (Baker  (quality  Two  (i)  using  Control  the sheets  the iodide  IPPA  any contaminant  the solvent.  o f IPPA  1 2 3  ethanol  Quality  o f the  evaporated.  The product  g e l plates as  of  of the solvent  i n 200/il 99%  Si0  i n methylene  and the solvent  (v)  -  Purification  (Waters  2.5% m e t h a n o l  collected  evaporation  column  2  -  68  - Punch  examination  o f any ischemic  i n cold  glutaraldehyde  glutaraldehyde-fixed  buffer  biopsies  solution,  prior  to sacrifice,  changes.  The  samples  and r e f r i g e r a t e d  samples  i n which  o f the l e f t  were  t h e sample  then  ventricle  providing  were  f o r 12-15 h r s  transferred to  can be  were  stored f o r  a  -  (ii)  Processing  glutaraldehyde-fixed razor The  blade.  samples  These were  intervals. minutes  in  increasing  final  then  a t 37°C,  exposed  effapoxy  30  from  examined  capsule  light  block  was  These  s e c t i o n s were  for  then  8 minutes  sections  (e)  were  then  examined  ventricle,  examination.  placed covered  was  water  aqueous  was  50% p r o p y l e n e incubated,  The samples T h e Beem  f o r 48  under  unused  water  at4°C.  acetate f o r  and  dehydration  oxide.  The  effapoxy  t o a i r , f o r 3h h o u r s  then  embedded were  i n fresh  and 100%  incubated  hours.  a microtome, 1%  suitable  sections  on g r i d s  an  minute  uranyl  a n d 50%  capsules  1 /im t h i c k  toluidine  s e c t i o n s were A  Petri  were  at 5  propylene  oxide  closed  with  placed  section  (60-100  nm)  and s t a i n e d with  dish  was  i n 1%  slides chosen  an  were  borax f o r  and and  that  ultramicrotome.  Reynolds  c o n t a i n i n g NaOH  the electron  blue on  using  sections  pellets.  lead The  citrate final  microscope.  Microscopy  Following right  with  series,  f o r 14 h o u r s  d i s t i l l e d  These  thin  acid  d i s t i l l e d  and s t a i n e d with  i n a  Light  osmic  of the  cubes,  rinsing  microscopy.  cut into  with  mm  5%  - Using  on a hot plate.  under  i n 1%  1-2  stained with  capsules.  Sectioning  the completion  o f alcohol and f i n a l l y  and at 60°C  t h e Beem  seconds  then  to a i r .  i n Beem  a t 37°C  fixed  followed by  overnight  ( i i i ) cut  was  -  cut into  3 times  the sample  mixture  overnight  washed  f o r dehydration  i n which  were  were  concentrations  mixture  mixture,  then  The sample  15  - Following  specimens cubes  69  sacrifice,  septum  Small  the hearts  and l e f t  sections  were  ventricle  of tissue  were  excised  taken  and samples  f o r light  cut with  a  of the  microscopic  scalpel  and  then  -  placed  into  tissue  sample  Processor.  This  dehydration  steps  followed  clearing  wax.  by  The  onto  eosin,  which  cytoplasm  were  Imaging  The  the  scans  and  one-half  128  x  matrix  over  Frames  minutes  every  (ii) Corning Blood system  175  + m  dog  samples  30  measured  pH,  imaged  minute  from  Analysis  pH/Blood  injected pC02,  2  into  p02  and  was  week  i n  microtome  overnight  with  and and  nature  the  and  a  to  minutes.  a  were  Picker  (ADAC-Cam of  II).  3-5  (Corning through  collected  immediately over  were  pressure  on  a  of and  128  x  after f i r s t  2  assessed  using  a  Medical,  The  mCi  the  the  was  energy  injection  seconds  gases  barometric  pentobarbital  with  low  anaesthetized  pre-operatively (control)  five  system  and  sodium  terminal  every  the  a  of  alcohol,  embedding  basophilic  commencing  System  of  series  hematoxylin  performed  Images  - Blood  Gas  fasted  following  30  and  a  pink.  computer  one  Tissue  through  concentrations  their  (fitted  period,  collected  Blood-Gas  were  camera  performed  minute  Automatic  imaging  mobile  sample  Supplemental  post-operatively.  were 1  a  was  were  a  gamma  and  were  Histomatic  stained with  of  of  mg/kg).  -Mobile  hours  injection. and  Mo  shades  the  a  sections using  then  because  animals  (25  Planar  collimator)  two  8  - The  pentobarbital  of  through  impregnation  thick  were  blue  tissue  (i)  f i n a l l y  into  slides  connective  Data  and  cut  stained nuclei  view  IPPA.  then The  i f necessary.  anterior 1 2 3  i n xylol  Acquisition  all-purpose  passed  i n progressively increasing  slide.  International  and  -  automatically passes  Data  sodium  given  a  and  (f)  with  machine  blocks  placed  boxes  70  Medfield,  intake  directly.  port. The  MA). The  -  system  also  saturation is  calculated bicarbonate, based  incorporated  (g)  data  into  Image  Areas  (Research  These  System/1:  was  squares  f i t with  +  SD  second  created  analyze peeling,  the  using  half-lives  program Corp., using  i n  a  were  into  one  vena  cava  heart. The  was  an  IBM-PC.  s u p p l i e d by  RS/1  MA).  biexponential  best  ADAC  total  (SVC)  Cambridge, a  which  manipulations.  t r a n s f e r r e d to  a  curves  (th)  data  background  then  resulting  summed  and  Products  the  an  septal wall,  the  were  were  on  superior  and  data  performed  the  numerical  oxygen  printer,  around  for  counts  A  and  data.  frames  u t i l i z e d  Software  IPPA  sample  wall,  generated  F-test  paired  Analysis  Student  d i f f e r e n c e s between  IPPA  for  Statistical  and  half-lives  normality  post-operative an  BBN  curve 1 2 3  curve.  significant  test  were  were  the  a n a l y s i s was  five  content  previously.  apical  peak  to  The  oxygen  f i t line  and  c a l c u l a t e d from  This  same  least equation  the  slopes  are  reported  lines.  mean  1 2 3  to  u t i l i z e d  (ii) as  were  l i s t e d  Image  interest  numerical  curves  program  the  data  excess,  recorded  -  I I ) .  wall,  normalized  Time-activity  of  of  lateral  compressed  each  (Cam  -  base  values  machine,  Analysis  Computer  subtracted.  for  the  (i)  images.  were  measured  Analysis  (background), These  the  Data  Laboratories minute  on  71  for  was  values. testing  (th)  are  performed Changes the  - Hemodynamic  T-Tests  were  control  and  reported on i n  the  th  homogeneity  used  as  mean  percent  the  to  test  post-operative  between of  assessments  +  SD  change  groups  and  any  values. a  Wilk-Shapiro  between  were  variance.  for  I f  then the  control  and  subjected data  were  to  72  homogenous,  a  pooled  variance  not  homogenous,  a  the  data  Mann-Whitney  Changes  with  between c o n t r o l  assessed pooled any  (2)  a  using  a  f o r each  differences  Regional  (a)  analyzed  group  Supplemental  dogs were  12-channel  intubated  space  1.0-2.0  dissected  distal  out  size  was  s t a t i s t i c a l o f th  within  apical  wall,  Testing results.  groups of  th  septal  were  were wall)  and  Ischemia  twelve and  canine  p e n t o b a r b i t a l was on  Corporation).  The  with  The  cm  ECG  (Three  pocket  Products,  A t r i a l lying  at  heart  digital John  with  to extend  pacing  the base  was  of  sodium  given  as  were  readout  descending the l e f t  the artery  were  Quebec,  necessary.  v i a a  a  L t d . , Canada).  coronary  and  fourth  recording  circumflex an  Canada)  implanted  the neck  pentobarbital  d i s p l a y e d on  and  Mfg.,  dogs  ventilator  exposed  rate  Fortin  Montreal, wires  Adult  pressure-limited  anterior  to the b i f u r c a t i o n  Points  positioned.  of the l e f t  a  and heart  concurrent  u t i l i z e d  experiments.  anaesthetized with  and maintained  V e s s i l o o p s were  subcutaneous  applied.  were  ANOVA.  (SE L a b o r a t o r i e s , England;  Approximately  constrictor  of  sodium  thoracotomy.  oscilloscope  capabilities  similar  wall,  of Regional  overnight  Respirator-Bird  intercostal  T - t e s t was  I f the data  C o n t r o l measurements  (lateral  f o r by  consisted  IV.  The  artery.  Model  fasted  mg/kg)  (Mark-7  area  were  (25  produced  applied.  Ischemia  study  kg)  test  estimate  Paired T-test.  individual were  variance  T - t e s t was  and p o s t - o p e r a t i v e values  Student  Experimental  The (17-33  separate  estimate  -  and  artery  was  coronary  ameroid of  appropriate  directed  o f the animal.  The  to  a  -  pericardium  was  stabilized. holding a  day  closed  The  incision  f a c i l i t i e s .  for  3  days  were  Automatic  DE)  Cobas  pack, -  Bio  levels, ACA.  This  procedure  and  loaded  parameter  - LA  days,  the  the  the  final  animal  animals  Derapen,  animals  7  days  a  were  was  returned  to  penicillin,  sacrificed  the  IM,  two  once  weeks  scan.  lactate  activity  analytical  Each  out  the  a  be  the  results.  minor  amount  reagents The  printed  out.  Systems  levels.  Lactate  samples  enzyme  has  LDL  sample  pack  prepared. test  acquired  a  key  analyzed  specific  Reagent  pack  determine are  through  Dupont Division,  were  the  The  sample  is  selected  test and  CK  into  the  test  and  preparation.  on  lactate  loaded  dehydrogenase  operator  appropriate  A  Clinical  and  the  samples  analysis.  To  Lactate  must be  for  pack.  pack  of  blood  days p o s t - o p e r a t i v e l y .  Dri-STAT  Reagent test  14  i n blood  - Beckman  CK-NAC  venous  and  Co.,  Analyzer.  LDH  on  vials  (Dupont  a u t o m a t i c a l l y advances  require  w i l l  when  The  appropriate  kinase  pack,  appropriately. l i s t  and  given  quantitate  optimized  prints  packs,  or  performed  (ACA)  to  creatine  appropriate  determinations  be  5  into  used  machine  appropriate  hrs,  Analyzer  Dri-STAT  the  were  was  spectrophotometric  i e . lactate  Beckman  24  was  and  minutes closed  after  analysis  apportioned  dehydrogenase a  and  Clinical  Wilmingdon,  animals  -  Assessment  blood  pre-operatively  then  immediately  Metabolic  Metabolic  Samples  The  was  30  post-operatively.  post-operatively,  (b)  following  73  CK Using  tray and  can the  the then  -  (c)  Preparation (  1 2 3  of 15-p-  1 2 3  74  -  I-iodophenylpentadecanoic  acid  IPPA)  (i)  Radioiodine  (ii)  Production  -  Method  t h e same  as  i n Global  Ischemia  section.  Ischemia  1 2 3  IPPA  -  Method  t h e same  as  i n Global  section. ( i i i )  Hexane  Extraction  (iv)  Purification  (v)  Preparation  -  Method  t h e same  as  i n Global  Ischemia  section. -  Method  t h e same  as  i n Global  Ischemia  section.  as  i n Global  Ischemia  (vi)  of  1 2 3  IPPA  f o r Injection  -  Method  the  same  section.  Quality  Control  -  Method  t h e same  as  i n Global  Ischemia  protocol  t h e same  as  i n Global  Ischemia  section.  (d)  Data  Acquisition  (i) Section. 6  hrs.,  Imaging  The 5  scans,  days,  assessments  were  7  - Imaging  however,  days  a n d 14  performed  exposed  from  Medical  Inc., Los Angeles,  were  performed  days  post-operatively.  with  the subcutaneous  a t r i a l  pocket.  C a ) was  one week  pacing. A  used.  The  latter  The p a c i n g w i r e s  Medtronic Hearts  pre-operatively  pacing  were  unit  paced  two  and at time  were  (Medtronic  at a  rate  o f 185  beats/min. (ii) Beckman MA)  as  model  Blood-Gas 175 A u t o m a t i c  described  i n Global  Analysis pH/Blood Ischemia  - Blood Gas Model  gas a n a l y s i s  System  was  performed  (Corning Medical,  earlier.  on  a  Medfield,  -  (e)  Electron  biopsy  was  Remaining Ischemia  (f)  taken as  area  from a  area.  of  area  the l e f t  ventricle  distal  identical  to  were  a  o f any  proximal  specimen to  regional  microscopic  ischemic  to  the  also  A  ameroid  taken  the ameroid  changes.  from  the  constrictor.  those  described  i n the  Global  section.  (ii)  Processing  - As  reported  i n Global  Ischemia  section.  ( i i i )  Sectioning  - As  reported  i n Global  Ischemia  section.  Light  Microscopy  myocardial  Data  sacrifice, bed  t h e same  taken as  the hearts within  that  the  reported  were  excised  ischemic  area  i n Global  and  samples  and  the  Ischemia  o f the  non-ischemic  section.  Analysis  1 2 3  IPPA  Image  Analysis  -  see  section  E ( i ) of  Global  Model.  (ii) metabolic  the non-ischemic  o f the  f o r electron  evidence  and  (i) Ischemia  to sacrifice  specimen,  procedures  Methods  (g)  prior  - Punch b i o p s i e s  control  Following regional  taken  Collection  providing ultrastructural  constrictor, ischemic  Tissue  b e d were  examination,  -  Microscopy  (i) myocardial  75  data  Statistical and  assessment  of  Analysis 1 2 3  IPPA  - Statistical washout  rates  analysis were  o f the  performed  -  using  a multivariate repeated  between Data to 1 2 3  mean  were  (3)  a s mean  the correlation  washout with  Myocardial  Nine  adult  dogs  ventilator was  concurrent  readout  England; fourth clear  digital John  intercostal  various  l e f t  coronary oxygen  artery.  a  2-0  3 cm  on a  was  sodium  - Bird  twelve-channel  with was  a The  with  (SE Laboratories,  The h e a r t femoral  on  oscilloscope  was  exposed  a r t e r y was  of arterial  cannulated  pentobarbital  Corporation).  capabilities  The  monitoring  from  coronary  pressure  to obtain  given  a r t e r y was  the bifurcation  to ligation  suture  ischemia.  blood  v i a a  dissected throughout the  samples  at  the procedure.  o f sodium  dexon  of  and  and anaesthetized  and maintained  Respirator  and recording  vein  Prior  performed  Infarction  overnight  intubated  (Mark-7  to allow  f o r 15 m i n u t e s ,  and h ampule  using  were  anterior descending  approximately  intervals.  parameters  the progression  Supplemental  thoracotomy.  during  time  a n a l y s i s was  of Myocardial  M f g . , L t d . ,C a n a d a ) .  femoral  intervals  The point  The  over  fasted  IV.  displayed  space  and cannulated  procedure.  IV  Fortin  regression  any o f the metabolic  kg) were  The dogs  electrocardiograph  differences  and post-operative  Linear  Representation  (25 mg/kg)  as necessary.  to designate  Model  (15-23  pentobarbital  pressure-limited  SD.  between  Infarction  Experimental  given  +  -  design  the functional data  (a)  sodium  measures  o f the pre-operative  expressed  examine IPPA  values  76  5 0 mg.  o f t h e LAD  o f t h e LAD, Xylocaine,  bicarbonate, and t h e dogs  IV.  t h e dogs I V , 0.5  T h e LAD  allowed  dissected  was  clear  at a  from  the main  were  placed  gm  Calcium  ligated  to stabilize  left  o n 100%  gluconate, completely  f o r 30  minutes  -  prior  to closing  the incision.  77  -  The dogs  were  then  weaned  o f f the  respirator.  (b)  Metabolic  Metabolic  assessments  dehydrogenase, was  withdrawn  hours were  Assessments  creatine  o f venous  kinase  blood  a n d CK-MB  samples  isoenzyme  pre-operatively, pre-infarction,  post-infarction made  as d e s c r i b e d  (c)  Preparation Acid  (B  1 2 3  and immediately i n section  prior  1 2 3  lactate  determinations.  H-hour  Blood  post-infarction,  to sacrifice.  (B) o f Regional  of Beta-Methvl-15-p-  included  2  Determinations  Ischemia.  I-iodophenyl  pentadecanoic  IPPA)  (i)  Radioiodine  (ii)  Production  Global  ischemia,  - identical o f B  1 2 3  except  IPPA  to section  C(i)  - identical  f o rsubstitution  o f Global  to section  Ischemia.  C ( i i ) of  o f beta-methyl-PPA f o r  PPA. ( i i i )  Hexane  Extraction  - identical  to section  C ( i i i )  of  Global  Ischemia. (iv)  Purification  - identical  to section  C(iv)  o f  Global  Ischemia. (v) section (vi)  Preparation  o f B  C(v) o f Global Quality  Ischemia.  Control  1 2 3  IPPA  f o r Injection  - identical  to  Ischemia. - identical  to section  C(vi)  o f  Global  -  (d)  Data  Acquisition  (i)  Imaging  computerized  tomography  (Siemans  GammaSonics  scanning  was  2 0 1  20  taking  minutes.  was  Images  only  at  one  images animals  and  were each  of  were were  the  a  Des  serial  angle.  In  2 0 1  dual over  the  camera a  total  2oi  heads  on  64  8  the  T1  final and  x  two  similar  alone,  following  64  the  as  3.5  animals,  imaging  and each  analysis as  9 of  m  C  time i  of  emission  Rota  Camera  dogs,  i n  2  of  mCi  at  situ  6°  of B  1 2 3  IPPA  6).  matrix  well  of  rotated  scanning  (Figure  x  7  injection  performed  a  Siemans  In  s c a n >  T 1  single-photon a  Illinois).  following  the  using  scan  radionuclides for  performed  The  following  collected  sacrificed  was  images  -  post-infarction,  Plaines,  (Dupont).  similar  obtained  hours  immediately  Immediately  injected  seconds  30  6  (SPECT)  Inc.,  commenced  Thallium-chloride  increments  - At  78  B  recorded dog  carried 1 2 3  IPPA  procedure.  was  for  40  imaged  out.  Thus,  alone.  The  with  -  2 0 1  Thallium  at  6 hours  cavity  as  B  1 2 3  IPPA  black  hole  infarct  activity SPECT-scan  projection infarct  SPECT-scan  The  decreased  at  (INF),  myocardium  -  i n dog  post-infarction), a  activity.  79  (N)  6  ventricular  a  appears  an  area  the  i n same  the  the  by  as  dog  as  cavity  ischemic  ring  of  of  ring. above  post-infarction),  ventricular and  showing  projection  surrounded  within  hours  (anterior  (VC),  risk  (anterior showing  the  normal  zones  (IRZ).  -  (ii) were (to meat the  Histochemical  sacrificed, the  level  slicer. slices  buffer  (pH  of The  was  were  the  mitral  valve)  into  slices  varied  number  0.4  Chemicals  Inc.,  myocardium  37°C.  (St.  and  latter  MO).  technique  1976,  into  triphenyl  These  -  excised,  placed  Louis,  This  (Hearse,  of  %wt/vol  tetrazolium.  at  Assessment  hearts  nitroblue  minutes  -  the  weighed  7.4),  80  The  et  mm.  A  to  two  for  a l . .  and  were  remained  0.2  an  electric  7). M  Each  phosphate  0.04%wt/vol  obtained i n  animals  transversely  using  the  visualization  1984).  the  (Figure  containing  agents  slices  9  after  sliced  sections,  from bath  and  tetrazolium,  allowed  Caldwell  weighed  10  a  Immediately  of  from bath  Sigma for  20  infarcted  of  - 81 -  Figure  7  -  Heart  showing  technique.  ligation  and  section  cutting  - 81a -  -  ( i i i ) imaging zones  was  were  intact  completed determined  slices  marked.  The  film  then  was  whole  using over the  The an  interposed  automatic  the marked infarct  appeared clear  as  ischemic infarct tracings  zones  border  and  between i n a  removed  and  interval  acrylic  -70°C  one  light-proof at A  the end sheet  while  the radiodense  was  between and by  area  second  The  A  risk  position sheet  at  of  X-ray The  -20°C  f o r 24  period  and  developed  paper  was  placed  manually  including  macroautoradiographs regions appeared  opaque.  the macroautoradiographs  (Figure  8).  quantitated by  which  stained,  o f underperfusion between  areas were  drawn  ischemic  the  stored  time  i n  the s l i c e s .  acetate  slices  onto  and  and  this  unperfused  completed a  box  the  and  minutes.  sheet  of  on  alone,  sheets  of clear  superimposed  i e . that  IPPA  f o r 20  acrylic  perfused areas  were  quantification  and B  the individual  areas,  seen,  two  at  and macroautoradiographs  Planimetric month  tracings  risk  frozen  The  radiodense  alone  between  processor.  borders.  acetate  a  placed  slices  experiments,  macroautoradiographic technique.  were  were  1 2 3  two  by  slices  films  - In the f i n a l  201^1  placed  was  -  with  were  apparatus  hours.  Autoradiography  82  one  observer  Both  using  observer once.  the  The and  the  acetate  planimetry. twice  with  a  three  -  The  findings  u t i l i z e d  i n  Perfusion  of  experiment  the  the  i n  83  the  with  slices the  autoradiograph,  and  infarcts,  closer  onto  one  view slice  demarcation risk  zone.  of  autoradiographic  present  the  A  -  i s of  study of  slice  are  heart  shown. from  tracings  showing  technique  one  overlaid  borders  of  the  onto slices  seen. the  of the  the  clear  acetate  paper  autoradiograph  i n f a r c t i o n and  the  overlaid  showing ischemic  - 84 -  (iv) removed  from  weighed. and  the  -  apparatus  and  Samples  infarcted  staining boxes  Histology  and  and  were  region  then  and  through  automatically  passes  progressively  increasing  xylol cut  and  into  slides blue  finally thick  were  because  shades  of  (e)  of  ADAC  were  through  a  using with  a  of  alcohol,  clearing  The  blocks  hematoxylin  and  eosin,  which  -  machine  f o l l o w e d by  onto  analysis  sample  steps  placed  and  tissue  This  and  nature  tissue)  dehydration  i n wax.  cytoplasm  a  and  and  histological  into  microtome  basophilic  were  out  (viable  subsequent  Processor.  embedding  dissected  area  placed  series  concentrations of and  for  then  Histomatic Tissue  Systems  1 2 3  IPPA  Image  L a b o r a t o r i e s computer was  completed  by  computer-reconstructed  slices  and  the  travelling of  corresponded  towards  0.53  cm  to  single  a  for accuracy  length.  Images  level  the  of  formalin  stained  slices  i n  were  slide. stained  i n  then  The nuclei  connective  tissue  Analysis  B  reconstruction  checked  the  carefully  the  pink.  Data  thickness  tissue  from  tissues  impregnation  their  into  sample  stained  (i) an  dissected  The a  the  sections  then  infarcted  placed  examination.  passed  Following macroautoradiography,  were  mitral  i n real 1  cm  Each  analyzed  was  performed  I I ) .  Standard  and  oblique  back  projection.  single  excised  2  slice. heart  quantitatively  Quantification  and  from  was  the  image  short-axis Total the apex  on  Thirty  from  short-axis  Therefore,  myocardial the  analysis  obtained beginning  space.  between  valve.  f i l t e r e d  were  base.  (Cam  Image  heart  apical  region  represented  a  images length  was  computer-calculated to  completed  base by  ending  at  calculating  the the  -  total  number  infarct, known  the  pixel  pixels  twice  with  differences observations (Kaul  regression determine the  the  ischemic  month  UBC  a l . . 1985).  analysis the  3  more risk  as  well  accurate zone.  the  could  computer period  the  as  method  interest,  ischemic be  i.e.  risk  zone.  calculated.  As  between  a  -  and  by  the  slice, Then,  was  the  completed second  the  based case by  one  observer  once.  and  intra-observer  computer-generated  and  histochemical  Package, expressed  correlation of  assessing  Genlin as  a  and  mean  coefficient perfusion  performing +SD. were  on  for  Inter-observer  were  the  of  was  Statistical Data  -  quantification  Analysis  calculated for  using et  a  area  and  percentages  Statistical  were  each  cavity  quantification,  (ii)  ANOVA  within  ventricular numbers,  planimetric observer  of  85  an  Linear used  defects  to  including  -  V  RESULTS  (1)  Global (a)  12 3 J P P A  4  i n  ventricle  the for  curve)  the  as  and  normalized  to 1 2 3  of  phase).  An  only  group  for  group  A  is  showed  decreasing apical  wall.  values  for  septal  wall.  Figure  group  B  i n  the  slight  decrease  septal  wall  the  at  the  shown by  th  i n  the  final  and  lateral group,  areas  lateral the  seen.  wall,  and  of  the  wall,  the  a  4  washout.  and  the  left  ventricle  10(B)).  and  and  normalized  of  the  no  for  showed  a  trend  i n  the  increased  lateral  for  wall,  the  wall.  In  apical  the  cardioplegic  are  the  i n  th  i n  trends  apical  wall  wall  change  change  i s  late  lateral  B  various  th  and  apical  with  i e . the  i n  listed  were  Increasing  increases  late  values  phase  Group  l i t t l e  The  (or  of  Elimination rate  (early  effect  is  portion  A  Curves  decreasing  with  IPPA  wall  10.  septal wall,  septal wall  lateral  Table  th  the  interval.  illustrates  (Figure  component  post-operatively. and  curve  triglycerides.  septal wall  apical  1 2 3  as  of  l e f t  (first  post-operatively i n  illustrate  of  wall  wall C,  and  phase  10  The  change  4  time  observed  10(A)).  wall  min  Figure  was  Table  late  2  acids  second  Figure  apical  were  while  i n mins)  the The  phase  i n  i n  i n  early  represented  lateral  and  the  calculate  significant  the  that  of  curve.  to  is  10(B)  T-A  utilized  counts  The  the  was  a l l three  wall  beta-oxidation,  of  (th  rate  septal wall  9,  Group septal  phases  and  Figure  on  i n  wall  elimination  fatty  techniques A  late  graphically  no  the  and  (Figure  trend  apical  the  the  increase A  wall,  of  of  peak  IPPA  mean v a l u e s  storage  shown by 4  Curves  i t is hypothesized  represents  curve,  (mins)  the  early  and  represents  Table  Time-Activity  lateral  phase)  in  of  reports  bi-exponential the  -  Ischemia  Analysis  Table  86  shown group  wall  and  for C,  a  -  Time-Activity  87  curves  the  myocardium  (A)  pre-operatively  following  2 hrs  -  1 2 3  for  (normalized  of  and  (B)  global  IPPA to  2  washout min  peak  from counts)  post-operatively, ischemia.  -87a-  0  10 20 Time (min)  30  -  Figure  10  -  Washout early  rate  phase  88  -  ( t 4 i n min) and  (B)  late  of  1 2 3  phase  IPPA of  f o r the the  T-A  (A)  curve.  - 88a -  (A) EARLY  PHASE (C) Septal Wall  (E) Apical Wall  ( ) Lateral Wall °r-( =0.018) A  4  ±11  p  ±24  .9 30  20  40 r  ^ 20  10  =  10 0  p<0.05  pNS p N S  Iso-osmolar (10)  10+ SOD  10+ ALLO  • Control = Ischemia (A)  0  10+ SOD  (B) L A T E  Lateral Wall  20 0  pNS  PNS Iso-osmolar (10)  I  pNS  pNS pNS  Iso-osmolar (10)  10+ ALLO  10+ SOD  (C)  Septal Wall  300  400 -  = ±1162  600 _ 300 c  200 -  '6  400  200 100 0  10 + ALLO  PHASE  Apical Wall  (B)  ±33  m p=0.051 p N S pNS Iso-osmolar (10)  10+ SOD  io+ ALLO  Control  Ischemia  p<0.05 pNS (p=0.034) Iso-osmolar  (10)  10+ SOD  pNS IO+ ALLO  2 0 0  JL  pNS Iso-osmolar (10)  H  i  pNS pNS 10+ SOD  10+ ALLO  -  Table  4  Washout Acid  rate  wall  SD)  Myocardial  o f 15-p-iodophenyl  and septal  intervals  included  Pentadecanoic examined  the lateral  by  T-A  wall,  wall.  A  -  Tyers'  Group  B  -  10 +  SOD  Group  C  -  10  Allopurinol  Group  A  +  time  regions  Group  Control  Iso-osmolar  S o l u t i o n (10)  Group  Post-operative  Control  B  Group  Post-operative  Control  C  Post-operative  PHASE  Lateral  Wall  Apex Septal  LATE  -  and post-operative  analysis.  apical  EARLY  ( t h i n mins +  at control  curve  89  Wall  11±  6  24+10(p<0.05)  20+17  14±12  19±24  13±  9  11±  5  13+10  16±15  14+  7  14±  7  14+  6  16±11  16+13  24+34  17+  9  13±14  15±23  PHASE  Lateral  Wall  Apex Septal  56±60 39±13  Wall  72+96  416±238(p=0.05) 89±  26(p<0.05)  109±  46  111±101  240±  270  146±215  132±85  217±336  281±  344  108±  62  122±80  194+272  699±1162  69±  16  116±95  - 90 -  Figure early  phase  ventricle. the  IPPA  11(A)  shows  t h e mean  i n the  lateral  Figure  11(B)  metabolic  wall,  depicts  time-activity  control apex the  and  washout  rate  (t^fi n min)  septal  wall  of  situation  curve.  found  the  f o r the  f o r the  l e f t late  phase  of  - 91 -  Washout  rate  (th  i n min)  for  the  (A)  early  phase  T-A  curves.  assessed and  (B)  pre-operatively  late  phase  of  the  - 91a -  40 30 20 10 0  Early Phase Lateral wall Apex  400  Septal wall Control (n^l^  300 200  h  100 0  Late Phase  -  Table  5  Measured =  and calculated  Cardiac  SVR  index,  =Systemic  pressure, 2-time control  Time  A  Pre-CBP  9±0  of cardiac SWT  =  SBP =  hemodynamic  Stroke  work  Systolic  Parameters  and "post"-cardiopulmonary  blood  were  "pre"-cardiopulmonary  status  index,  assessed  bypass  bypass  at  (as a  (as a  assessment).  CI  1  fraction).  including  assessment)  index,  resistance,  Ejection  intervals,  -  parameters  Stroke  vascular  EF =  post-operative  Group  SI =  92  SI  84  15±1  SWI  20±1  SVR  5153±  HR  SBP  EF  126±5  121+11  73±5  125+4  104+6  71±8  135±4  127±8  80±2  152±7  131+9  77±5  143±7  143+9  78±4  158±7  141+7  79±4  713 Post-CBP  2  6+0  3  22+3  22+3  3079+ 582 (p<0.05)  Group  B  Pre-CBP  2  6±0  3  19±2  24±3  3906± 394  Post-CBP  3 0±0  4  19±2  23±3  3517± 584  Group  C  Pre-CBP  2  5±0  3  18±2  25±3  4579±  (p<0.05)  605 Post-CBP  2  6±0  2  16+1  21+3  4023± 511  -  (b)  Hemodynamics  Cardiac Stroke was  no  C.  Ejection  index Index  change  Systemic  C,  (c)  of  groups  remained  ventricular ( E F ) was  B  and  increased  i n a l l three  i n groups unchanged  stroke  unchanged  work  A,  B  and  Heart  i n group  rate  index  i n group  B.  (HR)  Systolic  (Table  i n a l l three (SWI)  A,  was  A,  groups.  B  and  but  unchanged  blood  5). There  i n groups  group  (SVR) d e c r e a s e d i n group  C.  C  pressure  A,  B  group  and  C.  remained i n group (SBP)  A  and  was  groups.  Histology  Electron Microscopy  - Ultrastructural  the cardioplegic solutions show  minimal  mitochondrial the  unchanged  resistance  i n groups  (i) each  i n left fraction  but  unchanged  ( C I ) was (SI) also  vascular  unchanged group  93 -  ultrastructural  swelling,  sarcoplasmic  are demonstrated  i n t e r s t i t i a l  reticulum  and  changes and  changes  associated 12.  i n Figure  i n myofibrillar  intracellular  with  A l l three  integrity,  edema,  disruption of the mitochondrial  vacuolation cristae.  of  - 94 -  Electron at  (A) (B)  the  microscopic  evidence  ultrastructural  normal  tissue  (X  ischemic  change  levels.  8550).  ( i )  Iso-osmolar  (Tver's)  (ii)  10  +  SOD  8550).  ( i i i )  10  +  Allopurinol  (X  of  (X  MY  =  PL  s  plasma  Z  s  Z-line  G  =  glycogen  M  =  mitochondria  solution  8550).  myofibril membrane  (X  8550)  - 94a -  -  94b  -  - 94c -  - 95 -  (ii) three  specimens  distinction gross  Light include  could  cellular  be  Microscopy edema  and  made b e t w e e n  anatomy.  - Gross  cellular  cellular the  three  changes  i n f i l t r a t i o n cardioplegic  found  (Figure  i n a l l 13).  solutions  No  based  on  -  Control the  specimen  myocardium  Ischemic cellular  (X  specimen  96  -  showing  macroscopic  anatomy  63). showing  gross  changes  at  level.  (i)  Iso-osmolar  (Tyer's)  (ii)  10  +  SOD  96).  ( i i i )  10  +  Allopurinol  (X  of  (X  solution  96).  (X  96).  the  (1  B(iii  - 97 -  (2)  Regional The  coronary study the  Ischemia  placement artery  group,  (a)  from  of  however,  trends  (lateral  wall  th  segments showed  as  no  14(A)).  of  1 2 3  of  large  excluded, indicating  IPPA  and  apical  values  were  phase  (Figure and  The  of  decreased  the  Seven  remaining of  left  dogs,  anterior  which  animals  infarction  1 2 3  and  descending  comprised  d i d not  IPPA  (Table  6  curves  showed  no  washout  i n the  ischemic  shown  thus  the  survive  to  were  The  showed  an  i n th  increase which  Results  obtained  deviation  85+40-p>0.05. of  phase  non-ischemic  change  the fatty  observed The  and  Figure  14(A))  significant  acid.  was  and  not  one  Similarly  (septal  wall)  phase  (Figure  s t a t i s t i c a l l y  study  i f this showed  changes;  ischemic  f o r the early  with  animal  i n the  segment  f o r  segments  i n c r e a s e d t^iv a l u e s .  14(B)).  significant  washout  by  f o r the late  14(B)).  was  as  observed  standard  the value l i t t l e  dogs.  on  curves  wall)  (Figure  late  mean  12  days.  washout  indicated  well  The  14  on  the time-activity  s t a t i s t i c a l l y  significant the  to  myocardial  phase  increased  completed  constrictor  study.  Analysis  early  ameroid  the experiment because  the  Regional the  was  survived  completion  excluded  o f an  a  animal  animal large  l e d to  was  th  value  - 98 -  Regional in  min)  Regional 1 2 3  IPPA  myocardial f o r the  early  myocardial f o r the  washout  late  phase  washout phase  rate of  the  rate of  the  1 2 3  of  T-A  (th T-A  IPPA  (th  curve.  i n min) curve.  of  - 98a -  IPPA A N A Y L S I S  Control  Immediate  6 Days  7 Days  14 Days  TIME *p<o.05 c o m p a r e d t o control  -  Table  1 2 3  6  IPPA  curves the  washout over  14  lateral, *  f o r both days  apical  large  Earlv  Phase  Lateral  the early  and septal  phases Areas  wall  deviation  HRS  and l a t e ischemia.  of the l e f t  i s due  o f t h e T-A examined  were  ventricle.  t o one dog.  POST-  OPERATIVELY  5  DAYS  7  DAYS  14  DAYS  i i n min)  Wall  Apex Septal  -  of developing  standard  6 CONTROL  99  Wall  22±10  34+14  13+11  21±13  60±107  23±10  29±  7  24+15  21±12  37±  22±14  27±  8  22+14  19+12  14+  7  71±  50  33  *  Late  Phase ( t h  Lateral  Wall  in  min) 34+12  45+12  114+9 (p<0.05)  Apex Septal  Wall  44+  8  34+  2  38±28  47+23  69±49  62+63  107±146  (p<0.05) 115±  104.  626+1325*  -  Control time-activity  and  post-operative  curves  and  values  100  -  scintigrams are  shown  i n  at  14  days  Figures  with  15(A)  associated and  (B).  -  Figure  15  (A)  -  Control scintigram 15-p-  1 2 3  101  i n dog  I-iodophenyl  (anterior  view)  -  with  injected  with  pentadecanoic  acid  T-A  th  curve  and  values.  (Cl). (B)  -  Post-operative scintigram 15-p-  1 2 3  I-iodophenyl  (anterior  view)  values. ( T l ) .  at  14  i n dog  injected  pentadecanoic days  with  T-A  with  acid curve  and  th  - 101a -  -  (b)  Metabolic  Metabolic any  but  Lactate (Table  value  and Figure  changes  (c)  experiment. heart  rate  IPPA  16(A)).  was  no  Levels  following 16(B)).  Assessments  resulted  (p<0.001), seven  during days  was days  (Table  unchanged  14  7  significant the  increased  and Figure  throughout  surgery  normal  (Table  (Table  levels 7  days,  a t 14  days  significant  17).  7)  i n heart  rate  s t a t i s t i c a l l y  days  16(A)).  rose  showed no  and Figure  i n  (p<0.002),  t h e 14  CK-MB  and were  changes  immediate  o f the isoenzyme  the assessment  and  i n which  significantly  Lactate  change i n a  s t a t i s t i c a l l y  values,  remained  significant  Pacing  at both  at 5  the experiment  Hemodynamic  There  levels  (Figure  throughout  f o r CK  levels  immediately  post-operatively  showed no  o f 6333.4+1728  dehydrogenase 7  7)  except  to control  significantly  1 2 3  (Table  o f the parameters  returned  -  Assessments  data  post-operative  102  throughout  significant  of myocardial  post-operatively.  the  increase  metabolism  i n using  - 103 -  Lactate  dehydrogenase  and  CK  levels  pre-  and  operatlvely.  CK-MB%  assessed  intervals.  at  control  and  post-operative  p  - 103a  -  Enzymatic  Analysis  A U/L thousands 8 r  C K - M B  Control  Immediate  %  5 Days  Time (days)  7 Days  14 Days  -  Figure  17  -  Lactate  assessed  intervals.  104  at  -  pre-  and  post-operative  time  - 104a  -  Metabolic Analysis Lactate meq/l  Control  Immediate  5  Days  Time(days) BBi  Lactate  -  Table  7.  Hemodynamic gradual *  VARIABLE  paced  andb l o o d  coronary  analyses  occlusion  t o a rate  CONTROL  105 -  o f 185  over  a t various  time  periods  beats/minute.  IMMEDIATE  5  DAYS  7  DAYS  ( p a c e d HR)  Pulse  120±36  135±19  127±29  beats/min)  7.36±0.04  pH PCO2 p0  2  HC03  mmHg mmHg mmol/1  during  a 14 d a y p e r i o d .  7.34+0.03  7.38±0.02  123±22  14  DAYS  ( p a c e d HR)  136±24  * (185)  * (185)  (p<0.001)  (p<0.001)  7.38±0.03  7.36±0.04  43±7  41±6  42±3  41.43±2.5  41+4  51±14  37±9  43+14  37.43±7.9  54+11  24±1.8  22±1.5  L a c t a t e meq/1  1.20±0.74  LD U / l  125±103  CK U / l  206±204  1.23±0.54 160±56 6333±1728 (p<0.002)  25.1+1.8  24.29±0.95  23.00±2.5  0.98±0.27  0.87±0.22  1.23±0.57  212±167  175+114  213±146  220+79  183±66  321±332  -  (d)  C)). day  patency  Ameroid interval  complete  closure  of  the  coronary  the  of did  A l l five  infarction ameroid artery  left  animals  however,  18(E)).  myocardial  normal  of  i n a l l seven  (Figure  of  a  examination  constriction,  evidence  shows  -  Histology  Post-mortem revealed  106  as  anterior the  with  study  result  animals  assessed  constrictor normal  descending group  i n severe which  by  had  (Figure closure died  tetrazolium  (Figure patency.  coronary  18(D)).  artery  18(B  and  at  the  showed staining Figure  and  18(A)  14  -  Microscopic showing  107  -  assessment  normal  diameter  of  with  Assessment  of  LAD  at  of  constriction  14  days  Different study  (X  degree  which  in  situ.  no  of  (X  closure  artery  constriction  coronary artery  assessment  complete  collapsed  Ameroid  coronary  i n one  (X  96).  experiment  96).  i n another  animal  i n  the  96).  Microscopic showing  LAD  of  closures from  constrictors  LAD  coronary  of vessel  artery  from  animal  myocardial infarction  (X  96).  -  14  days  at  0  days  and  after  -  (i)  Electron  showed  ischemic  (D)).  Gross  appeared must  severe is  seen  changes  be  (Figure i n  20.  at  that  19(D))  Figure  Damage  and the  days  and  the  regional myocardial  myofilament i n  shape,  ranged  study.  from  Normal  19(B)  clumping.  and  Mitochondria  with  thickened  mild  (Figure  myocardial  bed  cristae.  19(B))  to  ultrastructure  C).  microscopy  was  and  irregular  this  of  post-operatively, (Figures  ischemia  within  19(A  Light  14  -  studies  i n c l u d e d edema  swollen  noted  (ii) Figure  changes  grossly  also  microscopic  108  revealed  restricted  to  evidence  gross  of  changes,  ischemia such  as  as  shown  edema.  i n  It  -  Electron tissue,  microscopic (A)  Dog  Ultrastructural evidence  109  of  1,  -  assessment  (C)  Dog  changes  ischemia,  2  (X  of normal 8550).  of myocardial  (B)  Dog  1,  myocardial  (D)  tissue Dog  2  (X  showing 8550).  - 109a -  -  Light  microscopic  days  i n two  2  265).  (X  110  -  changes  different  produced by  animals  (A)  Dog  ischemia 1,  and  at  (B)  14 Dog  » 110a -  -  (3)  Myocardial (a)  Metabolic  Venous (CK) LDH  and  U/L  creatine-kinase-MB from  CK-MB  a  were  Model  of lactate isoenzyme  control value  o f 548.60+684.20  t o 5030.60+2232  -  Assessments  concentrations  increased  value  Infarction  I l l  U/L  318.50±151.1  U/L  U/L  and  (CK-MB)  The  CK  (LDH),  are depicted  o f 74.56+25.30  (p<0.05).  (p<0.05).  dehydrogenase  values  U/L  to a  increased  creatine i n Figure  U/L,  21.  pre-sacrifice from  160.33+46.44  c o n t r o l and p r e - s a c r i f i c e  829.87±81.38  kinase  respectively  values  f o r  (p<0.05).  - 112 -  Venous  concentrations  creatine  kinase  pre-  post-operative  and  and  of  lactate  creatine  dehydrogenase,  kinase-MB  intervals.  isoenzyme  - 112a -  Venous  LDH,CK,CK-MB ±2232^  £±4820  LDH=laciate dehydrogenase CK=creatine kinase CK-MB=creatine kinase 'MB' isoenzyme  Control  Pre-ligation  3 0 ' post-inf  Time  i 2 0 ' post-inf  6 hr post-inf (pre-sacrifice)  -  (b)  Analysis  Figure staining. the  three  ratios ratio  shows  Table  8  methods  of B =  22  1 2 3  of Perfusion  IPPA  the clear  l i s t s  1.01± 1.25).  2  0  Defect  1  T l  -  Assessments  demarcation  the planimetric  c a l c u l a t e d as to  113  %  of  f o r each  of the perfusion  infarct  total  slice  perfusion  defect  quantification size.  defect  Also  with  f o r each  listed  assessment.  TTZ of  are the  (Mean  - 114 -  Staining combining  of  a  myocardial  nitroblue  infarction  tetrazolium  tetrazolium.  The  staining  viable  can  be  tissue  infarcted  region  seen  remains  of as  and  using  pale.  stain  triphenyl  formazans dark  a  within  tissue,  while  the  -  Table  8  -  Perfusion each B  Dog  Slice  1 2 3  defect  o f the three  IPPA  and  2 0 1  (Histochemical) Mean  of  Observer  2 (%)  size  115  -  calculated  methods  as  %  of total  - histochemical  slice  (TTZ  size f o r  staining),  T1.  1 2 3  IPPA)  . Mean  of 2  (B  Observer  (%)  (  2 0 1  T1)  Mean  of  Observer  2 (%)  r [  B  Ratios i 2 3 I P P A l  2 0 1  T1  1  1  27  4  30  8  19  4  1.59  1  2  32  6  15  9  10  8  1.47  1  3  28  8  7  0  10  2  0.69  1  4  21  2  11  2  23  8  0.47  1  5  23  9  15  2  34  3  0.44  1  6  0  12  3  40  1  0.31  2  1  9  6  45  8  49  5  0.93  2  2  10  4  30  7  49  1  0.63  2  3  9  1  12  0  23  8  0.51  2  4  4  2  9  9  31  6  0.31  2  5  9  3  20  0  5  3  3.77  2  6  14  3  8  2  0  0  0.0  3  1  42  1  38  1  28  9  1.32  3  2  32  7  31  4  25  4  1.22  3  3  38  5  17  8  21  1  0.84  3  4  36  7  7  1  . 24 9  0.29  3  5  27  3  9  1  17  0  0.54  3  6  19  8  5  1  20  1  0.25  4  1  2  3  2  8  0  0.0  4  2  0  0  0  0.0  4  3  0  0  0  0.0  4  4  3  9  0  4  5  0.0  4  5  7  4  0  23  2  0.0  4  6  0  0  37  2  0.0  5  1  29  7  12  8  34  2  0.37  5  2  19  8  13  0  28  5  0.46  9  10  4  1.34  13  5  3  21  6  5  4  22  5  3 2 .8  17  0  1.93  5  5  7  9  39  3  14  4  2.73  6  1  24  7  31  5  24  4  1.29  2  20  4  23  4  25  8  0.91  2  10  5  11  4  0.92  5  2 2 .9  0  0  0.0  1  31  6  7  4.67  6 6 6 6  3  27  4  13  5  14  3  j  -  Table  Dog  8  116  -  (continued)  Slice  (Histochemical) Mean  of  Observer  2 (%)  (B  1 2 3  IPPA)  Mean  of 2  Observer  (%)  (  2 0 1  T1)  Mean  Ratios  of 2  Observer  (%)  (B [  1 2 3  2 0 1  IPPAl  T1  7  1  41  3  27  4  33.6  0.82  7  2  23  1  11  4  21.5  0.53  7  3  15  5  4  6  3.6  1.28  7  4  11  7  17  9  3.2  5.59  mean 8  1  48  5  8  2  38  0  34.6 50.2  8  3  47  2  36.5  8  4  40  6  39.1  8  5  38  1  37.4  8  6  41  7  32.5  8  7  41  3  9  1  20  3  24  9  2  16  9  10  1  9  3  10  4  0  0  5.8 8  9  4  0  25  5  9  5  0  16  9  9  6  0  7  6  ratio • •  j  1.01±1.25  \  -  The The B  1 2 3  correlation  actual IPPA  (r=0.65)  Figure (r=0.54 The  infarct  24  between  size,  as  (p<0.005)  demonstrates  each  of  assessed and  2 0 1  T1  117  -  the methods by  i s depicted  tetrazolium  (r=0.49)  the relationship  staining,  ratio  f o r B  1 2 3  IPPA/  2 0 X  T1  Figure  between  B  1 2 3  IPPA  i s 1.01  ±  1.25.  23.  i s compared  (p<0.005).  p<0.005). overall  by  and  ?  0 1  T1  to  - 118 -  Relationship the B  1 2 3  between  histochemical IPPA  and  (B)  estimates  method 2 0 1  T1  of  infarct  (TTZ s t a i n i n g )  size  vs.  (A)  by  - 118a -  % Inf - Histochemistry (TTZ)  - 119 -  Figure  24  -  Graph  of  B  1 2 3  relationship defect  size  IPPA  vs.  between by  these  201  T1  showing  the  estimation  two  imaging  the of  perfusion  agents.  - 119a -  -  (c)  Autoradiographic  Table well  as  the  9  l i s t s  the  ischemic  assessment  120  of  -  IRZ  planimetric quantitation  risk  zone  assessed  by  B  1 2 3  of  IPPA  the and  ischemic 2 0 1  T1.  risk  zone  as  -  Table  9  -  Autoradiographic risk  Dog-slice  zone  and  calculated  Autoradiography  121  -  scintigraphic  assessment  as  slice  %  B  of  1 2 3  total  IPPA  of  size.  201x1  8-1  0.0  _  24.9  8-2  67.5  -  16.5  8-3  69.7  -  0.0  8-4  56.3  -  0.0  8-5  60.4  -  0.0  8-6  48.3 49.1  -  0.0  8-7 9-1  0.0  9.5  9-2  0.0  0.0  -  9-3  0.0  18.7  -  9-4  0.0  0.0  9-5  0.0  19.2  9-6  0.0  23.2  -  0.0  -  ischemic  -  (d)  microscopy  associated  (e)  with  which  was  multiple p>0.05.  differences  at  marginal range  evident  gross  (Figures finding  and Intra-observer  tests.  cellular  changes  25(A) normal  i s tissue  often  and (B)  edema.  Variance  inter-observer variance  Intra-observer p<0.05.  t o examine  infarction  The most  Inter-observer was  used  myocardial  tissue).  There Duncan  -  Histology  Light  infarcted  122  Analysis  showed  variance  was  expressed  by  two homogenous  large  ANOVA  and  subsets  demonstrating  i n  significant  - 123 -  Light  microscopic  myocardium Gross  (X  cellular  infarction  (X  assessment  of normal  canine  63). changes 63).  following  acute  myocardial  - 123a -  124  VI  DISCUSSION  (a)  Global The  Ischemia  hemodynamic  afforded  by  the  Results  is  to  al.  (1986),  reported  results  addition  solution. similar  group  using  B  a  marginal  (10  of  group  SOD)  and  global  functional  cardioplegic  solution.  1985;  with  a l l o p u r i n o l demonstrated hemodynamic  respectively. preserving the  Thus,  left  failure  A l l  to  pretreat  hemodynamic  In  following  order  should  It  to  have  CPB  better been  i n  +  allopurinol).  isolated  rabbit  Myers  by  SOD  of  studies  have  i n which  preservation and  in  been  included  performed  pretreatment  of  left  study  may  the  the et  animals  function  as  preservation,  a l l o p u r i n o l and  this  in  to  (Stewart  the  ventricular  ultrastructural of  of  et  hearts,  afforded  function  be  SOD  a  i n  reflection  of  animals.  the  repeated  (10  solution)  protection  were to  made note  consistently  assess  C  cardioplegic  a l l o p u r i n o l added  important  may  cardioplegic  by  measurements is  the  protection  afforded  ineffectiveness  the  to  l i t t l e  (iso-osmolar  group  measurements  the  A  SOD  ischemia  a l . . 1986)  ventricular  post-operatively. shortly  et  indicate  protection  number  al..  by  Godin  no  A  study  that  of  and  this  a l l o p u r i n o l or  +  model  solution  and  of  indicate  cardioplegic  assessed  -  effects  after  be of  several  only that  30 left  depressed the  minutes ventricular (Swanson  interventions,  hours  or  ideally  et  function a l . .  1983).  measurements  24-48  hours  post-reperfusion. The and as  report  function the  by  reported  of  favorable  Godin  et  a l .  protection  of  preservation (1986),  of  using  mitochondrial  mitochondrial  ultrastructure  allopurinol pretreatment, oxidative  phosphorylation  as  well  using  -  SOD  and  catalase  suggests  i n  continued  the  cardioplegia  fatty  metabolism  by  indicating  mitochondrial  acid  radiolabeled  125  -  solution  metabolism.  fatty  acids  integrity  The  may  and  by  Shlafer et  assessment  provide  deserves  a  a l .  of  useful  future  (1982),  fatty tool  acid  for  consideration  as  such.  The  u t i l i z a t i o n  increasingly 1 2 3  IPPA  global  i n  the  and  results.  In  Fridrich  post  (Conti mixed  a l .  zone,  period  from  an  In  the  p<0.05.  It  and  hearts Figure was  compared  a  study,  is  some  state,  as  the  metabolism on  our  artery  functional  iso-osmolar must be  group  noted,  of  functioning aerobically,  ligation indices (Table  however,  of  over  et  glucose  there  a l .  during  the  i n i t i a l  that  systemic  only  3  hours  production exist  the  the  interval.  a  majority  (1973).  within  hour  minutes  ischemic  may  while  two  although  30  the  energy  times,  indicative  assessed  a  5)  are  During  Opie  similar  assessed  reperfusion,  by  similar  at  was  trends  supplemented  hemodynamics  which  of  maintaining  showed  were  of  reversible  i n  metabolism  results.  demonstrated  to  solutions  dominant mechanism  following  Metabolism  Examination  a l l groups and  become  1987).  effective  the  normal  increased u t i l i z a t i o n  coronary  10.  less to  has  subjected  hemodynamics  with  bearing  However,  cells,  that  arrest  (Roberts,  hemodynamics  this  have  increasing  for  4  of  solution  compared  1983).  years  Hemodynamically,  glycolysis  of  25  demonstrated  CPB,  demonstrated  of  i n Table  examining  could  cardioplegic  walls  metabolism,  anaerobic  following  trend  acid  (1986)  Kao,  past  iso-osmolar  study  population  authors  at  a  This  and  the  ventricular shown  the  anaerobic  maintain  over  metabolism.  CPB.  hypothermic  allopurinol.  weaning  period,  a  et  normal  after  is  fatty  SOD  of  l e f t  that  myocardial with  popular  ischemia  indicates  of  These  ischemic We  found  post-bypass  SVR  vascular  was  significant  resistance  was  -  decreased 5).  to a  Thus,  reflect  change  i n the Tyers'  dramatic  noteworthy.  affect  and  index.  stroke  which  A  influence was  but  answer  The  be  lead  to a  effects.  ±  60  rise The  As  compared  function  t o groups  o f group  fraction  A  8)(p>0.05),  B  show  and C  B  and C  could  remained  t o 71 +  w i l l  increase  Examining  A  of global  no  (Table  simply  relatively  indicating  significant  no  change  upon  Although  ischemia  this  cardiac  o f why  t h e SVR  SVR,  and thus  such  to an  i n  (noting  of variables  B  cardiac  i s  dependent  dramatically many  i s unknown,  f o r group  index  the formula f o r  that  ischemia  result  cardiac  the latter  one n o t i c e s cause  as  we  w i l l  increased  decreased so  of global i n HR  number  lead  SI, since  the exact  the increase  afterload  index  the formula,  the consequences  on  the latter, may  affect  Although  i s interesting.  influence  i n resistance  question  on  cannot  variables  our  SVR,  main  but  be  i n  on  accounted  which  w i l l  affect  hours  following  i t the  complex. assessment  already  lateral  238  wall  (p =  was  performed  mentioned,  population  ±  i n group  i n CI w i l l  significantly  t o 417  seen  dependent  of the large  very  mixed The  showed  f a l l  i n turn  a  metabolic  bypass.  56  The  Similarly,  from  and  5  Groups  i n SVR  i t sv a l u e .  i n view  may  i n SVR  f a l l  not with  metabolism. for,  (73 +  5).  A,  ejection  the consequences  i s unknown.  concern  improved  group  variables  the former.  group may  f a l l  w i l l  Similarly,  upon  i n group  Indeed,  (Table  The  indirectly  CI).  towards  i n SVR.  not examining  output,  extent  -  post-operatively.  The  is  f a l l  i n function  function  were  the trend  this  unchanged  greater  126  reperfusion,  of cells, plays  0.051)]  th  as w e l l  i e .variable  a major  increased  three  role  values  degrees  i n left [ 1 1 + 6  f o r the early  as of  ischemia,  may  ischemic  ventricular to 2 4 + 1 0  and l a t e  weaning  phases,  function  (p<0.05)  and  -  respectively,  (Table  of  oxidation.  fatty  acid  unchanged  immediately  metabolism more  several  meaningful  The  4)  127  -  i n the iso-osmolar Although  following  (ideally  group.  ejection  bypass,  24-48)  fraction  assessment  hours  after  o f SOD  and a l l o p u r i n o l  to abolish  i n the b e t a - o x i d a t i o n phase  o f metabolism  known  that  global  ischemia  a  metabolism  (Opie,  1976a,b),  phosphorylation,  thus  Fatty  (Trump, as  acid.  results  The  group the 1 2 3  A  two  other  IPPA  solutions have  proven  However, masked  (Figure B  the large  Therefore o f th  the fact  again  values.  and  have  provided  demonstrate  Thus,  remaining  aerobic  a  as  i t would  be  anaerobic  since  affected  by  both  to impairment washout only  altered,  appear  that  oxygen  i n this  i n  compared  to  phase  of  cardioplegic  cytotoxicity,  fatty  fatty  wall  the early the  acid  of the  the lateral  by  of myocardial  membrane  of fatty  rates  assessed  at preventing  processes  oxygen-derived  and mitochondrial  that  I t i s  i n oxidative  metabolism,  deviations obtained  only  ischemia-related  to  decrease  i s significantly  i n the other  that  a  this  i s questionable.  myocardial  f o r maintenance  t h e SD  lead  formulations,  f o r the lateral  well;  by  also  may  solution)  10).  i n th  The  however,  study  standard  preservation.  from  acid  may  events  and C ) , aimed  beneficial  any changes  increase  of this  cardioplegic  (groups  fatty  i n decreased  iso-osmolar  washout  evidenced  metabolism  These  reflected  (Tyers  as  shift  h y d r o l y s i s o f membranes  1982).  metabolism  causes  decreasing  acid  free-radical-induced damage  to be  of function may  impairment  comparison.  a b i l i t y  coupled.  implies  appeared  bypass  shift  are  This  acid  study  may  oxidation.  may  have  solutions.  the iso-osmolar  group  showed  a  significant  wall  may  o r may  not signify  poor  groups  may  o r may  not protect  the myocardium  values  are large  a n d may  mask  myocardial  significant  -  Variability completed that  by  Fox  washout  of  the  results  et  a l .  (1985)  rates  of  those  metabolized  could  affect  v a r i a b i l i t y  i n  values.  myocardium influence  th  and the  washout  this  and  fatty  the  the  These  -  study  Lerch acids  washout  They  of  results.  of  128  which  found  t r a c e r by  be  (1986).  curves  also  may  thus,  not  taken  or  of  the  work reported  are  account  supply  coronary  by  authors  back-diffuse  that  f a c t o r s were  These  and,  the  explained  not  for  the  tracer  circulation  may  into  i n  account  to  the  this  study.  Late acids and  as  of  store  the is  beta-oxidation the of  late this  report  pharmacokinetics  triglycerides  decay  energy  phase  isotope  phase.  triglyceride values  i n  results  may  reflect  account  for  only  examining minutes the  late  phase,  et  were  s t a t i s t i c a l l y  the  pool,  th  or  the  could  of  the  of  beginning  of  this  now  wall  significantly  triglycerides  The  c l i n i c a l l y rates  pool.  Van  der  i n  this  phase.  of  only  30  wall  or  Many  of  for  the  from  may  are  greater  i n  et  (1981)  a l .  which of  the to  i n  studies 60-90 i n  imply  of  th  for  However,  iso-osmolar 10).  our  would  increase  this  esterification  this  u t i l i z a t i o n  (Figure  interval,  storage  slower  time  an  fatty  relevant  assessments.  (p<0.05)  the  V a r i a b i l i t y  scanning  phospholipids the  a  Wall  demonstrated  ischemic  (th)  minutes,  phase. the  apical  i n  more  indicating  late  1985)  importance  phase,  increased  increase  incorporation of  Wall,  post-operative  and  and  der  washout  extend  and  f o l l o w i n g the  an  the  A l l walls  control  lateral  min  period  metabolism  reflect  to  early  100  the  a l . . 1986).  phospholipid  a l . . 1986).  values,  release  to  (Van  myocardial  scanning  between  values  in  a  the  only  prolonged  for  Control  and  et  secondary  excess  myocardial  (Schon  (Visser  relative  either  phospholipids  relatively  phase,  th  and  reflect  group  These impairment  secondary  energy  intracellular  - 129 -  free as  fatty  acids,  postulated  the  by  effects  that  a l l three  pool  and,  by  Teoh glucose bypass  et  by  Patient  a l .  mls/hr  in  the  high mmol/L  of  The  preferred  This  levels  were  before  and  patients  group  as  after  were  energy  used  exertional In  angina  group  150  C  mls/hr  was  used the  recovery  after  support  fatty  acid  increases  cardioplegic  study,  arrest  was  groups,  l i p i d  while  of to  an  the  assess  the  and  double-  Ringers  infusion  hypothesis  also  on  group  that  or  within  patients  the  of  substitute.  myocardial  to  and  coronary  effect  intravenous  Lactated  compared  acids  for  patients  perioperative  cardioplegic  the  this  acids  pectoris,  received  perioperatively,  received  the  as  randomized  mmol/L)  free  of  fatty  the  an  functional  in  examine  be  after  measured  to  can  1 4  showed  implying  arrest  lactate  substrate  not  cardioplegic  fatty  which  explain  of  of  received  and  comparing  oxidation  used  may  also  by  metabolism  Lactate  from  content  assessed  that  which  away  the  thus  the  (0  solution  allopurinol  on  saline  group  iso-osmolar  and  i n  beta-oxidation,  values.  impaired  LVEF>30%.  normal  for  metabolism,  increase  levels  shift  may  and  improved  lactate  th  SOD  IPPA  protection  stable  lactate).  showed  low  arrest,  CAD,  with  1 2 3  an  availability standard  demonstrated  is  since  were:  The  of  in  concentrations  lactate  metabolism.  with  have  concentration  150  phase  poor  Nineteen  function  of  (1973).  result  myocardium  acid  supplemented  late  (1988)  c r i t e r i a  lactate  the  fatty  post-operative  lactate  lactate  (24.3  on  to  triple-vessel low  a l .  solutions  the  ventricular  et  solutions  grafting.  arterial  reducing  implication,  pre-operative  the  Opie  cardioplegic  similar  thus  the  infusion who  were  solution lactate with  high  infused  lactate  may  be  arrest.  metabolism,  following  in  th  so  confirmation not  seen  in  this  possible.  of  cardioplegic  study.  Lactate  lactate  metabolism  -  Regional addressed  i n this  difference the  left  This  heterogeneity of  i n normal  ventricle  validates  single  (b)  heart,  The  significant occlusion,  which  have  control 14  et  days  animals,  flocculent  manifested or  as  this  degree  of  a  was  and  rates  heart  of  the  similar  was no  significant  were  areas  washout  also  various  deviations  experimental  within 14  the  oxidative  with  acid  Dudczak  confirmed  free  areas  of  noted.  within  a  rates.  et  electron within  gradual  coronary  occlusion  to  shape of  degree  thus,  ischemic  and  of  clearly  injury  to  cristae  specks,  between  acid  c l i n i c a l  studies,  rates within  the  those  19). Reimer  and  swelling  Variability  observed. the  However,  animals.  Wall  myocardial  r e p o r t e d by  within  der  examination  mitochondrial  discrepancy  ischemic  Van  regional  thickening.  found  metabolism  microscopic  c o u l d be  ischemia. some  and  (Figure  clumping,  ischemia,  amorphous  certain  similar  myofilament  extent or  are  fatty  showed  coronary  a l . . 1982a,b;  by area  ventricle  gradual  washout  ischemic  changes  of  experimental  fatty  a,b;  left  days  an  change; of  the  demonstrate  standard  and  after  of  decreased  i n their  densities,  representative  concur  i e . edema,  irregularities  large  wall  values  a l . . 1982  of  washout  areas  of  results  demonstrate  impairment  ischemic  (1987),  again,  apical  i n th  Ischemia  Ultrastructural  between  and  specimen  The  areas  Model  results  (Reske  11).  control  -  various  myocardial  areas  demonstrated  a  level  wall  These  of  with  of  the  suggesting  a l . . 1983).  Jennings  use  Ischemia  et  after  canine  increases  6).  myocardium  bed  the  lateral  (Figure  although,  since  Regional  (Table  study  the  130  The  mitochondria  not  exists  a l l as  animals  to  the  are  -  A  study  aliphatic  by  Railton  fatty  acids  sensitivity  assessment  of  angina  reliably  cardiac  pectoris  diagnosed  required  or  1 2 3  and  a  that  I-heptadecanoic to  These  positive  this  -  suggests  specificity  17-carbon  background  (1987)  patients.  using  terminally-labeled  a l .  (e.g.  sufficient  with  et  131  be  imaging  authors  and  this  may  for  with  not  be  routine  reported  However, fatty  c l i n i c a l  that  40%  of  patients  could  not  be  the  acid  used  may  have  procedure  iodinated of  electrocardiogram  agent.  straight-chain  subtraction  acid)  used  exercise  imaging  (123I-HDA) decreased  i t s  sensitivity.  Recently, washout early  rates  studies in  from  terms  elimination  beta-oxidation, the  suggest  conditions  into  be  the  releases  free  order  to  a  labeled  fatty  acid,  a  murine  model.  concentrations  IPPA  myocardium.  attached require  to  et  labeled and  iodine  the  further  a  which the  used  phenyl  of  washout  the  is  (1985a,c)  washout  1 2 3  IPPA 1 2 3  of  should  the  iodide  w i l l  washout  investigation before  the  free  be of  demonstrated  under  ischemic  of  the  radioiodide. to  catabolism, Machulla  following  kinetics  and  be  found  et  a  radiolabeled completely  acid  of in  tissue  rapid  influenced from  a l .  injection  of  catabolites  removed  i t becomes  iodine  authors  IPPA  not  the  These  omega-phenylpentadecanoic  values  The  that  a l . . 1985).  radioiodide  th  ring.  reported  d i f f u s i o n of  recirculate.  examined  of  is  myocardial  represent  subsequent  to  of  It  to  washout  acid,  free  et  rates  decreased  catabolites  the  since  assumed  radioiodinated a l .  washout.  (Visser  release  subsequent  Therefore,  recirculating  reflection  of  interpretation of  of  curve,  heptadecanoic  prevent  Reske of  a  T-A  bloodstream  radioiodide,  i n  of  the  result  the  mechanism  i n myocardial  radioiodinated  oxidation  the  of  the  However,  (1980)  questioned  actually  decrease may  of  phase  is  myocyte the  have  the fatty  from  the  by body  s t i l l  acids  understood.  will  -  The results  phenylated i n  the  circulation, 1 2 3  1980  and  clear  release  where  I-hippuric  derivative  i t can  acid  Reske  et  of  and  1 2 3  of  I-benzoic  be  further  finally  of  left  -  pentadecanoic acid  acid  into  the  metabolized  excreted  a l . . 1982a,d).  demarcation  132  The  i n  the  by  walls  as  i n  this  study  peripheral the  urine  myocardial  ventricular  used  liver  and  (Machulla  images  kidneys  et a l . .  obtained  reported  by  to  allowed  Reske  et  a l .  (1982a,d).  The  time-activity days in  may  th  prolonged  be  curves  values (Table  attributed  coronary  i n both  diameter  to  by  6  a  and  way  of  additional  benefit  of  compensatory  flow  ischemic  (Brazier  et  a l . . 1976).  those  of  coronary  Van  The  der  artery  stress  the  an  the  bed  results  Wall  et  disease  regions  showed  (normal  volunteers), at  study,  a t r i a l  ischemic  regions  demonstrated 1 2 3  IPPA  with by 1 2 3  the  IPPA  reduced  a l .  washout  the et  i n oxygen  this  i n which  e x e r c i s e d and  th  increased had i n  increased  normal  washout,  study  (1986).  or  both.  The  latter  i n patients with  here  and  the  control  rates.  In  CHD  the  ischemia  also  with  rates  i n  to  group  and  the  altered  consistent  report  dramatically  compared  ischemic  (1988)  are a  with  present  results  results  Hornby  with  while  demonstrated  severe  patients  a l .  any  circulation  The  et  decrease  removing  HDA.  Hansen  14  pacing  i n agreement of  at  a l . . 1979;  increased heart  These  a  with  values,  values.  performed  group  washout  thus  et  are  scanned  significantly  th  a  by  collateral  Schell study  segments  A t r i a l  demand, of  the  induced  constrictor. oxygen  of  ischemic  supply  a l . . 1975; i n  phases  the  development  (1981),  rest,  late  of  exercise-induced myocardial  longitudinal et  were  14)  ameroid  obtained  a l .  and  increasing  v i a  resulted  showed  that  uptake,  Kennedy  by  significantly  pacing  Figure  reduction  induced  within  early  normal  published  reduced  volunteers.  -  Schon  et a l .  influenced factors acid  by  were  acid,  washout  oxidation  comparing  seen.  palmitic  rates  result  acid  rates.  However, This  acid  would  1 1  work  o f t h e T-A curve)  o f fatty  debate,  acid  however,  Schon  a n d may  around  what  that  and late provide  these  th  that  o f this since  early  HDA a n d  studies  metabolism  the physiologically  has stated  o f the early  metabolism  centres  from  that  IPPA  fatty  a r e such  However,  1 2 3  and  o f the  end-products,  on  two  i n fatty  o f oxygen  u t i l i z a t i o n  metabolism.  and cardiac  C.  an increase  suggest  phase i s  I f these  the effects  i n different catabolic  with  work.  availability  i n an increased  o f fatty  o f MV02  labeled  cardiac  as expected,  t o d i s t i n g u i s h any d i f f e r e n c e s  Y-intercept measures  and augmented  decrease.  result  the so-called beta-oxidation  The increased  washout  rates  that  washout  should  the effect  needed  The  MV02  i s not a reflection  IPPA  are  be  increasing  myocardial  1 2 3  should  workload  thus  phase  increasing  reports  to influence  washout  increased  (1986),  133 -  the sizes  phases  a more  (ie. the  are v a l i d  v a l i d  so-called  occurring  comparison.  elimination  phases  represent.  The  influence  various Reske  o f ischemia,  interventions,  et a l .  (1986).  concentrations  These  of lactate increased  et  i n which  (1988)  (3mM/kg) and  uptake  lactate that  prior  to  levels  1 2 3  lactate w i l l  authors  decreased  th v a l u e s . fasted  I-HDA  1 2 3  IPPA  demonstrated fatty  acid  Similar  patients  following  demonstrated  inhibit  of  were  scintigraphy.  decreased  and exercise  of regional  on the oxidation  significantly a l .  b y way  was  that  also  findings loaded  with  examined  reported  sodium  by  findings  as w e l l  by  Duwel  increased  intervention.  normal,  and  lactate  values  scintigraphic  under  flow  resulting i n  were  The h a l f - l i f e  similar  blood  increasing  washout,  the lactate  FFA oxidation  myocardial  as  Both suggesting ischemic,  -  conditions  (Duwel  determinant  of  in  this  oxygen  study  may  The  study  7).  and  number  rate  of  ischemic may  account  which  to  i n the  swelling  could  lumen  one  by  of  50%,  80%.  thus  were  categorized may  have  as  been  of  be  this  of  micrographs  were  the  degree  Therefore,  as the  of  group.  ischemia  and  degree  of  ischemia  might  have  reduction  i n blood  flow,  for  If and  i s , i f we  were  quantitate blood been  might  would  be  due  time, able  to  Thus,  alleviate  of  have  i n radius on  the  standard the  way  some  rate  reduced  could same  th  have day  and  were deviations  microspheres,  values  assessment the  of  central  categories based  a l l th  of  of  i n  grouped  been  standard  inject  been  the  of  ischemia  were  of  could  reduction,  have  degrees  to  (th)  assessments  recorded.  example,  This  flow  large  performed  the not  The  be animals  the  reduction  closure  not  radius  the  same  of  earlier,  constrictor,  were  this  mentioned  example,  assessments  i n  could  extent  rates  for  That  on.  Washout  reducing  ischemic  degree  the  also  five,  th  day  i n  of  variable  major  reported  experimental  showed  may  However,  The  a  thus  increase  i n  values.  th  of  grouped.  controlled. at  th  flow,  constrictor  ischemia  as  values  end-product  study.  ameroid  degrees  th  i n  significantly  i n  the  assessment.  both  so  of  assessment  study  reduced.  and  to  i n  earlier,  2,  not  an  seen  discussed  assessment  lactate,  variability  into  to  i n  identified  i n blood  discrepancy  i n another  placed  reduction  apparent 18)  changes  this  time  However,  The  also  and  the  not  a  electron  19)  constrictor  while  been  The  associated with  animals  according  are  variable  (Figure the  shown  (Figure to  of  increase  was  -  P e r f u s i o n was  uptake.  result  concerns  earlier.  for  IPPA  an  latter  of  damage  deviations  not  leading  mentioned  1 2 3  the  swelling  controlled, as  be  but  metabolism.  A  a l . . 1988).  cardiac  supply,  (Table  et  134  at 1,  50% 60%  s t a t i s t i c a l  as on  -  problems data.  we  The  technique  experienced assessment  was would  problems  associated  realize  forward.  Five  assessment  The 6,  Donald  and  to  of  however, This  the  may  the  1 2 3  IPPA  by  removal were  not  of  1 2 3  died  as  a  the  the  may  this  of  The  have of  of  and  branch  the  septum  14  days.  time The  study. i s  14  We  to  closure  move  of  the  days  remaining  anatomy of  the  and  of  the  LAD  may  or  or LAD  anatomy  walls dog.  supplies  70  septalis),  (Miller, other  the  two  (ramus  distally  through  coronary  each  the  final  locations  ventricle  flow  at  research  branch  placed  the  the  coronary  the  for  complete the  the  technique.  septal  been  reduction i n blood studies  to  different  between  area  wall  the  of  of  microsphere  from  i f this  this  septal  septum.  difference  of  a  maintained  prior  septal  that  be  by  analysis  microspheres  result  infarction  number  these  overcome  e x p l a i n e d by  Thus,  1964).  two  walls,  proximally  may  not  distal  might  to  have to  the  have  problem. (1986)  tissue  tissue, IPPA  Reske  states  washout back  and  considered  literature.  of  constrictor  the  must be  the  i t s exclusion  variability  report  Fluoroscopy  this  i n  be  i n a  the  septalis.  Schelbert  of  may  (1954)  ameroid  the  the  i n  i n  bloodflow  cannula  resulted  animals  responses  originate  affected  of  atrial  interventricular  constrictor.  slope  an  showing  explain  alleviated  injecting  myocardial  14)  Essex the  However,  this  twelve  deviations)  myocardial  d i f f i c u l t y  causing  Figure  ramus  been  of  period,  could  since  this  different  (Table  75%  with  standard  -  regional  necessitate  that  constrictor,  of  proposed.  interval  do  (large  135  i n et  that  a  number  curve.  These  diffusion,  i t s metabolic this  study,  a l . (1984d)  of  factors  include  the  recirculation by-products.  they  w i l l  influence  volume  and  of  the  distribution  flow-dependent  Although  have  been  addressed  calculated  that  4.5  -  6.0%  these i n of  factors  the the  injected  -  dose  1 2 3  of  coworkers but  at  spleen  acid  produced  and  extensive  parameter  i s minimal  Since  15-p-  1 2 3  could  not  be  the  circulation  of  to  lack  an  metabolic 1982) , has perfusion  rate  of and  shown  also  have  size,  our  acid  myocardial  be  the  of  1986).  this  u t i l i z e d caused  et  and  metabolic  1 2 3  v a r i a b i l i t y  of  (Machulla  The  final  IPPA  (Fox  i n th  values.  study to  by  indicate  that  examine  ischemia.  Model  increased  aimed  at  quantifying  fatty  comparison show  In  a  to  low  this  acid,  intramyocardial  effectiveness  results  to  of  and  incomplete  unmetabolized  metabolism  beta-methylated  In  was  of  liver  use  the  acid  recirculation  (Lerch,  results  radiopharmaceutical. a  of  may  The  liver,  effect  and  IPPA,  majority of  1-benzoic  removal  contributed  the  of  the  and  1 2 3  lung,  the  kidneys  artery  continued  shortcomings,  l i t t l e  defects.  problem  present,  have  1 2 3  urine.  coronary  was  included  body,  the  the  i n the  the  the  that  Reske  extracted  although  i n the  by  1985(a),  tissues  tissues  back-diffusion  techniques  ideal  fact  body  avoided  was  Infarction  u t i l i z a t i o n  defect  the  the  In  Therefore,  to  assumed  i n regional  Radionuclide  the  These  elsewhere  circulation  these  other  due  thus  may  of  muscle.  occur  -  myocardium.  number  I-iodophenyl-pentadecanoic  Myocardial  s t i l l  the  rates.  occlusion  This  of  a  from  addressed  spite  disturbances  (c)  from  collateral  a l . . 1985).  In  may  derivative  by-products  that  eliminated  1980).  by  skeletal  i s removed  phenylated  up  slower  metabolism  subsequently  et  taken  demonstrated  recirculation  al..  was  significantly  kidney, fatty  IPPA  136  myocardial  experimental chosen  residence  for assessing a  infarction  the  for time  endeavour,  i t s  (Livini  size  of  histochemical assessment  degree  of  correlation  reduced  for  et a l . .  myocardial of  the  perfusion perfusion  -  defects and  estimated by the iodinated 20171  by  demarcation  (  =  r  0.49-p<0.005).  problems  which  will  137 -  fatty Both  acid  analogue  agents  greatly  suffer  limit  their  (r =  from  0.65-p<0.005)  border  usefulness  i n such  a  manner.  Significant enzymes  i n this  (Figure  21).  infarction been  has been  Although  2 0 1  more  1985;  by a  degradation (1987).  s t i l l  These  between  1 2 3  IPPA  authors  with  a mean  f o rthe late  phase.  th  =  following  218 m i n .  were  distribution. (1985a).  These  curves  Dudczak  Ambrose  infarct  size  i nt h e (Kaul  values  may  e ta l . . be  of metabolic as Ambrose  retention  times  e t a l . (1986)  i n 19 p a t i e n t s  using  i n heart  a l .  within  a  w a s h o u t was b i - e x p o n e n t i a l i n 11 o f phase  w a s h o u t was  e t a l . (1987a)  retention  distribution  measured  et  generated  th  a n d mean  washout  was  times  reported  also  times  and  examined  = 187  mono-exponential that  o f beta-methyl-iodophenyl-pentadecanoic  differences  authors  agent.  13.8 m i n f o r t h e e a r l y  Similarly,  Subcellular  because  myocardial  I n 8 o f 19 p a t i e n t s ,  IV a d m i n i s t r a t i o n  there  of infarct  of  to that of  e t a l . (1986) , as w e l l  Myocardial  th =  e t a l . (1986) .  reported  low correlation  reported decreased  acid.  relative  t o those  availability  by Dudczak  e t a l . . 1960) and has  and Heyndrick  was h i g h e r ,  These  i n tracer  myocardial  histochemical assessment  assessment  o f a beta-methylated  fatty  (1980)  a n d CK-MB  infarction  following  (Dreyfus  low, compared  and b i - e x p o n e n t i a l washout  patients  rats,  by Sylven  kinase  of myocardial  enzymes  t h e 1960's  e t a l . . 1985).  decrease  beta-methylated  with  by B  as suggested  myocardium  mono-  since  recently  were  the presence  f o rthe scintigraphic  and Wolfe  explained  min  known  increases o f creatine  i n C K a n d CK-MB  the correlation  the values  literature  19  confirmed  and the assessment  T1,  the  study  The increase  confirmed  size  post-infarction  acid i n  subcellular by Otto  et a l .  f o r iodophenyl-pentadecanoic  -  acid  (IPP),  increases min,  beta-methyl-IPP  i n washout  30-45  min,  catabolism involving  of a  the  after  taken of  quality  place,  Of  our  from  apical  region,  that,  scan  impression.  Such  volumes,  In  was  order  possible  this  found  mechanism  entry  into  up  our  which pathway  images  120  Dudczak  associated  5-10  the  to  fatty  IPP,  complex  Scintigraphic  obtained  be  to  by  i s a  r e p o r t e d by  would  significant  compared  occurs  to  be  as  each  of  study,  the  occlusion. at  the  of  the to  also  stated  estimates pool  were  borders, problems  were with  apex be  our  This not  as  images, et  et a l .  acid with  of  minutes  may  have  minimal  be  a  i f the  loss  the  at  necessary  subjective i n view  than  the  to  visual of  our  assessed  actual  values.  ventricular  cavity.  blood pool-endocardial  and  subsequently  was  d i f f i c u l t  well-defined  resolution.  this  reports  d e f e c t s were  higher  study,  i n  especially  i t was  from  within  studies  a l . (1984)  inadequate,  that,  would  defined  other  region,  activity from  image.  many  Caldwell  apical  appears  problem  slice  and  tomographic  8).  blood  tomogram  epicardial because  prior  (Table  tomographic  exclude  from  agent  s t i l l  min  location  a l . (1984)  the  20  on  approach  to  subtracted as  an  to  on  The  degradation of  this  LAD  the  attributed  boundaries  well  with  differences  the  agents  a l . . 1986).  could  of  infarcts  estimate  This  time  demarcation  et  two  and  myocardium.  i n myocardial  Caldwell  et  metabolic  following  intra-observer  steps  beta-methyl-IPP,  some  occasionally  as  (Dudczak  greater concern i s border  latter  respectively.  additional  the  the  field,  beta-di-methyl-IPP the  hours,  , however,  of  Although  tracer  of  pathway  injection  (1986).  6-7  for  -  mono-methyl-substituted  number  beta-oxidation sufficient  and  times  and  138  This  the  since as  central  cavity  endocardial,  may  have  been  problem  with  border  as  -  clarity  may  have  interpretation often  this,  borders  Prigent  analysis derived values  image  be  et  a l .  with  an  myocardial  these  SPECT  enhancement  and  volume  method,  increases  the  accuracy  of  volume  computer  programs  the  method  only  Although technical become  a  fully  defects. f i l t e r s for  i n  image  the  usefulness from  a  64  of x  64  this  by  SPECT.  either  to  us,  ie. a  manually,  which  to  possible  was  offer  require means  too  source  masking  technique. I t was  the  These or  u t i l i z e d  many  i n  that  use by  may  of  new  edge  thus  there  of  images at  i n  the  this time,  the  required  study  remain this  so  that  were this  some can  perfusion u t i l i z a t i o n  Although  activity  that  increases  with  before  been  any  The  good  study.  1988).  levels  with  unavailable,  (Jaszczak,  of  et  thresholding  assessing  have  technique  techniques  investigation  error  of  Mortelmans  SPECT  a  profile  number  this  1986;  this  advantages,  a  for  correlation  subjective assessment  out  felt,  compensate  detection.  d e t e c t i o n and  quantitatively of  placing  using  edge  Henkin,  expensive,  further of  of  on  to  linear  described  determination  appears  matrix.  have edge  were  high  volumes  of  drawn  the  and  reported  (1986)  size  indicates  estimate  reconstruction process  quality,  SPECT  i n  our  geometry  circumferential  infarct  (Halama  to  order  count  independent  by  influenced  heterogenous  In  demonstrated  were  and  d i f f i c u l t i e s  exist.  quantify  study  the  accuracy  acceptable  Another  of  maximum  (1986)  a l .  the  which  SPECT  problems  which  et  available  areas-of-interest  to  projection  Mortelmans  do  utilized  Henkin  correlation. which  area  determination  and  view  the  infarction,  diagnostic tool  Halama  -  within  In  authors  methods,  accurate  an  images  These  i n volume  1986).  such  (1987)  algorithms.  error  geometry.  around  2 0 i ~ i  of  Refinements  al..  of  associated with  accurate  may  contributed to  139  may  of  beneficial limit  the  reconstructed  -  was  appropriate;  quality. in  this  Thus,  which low  were  of  mm.  or  are  a  into  u t i l i z e d  assess  128  matrix  number  very  of  matrix  size  may  may  have  have  any  improved  contributed  size  and  factors  thus  i t must be  may  kept  small variations  substantial  the  technical  study  However,  precision,  transmitted  x  i n this  values.  cm.  to  128  -  image to  the  error  study.  addressed  correlation  with  the  there  not  a  inappropriate  portion  Clearly,  however,  140  of  errors.  It  perfusion  associated  have  contributed  i n mind  t h a t when  i n  image  i s clear  defects  with  i n  fuzziness  that  this  the  SPECT, to  the  dealing could  be  method  study  was  inappropriate.  As may  mentioned  allow  for  indication  a  of  demonstrated  FFA  severely greater was  may  myocardium. fatty  acid  infarction. 1 2 3  that 2 0 1  but of  T1.  had  2 0 1  T1.  flow  thallium  between  et  Following acute  authors  LAD  or  various  i n  I t was or  i n which  collaterals,  that  the  of  and found  that  severely the  vessel  FFA  assessment  relative  of  i n mongrel were  excess  of  role  of  fatty  was  FFA  uptake  of  both  the  combined ischemia  both  injected the  was  uptake  myocardial dogs,  i n  stenosed,  u t i l i z a t i o n  the  some  (1987)  ischemia within  examined  acid  together  give  a l .  201x1  occluded  zones  occlusion  a  et  and  r e p e r f u s e d myocardium,  heptadecanoic  observed  agents  zone  Strauss  areas  also  the  risk  acid.  good  of  imaging  u t i l i z i n g  i t i s clear  a l . (1988)  imaging  In  zones  Therefore,  Fischmann  The  ischemic  totally  uptake.  In  both  myocardium.  were  some  I-para-iodophenyl-9-methyl  performed.  the  p a t t e r n s when  which  201x1  to  differentiate  and  injured  uptake  vessels  equal  stenosed,  than  of  of  I-iodophenylpentadecanoic  by  was  than  less  agents  1 2 3  u t i l i z a t i o n  assessment  variable  supplied  uptake  better  the  irreversibly  beta-methyl-pareas  earlier,  2  °IT1  and  and  and  scans  acid  i n  the  -  infarcted area  had  Thus, of  area taken  (mean  other  up  the  a n  infarction  B123IPPA/2OIT;L size  7  20171  both  the  i n  or  et  dogs.  fatty  and  the  a l .  infarction.  Results  within  of  the  size  agent.  of  the  ischemia vary, case the  may  thereby  infarcted  possible  an  of  [20171] at  pH  from 20171  8  a n  as  to  study,  of  the  extent  however,  perfusion  of  indicated  that  both  agents  also  shown  I t was  of  influencing work. could  infarction, circulation  Thus,  fatty our  using  image.  Therefore, to  this  image  the  defect  one  over  i n view  the  type  was  of  fuzziness  phenyl-  of  acid of  myocardial activity  imaging  the degrees  of  these  cells  may  also  shown  to  residual and  0  overestimated  various  This  d  decreased  fatty  within  0  model  20171  that  dog,  uptake  .i4.i  showed  to  the  p  canine  however, i n  acid  SPECT  lead  i n a  relative  i2 3 i .  d  SPECT  interesting  from  (1/iCi)  circulation.  thus  also be  activity give  the  within  rise  to  error.  In cells  2oiTi  evaluated with  collateral  area  this  advantage  acid  zone  i n Kairento's  In  infarcted  together.  (1988)  exist.  the  collateral  estimations no  that  information  ischemia.  similar  damaged myocardium  Within  well-developed  of  v i a  provide  indicating  infarction.  the  i t appears  presumably  would  degree  Beta-methyl-tetradecanoic  areas  acid  indicated  both  -  Therefore,  acid,  1.01+1.25),  using  Kairento  d  7  fatty  ratios  ratio  of  of  141  W  3 2 0 1  as  day  o l d newborn  T1.  The  c e l l  at as  pH pH  accumulation  decreased  effect  investigated.  than  the  study  pH.  6,  At  by  rats of  20  inferring  increases. within  Maublant  cells  were  et  a l .  c u l t u r e d and  extracellular  min,  pH  on  intracellular  some  alteration  This  may  due  (1988),  to  i n  indicate  acidosis,  beating  incubated  ventricular  with  kBq  37  intracellular  [20171] the  that which  w a  s  removal there is  higher 20171  of  may  be  indicative  less of  a  - 142 -  Our as  a marker  indicate and  data  do n o t s u p p o r t  of tissue  perfusion.  i t ss u p e r i o r i t y ,  developmental  myocardial  the choice  Although  FFA imaging  refinement before  perfusion  defects  c a n be  over  20171  characteristics  would  o f the beta-methyl-FFA physical  s t i l l  accurate made.  requires  some  quantitative  further  technical  assessments  of  -  VII  SUMMARY A N D  CONCLUSIONS  The  of this  purpose  pentadecanoic in  the assessment  and  was  -  to u t i l i z e  15-p1 2 3  and 15-p-beta-methyl-iodo( of myocardial  metabolism  1 2 3  I-phenyl-  I)phenylpentadecanoic  and p e r f u s i o n  following  acid  ischemia  infarction.  We  can conclude  (1) 15-  acid  study  143  1 2 3  I n a model  IPPA  control  does  solutions  (2)  by  these  occurring  ischemia, prior  substrates  (3)  as  i n regional  agents  washout  developing  the size  clarity  oxygen 1 2 3  ischemia,  solution).  washout rates  regional  rates  of 15-  to the  Iso-osmolar as  do  I t i s important  to  mention  may  modify  may  be  During  a  the extent  of  Since acids,  IPPA  useful  the period  i n metabolic  pathways  the primary early  (utilization)  1 2 3  were  of may  be  energy  ischemic o f these  demonstrated  injury fuels. a t 14  ischemia.  o f the beta-methyl defects  demarcation.  of  FFA washout  IPPA  impairment. fatty  washout  cytotoxicity.  derangements  are free  myocardial  or allopurinol  i n maintaining  o f the myocardium.  of perfusion  and border  that  o f SOD  iso-osmolar  against  biochemical  altered  found  of administration  of regional status  we  or allopurinol.  and time  The e f f e c t i v e n e s s  determining image  SOD  f o r the myocardium  of slowly  (Tyers  t o any f u n c t i o n a l  be manifested  days  ischemia,  as e f f e c t i v e  with  two  of metabolic  developing  study:  the addition  solution  regime  I n a model  indicator  Changes  modified by  not appear  the dosing  this  of global  supplemented  protection  may  be  cardioplegic  solution  that  may  from  fatty  i s minimal.  acid  analogue  Problems  i n  remain  i n  -  (4)  The use o f i o d i n a t e d f r e e  diagnostic  tool  ischemia.  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Cardiovasc Dis 20(2):81-94, 1977.  -  IX  168  -  APPENDICES  Appendix  I  -  Histochemical size  using  assessment  planimetric  Total 0  Dog-Slice  1  thick(cm)  2  Slice  vol(cm3)-lst observer  (TTZ  staining)  of  perfusion  defect  quantification.  Total 3  Slice  Total  vol(cm3)-2nd  observations 1st  by  4  Slice  vol(cm3)-2nd observer  observer  1  1-1  1  0  2  60  2  95  3  20  2  1-2  1  0  7  00  7  25  7  05  3  1-3  1  2  12  80  13  50  13  50  4  1-4  1  0  20  80  21  76  21  12  5  1-5  1  0  18  56  18  24  18  32  6  1-6  1  2  28  90  28  70  28  80  7  2-1  1  0  5  08  5  12  5  56  8  2-2  1  0  12  12  12  30  12  96  9  2-3  1  0  10  25  10  10  10  35  10  2-4  1  0  23  12  23  36  23  44  11  2-5  1  0  16  80  17  44  16  88  12  2-6  1  0  22  82  22  54  22  61  13  3-1  1  0  1  80  1  68  1  80  14  3-2  1  0  8  65  8  60  8  90  15  3-3  1  0  16  75  16  95  16  80  16  3-4  1  0  28  63  28  49  28  63  17  3-5  1  2  33  80  33  60  34  00  18  3-6  1  0  32  40  32  56  32  48  19  4-1  1  0  5  45  4  90  5  10  20  4-2  0  3  5  28  4  75  5  55  21  4-3  1  0  8  47  8  33  8  82  22  4-4  1  0  19  74  19  39  20  72  23  4-5  1  0  16  80  16  40  16  88  24  4-6  1  0  17  52  17  76  18  08  25  5-1  1  0  9  54  9  12  9  12  26  5-2  1  0  11  69  12  39  12  25  27  5-3  1  0  21  77  21  77  23  34  28  5-4  1  0  24  50  23  59  23  80  29  5-5  1  0  23  04  25  56  23  22  30  6-1  1  0  16  32  16  96  16  72  31  6-2  1  0  19  60  19  52  19  84  32  6-3  1  0  22  24  22  24  22  88  33  6-4  1  0  25  76  23  80  24  22  34  6-5  1  0  25  20  25  12  25  76  35  7-1  1  0  18  88  19  60  19  76  36  7-2  1  0  36  24  39  04  36  80  37  7-3  1  2  32  10  31  40  31  40  38  7-4  1  0  25  84  25  52  24  24  39  8-1  1  0  4  00  4  10  3  45  40  8-2  1  0  9  84  10  38  9  90  continued  -  Appendix  I  -  (continued)  Total 0  169  Dog-Slice  1  thick(cm)  2  Slice  vol(cm3)-1st observer  Total 3  Slice  Total  vol(cm3)-2nd  observations 1st  by  4  Slice  vol(cm3)-2nd observer  observer  41  8-3  1  0  1 5 .84  15  24  16  08  42  8-4  1  0  17 .52  18  12  18  60  43  8-5  1  0  1 3 .35  14  30  13  25  44  8-6  1  0  1 8 .06  18  00  17  70  45  8-7  1  0  1 7 .70  19  02  15  78  46  9-1  1  0  4 .45  4  95  3  95  47  9-2  1  0  6 .40  7  85  7  10  48  9-3  1  0  1 1 .90  12  50  12  30  49  9-4  1  0  16 .14  18  06  16  80  50  9-5  1  0  9 .80  11  25  10  10  51  9-6  1  0  13 .44  14  94  13  08  - 170 -  Appendix I (continued)  0 Dog-Slice  1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40  1-1 1-2 1-3 1-4 1-5 1-6 2-1 2-2 2-3 2-4 2-5 2-6 3-1 3-2 3-3 3-4 3-5 3-6 4-1 4-2 4-3 4-4 4-5 4-6 5-1 5-2 5-3 5-4 5-5 6-1 6-2 6-3 6-4 6-5 7-1 7-2 7-3 7-4 8-1 8-2  5 inf-vol(cm3)-1st observer  0 2 3 4 4 0 0 1 0 0 1 3 0 2 6 10 9 5 0 0 0 0 0 0 2 2 5 5 1 3 3 5 3 3 7 7 5 2 1 4  95 40 60 96 32 00 76 62 95 64 36 22 69 65 45 43 50 68 00 00 00 70 48 00 94 17 60 25 56 68 52 60 22 52 60 52 10 48 50 74  6 inf-vol(cm3)-2nd observations by 1st observer  0 2 3 4 4 0 0 0 1 1 1 5 0 3 6 10 9 7 0 0 0 0 2 0 2 2 4 5 2 4 4 6 3 4 8 10 4 3 2 2  75 35 90 16 48 00 28 66 00 28 92 60 78 00 45 43 10 04 25 00 00 70 64 00 88 66 41 53 22 48 56 72 29 00 48 32 80 12 65 94  Continued  7 inf-vol(cm3)-2nd observer  0.65 2.20 4.00 4.40 4.40 0.00 0.48 1.62 0.85 1.04 1.52 0.91 0.75 2.90 6.55 10.64 9.10 6.64 0.10 0.00 0.00 0.98 0.56 0.00 2.46 2.38 4.41 5.39 1.92 4.24 4.00 6.00 3.50 3.20 8.00 8.24 4.90 3.28 1.50 3.72  -  Appendix  0  I  171  -  (continued)  Dog-Slice  5  inf-vol(cm3)-1st observer  6  inf-vol(cm3)-2nd  observations 1st  by  7  inf-vol(cm3)-2nd observer  observer  41  8-3  7.08  7.62  42  8-4  5.58  9.06  7.44  43  8-5  5.15  5.55  4.90  44  8-6  7.50  8.34  6.60  45  8-7  7.92  7.20  6.54  46  9-1  0.60  1.35  0.80  47  9-2  1.25  1.35  1.00  48  9-3  0.95  1.60  1.30  49  9-4  0.00  0.00  0.00  50  9-5  0.00  0.00  0.00  51  9-6  0.00  0.00  0.00  7.56  -  Appendix  II  1 2 3  -  Scintigraphic and  Bi2 3 i D- S-•A  1  172  F  1st  observer  F  A  (cols  2  20  of perfusion  1-3) 2nd  2oi.xi  3  2nd  observer  4  1st  observer  1st  s  54.25  6 3 .19  V  i  1 4 9 .19  s  84.19  V  i  19.75  r  6 3 .19  1- 3  s  108.50  V  i  32.69  r 1- 4  s  140  00  2 1 .31  14  81  3 3 .69 56  2 4 .13  15  56  3 4 .00  15.13  14  6 2 .31  10  38  12  81  s  205.69  94  187  69  1 7 .69  15  81  00  V  i  20  s  19 222.56  V  i  81  s  33  69  106  56  94  31  25  88  19  06  111  75  38  44  s  88  88  15  81  72.56 218.81  14  19  180  75  152  63  33  31  20  75  51.50 71 252.06  V  i  06  ,44  30.94 149.19 31.63  24.56 171.50 25.63  129  44  16  00  32  13  43  63  29.38  178  31  160.31  23.25  06  25  19  47  75  52  25  34  00  198  50  185  75  188.19  24  38  25.19  67  63  60  25  20  00  216  25  227  63  185.63  27  19  19.00  38  69  89  68 38  94  187  44  170  00  38  88  44  50  48  25  219  75  60  00  203.75 25.00  31  149  69  146  38  25  69  14  94  72  94  73.13  161.50  171  06  r 1- 8  16  168  22  V  i  31  1 3 7 .69  r 1- 7  152  68.00  r 1- 6  1 1 6 .94  2nd  observer  19.44  r 1- 5  6  1st  29 163  109  2nd  81  82  1 3 0 .63  118.81  5  observations  49  1 5 .13  V  i  1 3 9 .81  29  BI P P A  4-6)  44  r 1- 2  using  observer  17 18.00  (cols  by  observer 1- 1  defect  1-rl  observations by  assessment  186.1 27.38  r 1- 9  s  109  06  151  38  197.81  V  26  31  13  19  32.88  i  22  00  117  19  r  27  44  61.75 continued i  -  Appendix  II  1  -  (continued)  B  D- S -A  173  i 2 3  1st  observer  I P P A  2  (  c o l s  i.2)  2nd  observations by  20 1.•Tl  3  2nd  observer  4  1st  observer  s  53.81  45  75  2- 4  2- 5  26  88  82  00  143.88  75  18.06 50.00  31  40  38  r  52.81  32  62  79  88  26  44  26.05  s  93.38  84  44  106  69  125  31  133.56  79  56  13  81  7  63  13  00  22  31  24.19  i  47.81  30  31  39  25  45  44  42  44  36.31  r  37.38  20  69  20  69  27  44  31  59  s  101.88  86  19  128  13  125  19  128  94  V  10.31  16  94  12  63  16  19  20  56  21.31  i  6.75  15  19  21  19  38  19  134  75  40.00  139.75  r  76.69  30  75  61  75  75  44  19  56  s  112.69  103  50  138  38  132  63  116  81  144.81  V  11.88  15  88  12  63  19  38  22  31  13.94  i  3.12  20  56  22  31  41  94  32  94  r  67.88  15  69  34  06  72  81  s  113.56  112  25  144  63  122  31  115  00  136.13  V  10.13  20  38  16  00  13  94  16  31  13.31  30  69  17  06  19  44  77.44  r  23.56  55  63  91  25  s  114.31  106  88  137  94  126  25  115  06  127.06  V  8.38  17  69  12  00  14  31  15  38  14.38  1  81  35  38  20.38  26  06  10.94  r  23.69  24  94  s  122.94  96  00  136  19  99  38  117  00  153.00  V  9.69  13  25  12  44  10  75  14  52  14.38  0  75  30  15  36.00  53  44  s  107  69  130  69  120.38  V  18  44  11  38  13.63  i  20  06 27  75  58  19  5  62  25  13  14  06  16  06  27  06  201  56  59  81  r s  47.38  75  26  V  3- 2  88  15 54  r  3- 1  94  62  i 2- 8  1st  32  i 2- 7  2nd  23.56  i 2- 6  6  observer  i  V  2- 3  2nd  observer  V  2- 2  5  4-6)  observations by  1st  observer 2- 1  (cols  33.69 62  19  118  44  184.13  17  19  19.69  51  50  32.63  162  56  190.94  i  13.25  r  34.13  s  54.19  90  62  9  44  16  88  25  19  32.13  i  10.50  37  94  65  50  16  81  31  75  61.88  r  27.38  17  19  39  44  14  50  50  56  18.63  V  36  19  Continued  76.56  -  Appendix  II  -  (continued)  B  D- S -A  174  1  123Tpp  1st  observer  A  2  (  c  o  i  s  1_3)  2nd  observations by  201-T1  3  2nd  observer  4  1st  observer  1st  s  6 4 .00  V i r 3- 4  3- 6  3- 7  29  1st  98  50  106  25  17  19  13  50  25  56  39  13  92.00 35.25  125  31  20  38  191.31 19.94  43  94  71.63  50  31  12  25  88  28.75  18  00  33.31  114  94  210  08  141.44  165  44  206.13  V  1 1 .56  14  06  29  19  17.63  27  75  85.63  i  22  44  29  38  82  50  57.94  19  38  54  69  35  00  35  13  34.44  31  94  30.88  1 7 1 .38  118  75  168  31  157.69  191  44  191.44  V  1 3 .31  17  00  18  13  17.69  29  69  24.13  i  39  19  30  00  41  31  26.38  12  31  23.44  r  54  31  35  00  31  69  63.06  48  00  44.13  s  135  s  19  126  19  170  38  189.29  120  38  172.31  V  1 1 .81  19  88  12  88  24.88  24  75  17.13  i  3 7 .50  19.44  33  19  r  37  81  33  63  26  00  79.63  48  00  75.44  s  167  00  121  31  145  88  187.69  134  74  131.19  1 6 .81  25  56  17  38  21.06  27  13  21.69  13.31  36  31  r  20  63  12  31  s  75  69  109  88  158  00  125  75  149.19  V  16  38  9  69  21  19  20.50  22  69  52  00  52.88  65  31  63.06  72  31  63.75  4  63  73.75  i r  31  94  56  31  92  38  V  8  94  14  19  i  9  19 11  94  11.81  77  14  91  38  59.19  14  81  10  31  77  69  95  06  17  00  11  75  14  13  8  19  s  49  88  r 4- 2  2nd  observer  observer  i  4- 1  6  1 1 6 .63  V  3- 8  2nd  s  r 3- 5  1 6 .44  4-6)  observations by  observer 3- 3  5  (cols  s  32  44  V  19.88 55.25  i 4- 3  12.63  r s  76  63  V  8  56  i r  Continued.  83.19  -  Appendix  II  1  -  (continued)  B  D- S -A  175  i 2 3 i p p  1st  observer  A  2  (cois  i_3)  2nd  observations by  2°i-Tl  3  2nd  observer  4  1st  observer  1st  4-6)  2nd  6  observations by  observer 4- 4  5  (cols  2nd  observer  1st  observer  s  86.31  73  25  102  19  8 1 .44  92  25  71.81  V  10.44  16  44  11  81  5 .69  7  13  1.44  r s  117.19  96  56  112  56  1 0 1 .88  100  00  102.94  V  14.81  16  13  10  54  6 .69  9  86  5.13  r s  101.38  107  13  90  62  1 1 7 .19  102  38  94.06  V  13.88  5  88  7 .06  7 .81  11  06  8.12  88  98  673  9 .44  15  31  23  25  i 4- 5  2 5 .88  1 4 .75  I 4- 6  2 2 .81  i 4- 7  16.44  r s  19  38  115.13  51  38  71  56  V  11.44  5  94  5  88  6 1 .63 124  i r 4- 8  32.50  3 1 .06  106.44 10.06 44.94  s  42  06  46  69  98  69  110.56  V  6  19  7  44  11  13  10.00  45  06  54  25  94  81  145.50  12  94  13.31  •1  J_  51.63  r 4- 9  s V  5- 1  i  34.94  r  41.88  s  50.19  V  5- 2  5- 3  84  56  151  63  16  88  14  30  30  88  124  88  151.13  18  00  21.69 59.81  i  11.25  13  81  6  00  37  75  r  38.38  39  88  7  94  23  69  49  06  181  63  166.00  25  50  19.63  55  00  71,63  186  38  157.81  24  13  21.94  43  38  62.38  s  51.81  117  31  177  63  V  5.62  24  56  15  94  i  15.13  11  81  8  19  r  33.50  51  38  13  88  49  50  s  40.69  130  44  177  81  V  3.25  25  75  13  78  i  9.06  11  88  9  75  73  44  18  31  r  Continued  -  Appendix  II  -  (continued)  B i 2 3  D- S -A  176  1  1st  observer  (  I P P A  2  c  o  i  s  ! _  2nd  observations by  2°i-Tl  3  3  2nd  observer  4  1st  observer  1st  5- 5  5- 6  5- 7  5- 8  5- 9  s  76.94  113.31  151  63  6.31  24.19  18  00  i  25.94  r  12.50  33.38 120.63  s  89.81 7.81  i  15.81  59.37 12.44  24. 44  6  2nd 1st  165  44  151.25  17  63  19.19  38  88  51.25  25.88 155  88  111.13  128  63  137.94  19  50  13.31  17  19  17.63  18.88  38  88  r  22.13  19. 25  20  25  32.69  23  81  41.69  s  118.25  126. 44  149  13  72.19  132  50  152.00  V  13.69  2 5 . 69  16  75  15.31  i  19.25  26  19  r  35.13  13  50  47  31  26.50 22.31  2 1 . 69  31  56  s  138. 81  135  50  122  00  190.56  V  19. 44  13  75  17  25  17.69  i  2 2 . 38  85  25  30  63  r  45. 69  s  94. 88  166  56  142  94  190.56  V  1 5 . 75  22  88  12  25  17.69  i  16. 31  26  56  39  94  56  169.50 19.75  39.88  54.06  r  18. 13  55  19  s  75. 63  135  50  146  V  12. 31  13  75  12  63  i  24. 94  85  25  31  69  100. 75  179  56  140  19  24. 31  22  63  29  19  36.44  2 8 . 12  65  75  58  88  45.63  54.06  r 6- 1  s  40.94 30.19  V i 6- 2  6- 3  2nd  observer  observer  V  V  4-6)  observations by  observer 5- 3  5  (cols  9.13  43.25  173.88  r  8.81  1 2 . 38  24  25  62  31  76.25  s  61.38  1 0 1 . 56  125  69  140.19  141  38  169.69  V  5.13  18. 88  16  25  11.50  29  06  13.94  i  19.25  15. 13  33  13  18.19  32  63  49.00  r  15.13  25. 44  44  50  49.50  s  110.31  73. 38  136  81  102.81  174  75  165.74  V  10.69  1 3 . 75  12  94  13.13  34  56  18.81  i  31.25  15. 13  33  31  17.19  43  00  35.94  r  14.31  22  81  17.88  Continued  -  Appendix  II  1  -  (continued)  B  D- S -A  177  i 2 3 i p  1st  observer  P  A  2  (  c  o  l  s  i_3  2nd  observations by  201-T1 3  2nd  observer  4  1st  observer  1st  6- 5  6- 6  4-6)  2nd  6  observations by  observer 6- 4  5  (cols  2nd  observer  1st  observer  s  110.44  86  00  133  50  129.88  162  81  V  9.37  17  88  8  63  15.00  23  13  14.25  i  17.44  13  63  38  00  43.06  20  159.19  r  19.81  s  111.69  100  06  114  38  114.63  152  00  155.19  V  7.13  18  44  8  50  14.81  28  38  16.06  i  11.25  34  88  56  r  16.56  s  118.56  113  63  128  63  113.31  127  31  121.50  V  9.88  14  38  9  31  15.19  18  63  16.25  r s  27  81  16  38  124.06  113  69  143  00  113.94  114  63  150.88  V  9.81  14  81  9  37  14.31  14  81  11.38  i  16  94  21  75  r  29  94  23  38  s  119  06  128  44  129  88  140.38  V  14  88  9  25  15  00  14.94  i  40  00  36  88  33.00  i 6- 7  6- 8  6- 9  r  25  19  s  117  50  147  25  102  81  136.63  V  17  44  12  75  13  13  13.25  i  44  00  56  88  17  19  21  56  30  19  80  50  153  56  130  88  13  88  r 7- 1  s  43.38  V i  18.25  r 7- 2  7- 3  15.50 45.13  187.06  21  38  22  00  30.50  62  81  35  75  127.81  42  69  27  56  39  44  s  103.81  100  50  136  69  V  16.75  23  56  19  94  i  18.44  21  56  r  15.94  32  38  s  121.50  111  19  156  19  V  22.63  22  63  12  25  i  18.81  23  00  r  22.13  31  25  36.13  189  69  185.25  36  00  27.88  44  13  93.50  28  93  15.75  111.19  194  13  188.38  13.88  25  63  18.69  11.13  39  69  39.63  7.50  35.75 Continued  -  Appendix  II  1  -  (continued)  B  D -S -A  178  123Tpp  1st  observer  A  2  (  c  o  i  s  i_3  2nd  observations by  2oi.Tl  3  2nd  observer  4  1st  observer  1st  7 -5  2nd  6  1st  s  149.13  114  50  1 4 9 .31  136.38  183  06  167.44  V  17.56  25  38  1 9 .31  15.38  29  06  22.44  i  13.25  25. 50  34.13  r  17.13  s  151.25  131  56  1 4 7 .44  141.38  154  94  212.13  V  16.06  27  44  1 7 .44  12.88  26  06  12.06  i  23.94  14. 31 31.88  s  157.19  130  19  V  22.25  30  00  i  8.19  7 -8  8 -1  8 -2  1 7 5 .19 21  25  166.13  141  38  216.63  18.81  12  88  16.44  14.69  r 7 -7  3 0 .44  s  149  13  196  38  136  38  144.69  V  17  56  21  13  15  38  12.19  i  13  25  37 .94  10  13  r  17  13  s  121  50  142  88  1 1 1 . 19  159.75  V  22  63  21  13  1 3 . 88  14.31  i  18  81  2 7 .44  r  22  13  30  11  13  88  s  43.50  151. 81  192.06  V  29  13  27.56  i  7 0 . 56  81.63  r  32. 50  38.88  151. 81  142.75  s  72.38  V i  56.57  r 8 -3  2nd  observer  observer  r 7 -6  4-6)  observations by  observer  7 -4  5  (cols  29  13  14.13  62  88  63.44  2 8 . 69  s  118.69  172  56  116.94  V  20.81  27  75  15.81  i  69.56  7 6 . 88  34.63  r  24.75  1 9 . 19  Continued  -  Appendix  II  -  (continued)  B  D- S -A  179  1  123Tpp  1st  observer  A  2  (  c  o  i  s  i _  2nd  observations by  aoi.Tl  3  3  2nd  observer  4  Lst  observer  1st  8- 5  8- 6  8- 7  8- 8  s  1 5 1 .81  131  00  V  2 9 .13  18  75  16.00  i  7 0 .56  19  63  49.31  9- 3  32 .50  23  26  11.25  s  1 5 1 .81  100  13  133.88  V  2 9 .13  13  25  12.50  i  6 2 .88  19  75  r  2 8 .69  s  1 7 2 .56  131  44  V  2 7 .75  13  19  11.81  i  7 6 .88  27  63  44.88  S V  1 3 1 .00  159  25  146.31  1 8 .75  16  81  12.44  i  1 9 .63  49  50  33.44  r  2 3 .26  55.88 183.00  r  s  149  69  137.69  V  19  31  10.56  i  54  00  24.63  s  5 9 .63  91  06  2 1 9 .31  21  06  1 9 .25 8 1 .50  i  1 7 .75  26  44  r  1 7 .13  28  06  s  1 0 0 .56  98  38  1 1 5 .81  V  13 .00  19  88  1 2 .94  i  2 6 .56  r  1 9 .69  35  62  2 8 .75  s  1 3 4 .31  127  81  1 2 8 .81  V  1 8 .81  18  00  12 .81  i 9- 4  155.00  r  V  9- 2  2nd  observer  observer  r 9- 1  6  2nd  observations by l s t  observer 8- 4  5  (cols 4-6)  r s  2 8 .19  50  50  1 3 2 .69  124  75  1 2 9 .88  V  1 0 .06  24  44  1 7 .25  2 7 .75  37  00  i r  Continued  -  Appendix  II  1  -  (continued)  B D- S -A  180  1 2 3  IPPA  1st  observer  2  (cols 2nd  observations by  201-T1  1-3 3  2nd  observer  1st  s  115.75  114  06  127  13  V  14.38  15  69  15  38  r  41.50  20  00  s  134.88  122  25  124  88  V  12.88  16  13  14  13  r  34  44  41  50  s  98  31  118  19  V  8  75  14  00  i  30  88  42  06  i 9- 7  r 9- 8  S V  100  75  121  44  10  94  12  13  i  30  94  47,44  r 9- 9  observer  5  s V  99  69  98  00  9  44  10  69  i  33  06  44  25  r  28  88  4-6)  2nd  observations 1st  observer  i 9- 6  1st  by  observer 9- 5  4  (cols  6  2nd  observer  - 181 -  Appendix  III  -  B  1 2 3  IPPA/  2 0 1  T1  corresponding  D-S -A  7  1st  Observer FA/TL 1-1  s  0  49  V i  3  19  8  2nd  ratios  f o r each  D-S -A  Observer  98  0  91  2  66  s  1  09  1  01  V  0  97  0  65  i  2  32 1  35  s  0  86  0  87  V  0  04  0  64  i  1  73  r 1-3  r 1-4  1  42  s  0  75  0  93  V  0  74  0  75  2-1  2-2  2-3  2-4  r 0  89  0  74  V  0  77  0  59  2-5  i r 1-6  0  96  0  88  V  0  73  0  82  2-6  1  16  0  92  V  1  22  0  63  2-7  FA/TL 0  19  60  i  0  r  1  23  s  0  67  0  V  0  62  0  32  i  0  71  1  08  r  0  66  s  0  67  0  92  V  0  82  0  59  i  0  11  0  53  r  1  57  s  0  89  0  96  V  0  71  0  91  i  0  62 0  91  s  0  98  1  06  V  1  24  1  20  i  1  58 5  09  s  0  93  1  09  V  1  15  0  83  s  0  82  V  0  91  0  61  0  32  0  29  i  r  r  s  1  06  0  82  V  0  77  0  59  2-8  s V  i  i  r  r  s  0  72  0  85  V  0  85  0  48  i  0  41  r  81  2nd  Observer  r  s i  1-9  48  8  i  r  1-8  0  r  s i  1-7  s  r  s  and  V  i 1-5  1st  FA/TL  r 1-2  7  Observer  FA/TL 0  experiment  area-of-interest  3-1  s V i  0  23  r  0  70  0  77  0  21  -  Appendix  D-S -A  III  7  l s t  FA/TL  3-3  3-4  3-5  3-6  -  (continued)  Observer  3-2  182  8  2nd  D-S -A  Observer FA/TL 1  06  s  0  79  1  42  0  37  0  53  V  2  31  8  20  i  1  19  1  06  i  r  0  34  2  12  s  0  79  0  56  s  0  97  1  09  V  0  84  0  68  V  1  63  2  04  4-4  r 4-5  i  0  58  0  55  i  r  1  73  0  78  r  s  0  69  1  01  s  1  05  0  96  V  0  51  0  34  V  0  53  0  87  r  i  1  52  r  1  10  1  38  4-6  i  s  0  62  0  88  s  0  52  0  67  V  0  57  0  75  V  0  39  0  58  i  2  44  1  76  i  r  0  73  0  71  s  1  05  0  99  s  0  43  0  42  V  0  80  0  75  V  0  56  0  74  r  0  70  0  34  r  s  0  90  1  11  0  48  0  37  V  0  94  0  80  r  1  68  s  0  87  1  06  V  0  77  0  47  4-7  r 4-8  i 4-9  s V i r  5-1  s  0  68  1  00  V  0  94  0  67  i  0  37  r  1  68  s  0  65  1  07  V  V  0  96  0  81  i  i  0  21  s  1  08  1  74  5-2  r s  r 1  s  0  70  1  13  V  V  1  07  0  63  i  i  0  27  s  0  68  1  00  V  1  37  0  94  18  1  45  5-3  r 4-3  FA/TL  0 .56  r  4-2  2nd  s  i 4-1  8  Observer  V  i  3-8  l s t FA/TL  i  3-7  7  Observer  r  s  1  07  V  3  67  1  49  5-4  i  i  r  r  -  Appendix  D-S -A  III  7  -  (continued)  1st  Observer FA/TL 5-5  183  8  2nd  D-S -A  Observer  s  0  94  1  13  1  42  1  10  FA/TL 6-5  i 5-6  r  0  81  0  49  s  0  95  0  98  V  1  53  0  88  6-3  66  0  74  0  65  0  53  s  0  89  1  06  V  0  77  0  57  0  79  14  0  71  r  V  1  13  0  78  i  0  73  s  0  66  0  87  V  1  29  1  29  i  0  41 1  02  s  0  52  0  80  V  0  97  0  70  i  0  79  s  0  72  1  03  V  0  83  0  i  0  48  1  r  0  20  0  32  s  0  72  0  74  s  V  0  65  1  17  V  i  0  46  0  68  i  r  0  57  s  0  42  0  82  V  0  40  0  69  i  0  35  0  93  6-7  0  99  0  95  1  00  0  82  s  0  92  0  91  V  0  99  0  62  r 6-8  i r s  1  14  1  08  V  1  32  0  96  i  2  56 1  95  s  1  14  0  82  62  V  1  20  0  70  44  i  1  56  0  49  0  62  0  74  0  63  0  72  r  0  65  s  0  53  0  83  V  0  65  0  66  6-9  r  s  0  53  0  84  V  0  77  0  61  i  0  36  r  s V i  7-1  r 7-2  7-3  r 6-4  0  1  r  6-2  s V  s  r  6-1  FA/TL  r 6-6  r  5-9  2nd  i  r  5-8  8  Observer  i  i 5-7  1st  Observer  FA/TL  V  7  7-4  i  0  49  r  1  12  s  0  57  0  89  V  0  88  0  86  i  0  58  r  Appendix  D-S -A  III  (continued)  7  1st  Observer FA/TL 7-5  8  2nd  Observer FA/TL  s  0  85  0  70  V  1  05  1  45  s  0  92  0  81  V  2  33  1  29  i r 7-6  i r 7-7  s  1  09  1  36  V  1  14  1  73  i  1  31  r 7-8  s  1  09  0  89  V  1  63  1  48  i  1  69  r 8-1  s V i r  8-2  s V i r  8-3  s V i r  8-4  s V i r  8-5  s V i r  - 185 -  Appendix IV -  Dog-Slice  1-1 1-2 1-3 1-4 1-5 1-6 2-1 2-2 2-3 2-4 2-5 2-6 3-1 3-2 3-3 3-4 3-5 3-6 4-1 4-2 4-3 4-4 4-5 4-6 5-1 5-2 5-3 5-4 5-5 6-1 6-2 6-3 6-4 6-5 7-1 7-2 7-3 7-4  Infarcted tissue as percent of entire s l i c e expressed f o r each o f the three techniques of perfusion defect assessment, including 123 201 histochemistry (TTZ s t a i n i n g ) , B IPPA and T1.  1 % Inf 1st observer  36 34 28 23 23 0 14 13 9 2 8 14 38 30 38 36 28 17 0 0 0 3 2 0 30 18 25 21 6 22 17 25 12 13 40 20 15 9  54 29 13 85 28 00 96 37 27 77 11 11 33 64 51 43 11 53 00 00 00 55 86 00 82 56 72 43 77 55 96 18 50 97 25 75 89 60  2  % Inf 2nd observations by 1st observer 25 32 28 19 24 0 5 5 9 5 11 24 46 34 38 36 27 21 5 0 0 3 16 0 31 21 20 23 8 26 23 30 13 15 43 26 15 12  42 41 89 12 56 00 47 37 90 48 01 84 43 88 05 61 08 62 10 00 00 61 10 00 58 47 26 44 68 42 36 22 82 92 27 43 28 23  Continued  3 % Inf 2nd observer  20 31 29 20 24 0 8 12 8 4 9 4 41 32 38 37 26 20 1 0 0 4 3 0 26 19 18 22 8 25 20 26 14 12 40 22 15 13  31 21 63 83 02 00 63 50 21 44 00 02 67 58 99 16 76 44 96 00 00 73 32 00 97 43 90 65 27 36 16 22 45 42 49 39 61 53  4123 B IPPA 1st observer  33.24 23.46 21.04 33.06 32.60 26.47 43.78 51.20 7.37 3.10 0.00 0.00 27.96 19.38 25.69 21.36 27.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 22.42 32.76 24.19 36.73 19.28 30.24 34.24 31.37 17.26 10.76 42.06 21.12 13.91 17.71  -  Appendix  IV  -  (continued)  1  2 %  Dog-Slice  186  Inf lst  observer  % Inf 2nd  observations by l s t  3  4 %  Inf 2nd  observer  B  123IPpA lst  observer  observer 8-1  37  50  6 4 .63  8-2  48  17  2 8 .32  3 7 .58  8-3  44  70  5 0 .00  4 7 .01  8-4  31  85  50 .00  4 0 .00  8-5  38  58  38 .81  3 6 .98  8-6  41  53  4 6 .33  3 7 .27  8-7  44  75  37 .85  4 1 .44  9-1  13  48  2 7 .27  2 0 .25  29.76  9-2  19  53  1 7 .20  1 4 .08  30.35  9-3  7  98  12 .80  1 0 .57  0.00  9-4  0  00  0 .00  0 .00  0.00  9-5  0  00  0 .00  0 .00  0.00  9-6  0  00  0 .00  0 .00  0.00  4 3 .48  -  Appendix  IV  Dog-Slice  187  (continued)  5  B^SIPPA  observation by  l s t  6  B  1 2 3  IPPA  2nd observer  7  TL  8  lst  observation  observer  by  TL  2nd  l s t  observer  9  TL 2nd  observer observer  1-1  18  5  40  6  20  84  16  0  21.4  1-2  24  2  0  0  24  28  8  0  0.0  1-3  0  0  0  0  30  48  0  0  0.0  1-4  0  0  0  0  34  07  37  4  0.0  1-5  12  9  0  0  32  31  47  8  22.8  1-6  0  0  70  5  26  59  45  9  48.3  2-1  54  1  39  6  66  23  45  5  36.7  2-2  22  8  18  0  48  49  82  7  16.1  2-3  17  0  0  0  34  96  27  6  8.7  2-4  11  7  0  0  37  03  29  4  28.4  2-5  35  1  24  8  15  74  0  0  0.0  2-6  24  5  0  0  1  62  0  0  0.0  3-1  48  2  38  2  22  61  34  9  29.2 22.1  3-2  30  2  49  5  28  10  26  1  3-3  14  4  13  4  38  31  17  5  7.3  3-4  0  0  0  0  46  80  27  8  0.0  3-5  0  0  0  0  15  05  30  2  5.1  3-6  0  0  15  4  7  99  34  2  18.2  4-1  8  4  0  0  0  0  0  0  0.0  4-2  0  0  0  0  0  0  0  0  0.0  4-3  0  0  0  0  0  0  0  0  0.0  4-4  0  0  0  0  0  0  13  4  0.0  4-5  0  0  0  0  0  0  54  5  15.0  4-6  0  0  0  0  0  0  59  4  52.3  5-1  16  0  0  0  19  44  35  3  47.7 42.4  5-2  6  1  0  0  16  69  26  5  5-3  0  0  17  4  19  70  11  5  0.0  5-4  19  5  42  1  20  95  30  0  0.0  5-5  38  8  59  8  19  6-1  27  2  37  1  0  6-2  22  5  13  4  6-3  0  0  0  0  6-4  28  1  23  2  0  6-5  36  8  46  2  0  30  23  9  0.0  0  41  0  32.3  21  3  28  9  27.1  19  17  15  0  0.0  0  0  0  0.0  0  20  21  0.0  Continued..  -  Appendix  IV  Dog-Slice  188  -  (continued)  5  B i 2 3  I P P A  observation by  1st  6  B  1 2 3  IPPA  2nd observer  7  TL  8  1st  observation  observer  by  TL  2nd  1st  observer  9  TL 2nd observer observer  7-1  62  63  0  00  0  00  45  21  23.36  7-2  0  00  0  00  20  75  32  83  23.54  7-3  26  93  0  00  5  10  26  02  0.00  7-4  0  00  0  00  0  00  16  56  0.00  8-1  0  .0  54  4  49.5  8-2  78  12  37  5  35.0  8-3  71  07  21  1  15.3  8-4  57  53  34  8  25.0  8-5  51  26  41  4  19.4  8-6  53  09  31  3  13.0  17  49  0  0  0.0  8-7 9-1  17  8  26  9  9-2  0  0  0  0  9-3  0  0  0  0  9-4  39  5  41  9  9-5  20  0  30  7  9-6  0  0  22  8  - 189 -  Appendix V  Dog-Slice  -  1 slice vol(cm3)-lst observer  8-1 8-2 8-3 8-4 8-5 8-6 8-7 9-1 9-2 9-3 9-4 9-5 9-6  Dog-Slice  8-1 8-2 8-3 8-4 8-5 8-6 8-7 9-1 9-2 9-3 9-4 9-5 9-6  A u t o r a d i o g r a p h i c assessment of the 9 using planimetric quantitation.  3 10 15 16 11 16 22 3 7 11 17 10 13  4  55 44 36 44 80 80 14 75 40 35 34 10 26  I R Z (cm3) observer  3 6 10 8 8 8 9 0 0 0 0 0 0  55 54 74 82 30 10 53 00 00 00 00 00 00  2 s l i c e v o l ( c m 3 ) - 2nd o b s e r v a t i o n s by l s t observer  3 10 15 17 13 17 19 3 7 11 17 10 13  lst  ischemic  3  95 84 92 60 00 52 71 00 00 00 00 00 00  zone f o r  6  d o g s 8 and  s l i c e vol(cm3)-2nd observer  3 9 15 17 13 17 19 3 7 11 16 10 13  95 14 66 04 25 64 80 65 15 45 28 10 32  5 IRZ (cm3) - 2 n d o b s e r v a t i o n s by l s t observer  3 6 10 9 8 8 9 0 0 0 0 0 0  risk  45 48 84 64 35 40 38 50 00 50 92 00 38  IRZ (cm3) observer  3 6 10 9 7 8 8 0 0 0 0 0 0  45 60 44 78 45 16 97 00 00 00 00 00 00  -  2nd  

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