1718 JACC Vol. 25, No. 7 June 1995:

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1 1718 JACC Vol. 25, No. 7 EXPERMENTAL STUDES Effec of Capopril and Enalapril on Lef Venricular Geomery, Funcion and Collagen During Healing Afer Anerior and nferior Myocardial nfarcion in a Dog Model BODH. JUGDUTT, MD, MSc, FACC Edmonon, Albera, Canada Objecives. This sudy compared he effecs of capopril and enalapril on lef venricular geomery, funcion and mass and on scar collagen and opography during healing afer anerior and inferior myocardial infarcion in a canine model. Background. The beneficial effec of prolonged angioensinconvering enzyme inhibior herapy on remodeling during healing afer myocardial infarcion migh be greaer in anerior han inferior infarcs and more effecive wih capopril han enalapril herapy. Mehods. The effecs of 6 weeks of herapy wih capopril (50 mg wice a day), enalapril (2.5 mg wice a day) or placebo on in vivo variables of lef venricular remodeling, funcion and mass (by echocardiography), hemodynamic funcion, posmorem opography (by planimery) and collagen (hydroxyproline levels) were sudied in 36 insrumened dogs randomized o receive herapy 48 h afer lef anerior descending or lef circumflex coronary arery occlusion. Resuls. Compared wih placebo herapy, boh capopril and enalapril decreased infarc expansion and hinning, progressive venricular dilaion, venricular mass and asynergy and infarc collagen levels in anerior and inferior infarcs. Despie similar small scar sizes, he effecs on remodeling and dysfuncion were greaer in anerior han inferior infarcs. n addiion, capopril produced greaer aenuaion of infarc expansion and venricular enlargemen, greaer improvemen in volume ejecion fracion and less decrease in infarc collagen levels han enalapril. Conclusions. On balance, capopril and enalaprii aenuaed lef venricular remodeling and preserved funcion in small anerior and inferior infarcs despie differences in he effecs of he drugs on individual remodeling variables. Furher sudies will be needed o deermine wheher inhibiion of infarc collagen migh be harmful, or differences beween capopril and enalapril herapy imporan, in large ransmural infarcions. (JAm Coil Cardiol 1995;25: ) nhibiion of angioensin-convering enzyme afer myocardial infarcion has he poenial for limiing cerain remodeling variables and preserving funcion (1-7). Alhough angioensinconvering enzyme inhibior herapy is recommended afer anerior infarcion in paiens a high risk for lef venricular dilaion and dysfuncion (8), here has been no sysemaic comparison of is effecs on anerior versus inferior infarcion. Wheher angioensin-convering enzyme inhibiors conaining hiol (e.g., capopril) are more effecive han hose wihou hiol (e.g., enalapril) is conroversial (9-12). Because hese agens inhibi hyperrophy and fibrosis during posinfarcion healing (13-17) in noninfarced myocardium, hey migh also increase collagen degradaion and inhibi collagen deposiion in infarc zones, inerfere wih scar formaion or cause regres- From he Division of Cardiology, Deparmen of Medicine, Universiy of Albera, Edmonon, Albera, Canada. This sudy was suppored in par by grans from he Medical Research Council and he Hear and Sroke Foundaion of Canada, Oawa, Onario. The work was done during he enure of Dr. Jugdu as a Scienis of he Albera Heriage Foundaion for Medical Research, Edmonon. Manuscrip received Sepember 30, 1994; revised manuscrip received January 10, 1995, acceped January 19, Address for correspondence: Dr. Bodh. Jugdu, 2(;2.43 Waler MacKenzie Healh Sciences Cenre, Division of Cardiology, Universiy of Albera, Edmonon, Albera, Canada, T6G 2R7. sion of he fibrous scar issue. is also no known wheher his effec migh promoe remodeling and impair funcional improvemen. Therefore, we compared he effecs of herapy wih he angioensin-convering enzyme inhibiors capopril and enalapril during healing afer anerior and inferior myocardial infarcion on remodeling variables, sysolic funcion, venricular mass and infarc collagen conen in a well defined canine model (15). Mehods Experimenal preparaion. The experimens were approved by he insiuional animal welfare commiee and conformed o he "Posiion of he American Hear Associaion on Research Animal Use" adoped by he Associaion in November Fify healhy mongrel dogs (16 o 29 kg) were chronically insrumened hrough a lef laeral horacoomy under general aneshesia (sodium penobarbial, 30 mg/kg body weigh inravenously), as described previously (3,4). Polyehylene caheers were insered in he exernal jugular vein, inernal caroid arery and lef arium, filled wih heparinized saline soluion and heir ends brough ou behind he neck. The mid-lef anerior descending coronary arery (n = 1995 by he American College of Cardiology /95/$ (95)00040-B

2 JACC Vol. 25, No. 7 JUGDUTr 1719 CAPTOPRL VERSUS ENALAPRL AFTER NFARCTON 25) or mid-lef circumflex coronary arery (n = 25) was ligaed wih a silk hread. Pairs of meal beads were suured on anerior, laeral and poserior surfaces of he epicardium a he mid-lef venricular level for consisen echocardiographic imaging. Visible epicardial collaeral vessels were ligaed o produce more ransmural infarcion (mean [+SD] 83 _+ 4% of wall hickness), as done previously (18). Afer closure of he pericardium and ches, penicillin (1 million U) and srepomycin (1 g) were given inramuscularly. Proocol. Two days afer ligaion, 48 healhy survivors were randomized o receive placebo (n = 16), capopril (50 rag) (n = 16) or enalapril (2.5 rag) (n = 16). Each group had eigh dogs wih a ligaed lef anerior descending coronary arery and eigh wih a ligaed lef circumflex coronary arery. Therapy was given orally, wice daily (every 12 h) for 6 weeks. The dogs were given free access o fluids, and no aemp was made o rea hear failure. A 6 weeks, he 36 surviving dogs were anesheized and he hears were arresed in diasole wih an overdose of inravenous poassium chloride, excised, washed in normal saline soluion and weighed. n vivo measuremens during healing. As described previously (3,4), simulaneous wo-dimensional echocardiograms (Toshiba SSH-65A [3.5-MHz ransducer]), elecrocardiograms (Gould recorder ) and hemodynamic variables (Saham P23Db for lef arial and arerial pressures) were recorded in he conscious sae wih he dogs sanding in a sling for suppor: before herapy a 2 days afer ligaion, during herapy a 3 and 6 weeks afer ligaion; and again 1 o 2 days afer herapy was sopped. Hemodynamic variables were also measured a 1 week. Recordings during herapy were made 3 o 4 h afer he firs daily doses. Echocardiograms were acquired a parasernal long- and shor-axis views a he miral, chordal, midpapillary, low papillary and apical levels and apical fourand wo-chamber views. Analysis of echocardiograms. As described previously (3,4), coded echocardiograms were analyzed on video playback (0.5-in. apes) by wo independen observers who were unaware of he randomizaion procedures for in vivo opographic variables; differences were resolved by consensus. Briefly, endocardial and epicardial oulines of he lef venricular images a end-diasole and end-sysole were raced wih a ligh pen (Diasonics CardioRevue Cener) and copied ono plasic overlays. Anaomic landmarks, such as papillary muscles and righ and lef venricular juncions, were indicaed on he racings. Asynergy, defined as akinesia (no sysolic inward moion and hickening) or dyskinesia (sysolic ouward moion and hinning), or boh, was marked on each endocardial diasolic ouline. The circumferenial exen of asynergy on each shor-axis view was hen digiized (Hewle-Packard 9878A and 9835A) and used o compue oal endocardial surface area of asynergy by a hree-dimensional reconsrucion algorihm. Oulines from five shor-axis and wo long-axis views were also used o compue volumes by means of a modified Simpson's rule algorihm. Global ejecion fracion was calculaed as end-diasolic volume minus end-sysolic volume divided by end-diasolic volume. nerobserver error was <5% in marking asynergy, segmen lengh, wall hickness and areas of oulines, in agreemen wih previous sudies (3,4,18). Topographic measuremens were made on end-diasolic oulines of shor-axis images a he papillary level, and he expansion index (raio of he lenghs of asynergic, or infarc-conaining, segmens o nonasynergic, or non-infarc-conaining, segmens) and hinning raio (raio of average hicknesses of he asynergic o nonasynergic zones) were compued. Lef venricular aneurysm was defined as he presence of a bulge in diasole and furher bulging in sysole. Lef venricular mass was calculaed by muliplying he volume of myocardium (difference in volumes of epicardial and endocardial shells a end-diasole) by an assumed specific graviy of 1.05 g/ml (19). Posmorem measuremen of scar size, geomery and collagen conen. As described previously (3,4), he risk region was measured on posmorem coronary areriograms recorded on whole-hear and ransverse secion (1- o 1.5-cm hick) radiographs. Oulines of lef venricular rings, risk regions and infarc scars were made on plasic overlays and subjeced o compuerized planimery (Hewle-Packard 9835A compuer and 9874A digiizer inerfaced wih a VAX 750 compuer) o assess infarc size and opography and o calculae he "hinning" raio (raio of average hickness of infarced wall o average hickness of normal wall) and "expansion" index (raio of endocardial lenghs of infarc-conaining o non-infarcconaining segmens demarcaed by papillary muscles). Average shor-axis opographic maps were made for each group (3,4). Hisopahologic analysis of exen of infarc scar and collagen conen (20) was performed on a 5-mm slice from he middle of he infarc zone, and riplicae 5-/xm hick secions were sained wih hemaoxylin-eosin, Mallory's sain or Masson's richrome, respecively. Myocardial hydroxyproline (mg/g dry issue weigh), a marker for collagen, was measured in 100- o 200-mg samples from he cener and border regions of he infarc scar (afer excision of normal issue on gross examinaion) and he cener of he noninfarc region (20). Saisics. Daa were analyzed in blinded manner by 1) analysis of variance for he significance of difference wihin and beween groups; 2) chi-square es for he significance of difference in even frequency beween groups; and 3) repeaed measures analysis of variance for comparison of serial daa wihin groups. Resuls are presened as mean value _+ SD, unless oherwise saed. Saisical significance was se a p < 0.05 (wo-ailed). Resuls Sudy groups. Of he 48 dogs ha were randomized a 2 days, 12 died over he 6 weeks (placebo n = 4, capopril n = 4, enalapril n = 4). The 36 dogs ha were killed a 6 weeks (12 in each group) form he basis of his repor. The disribuion of dogs wih anerior versus inferior infarcion in each of he hree groups was 6 anerior and 6 inferior in he placebo group; 8 anerior and 4 inferior in he capopril group; and 6 each in he enalapril group.

3 1720 JUGDUTT JACC Vol. 25, No. 7 CAPTOPRL VERSUS ENALAPRL AFTER NFARCTON Figure 1. Myocardial hydroxyproline conen in infarc and noninfarc regions. Resuls are mean value _+ SEM; p values ~g ~" beween bar graphs indicae beween-group differences. ~ p<0.001 p<o.01 T p<0.ool ] ~-r- p<0.025 L NFARCT CENTER i NFARCT BORDER m Placebo Capopril Enalapril p<o.05 i NON-NFARCT CENTER nfarc scar size. A 6 weeks, infarc scar size wih capopril (5-3 g) and enalapril (4 _+ 2 g) was no significanly less han ha wih placebo (6 _ 3 g), and hear size was g (7 -+ 4% of he lef venricle, or % of he risk region). Venricular and risk region mass was similar ( and 15 _ 7 g, respecively). nfarc scar, venricular and risk region size for anerior and inferior infarcion subgroups was also similar (p = NS). Regional collagen conen. Non-infarc region collagen conen was slighly lower (p < 0.05) for enalapril han for placebo, bu he difference beween capopril and placebo did no achieve saisical significance. n conras, collagen conen in he infarc cener and border regions was markedly lower wih capopril and enalapril han wih placebo, and he decrease was greaer wih enalapril (Fig. 1). There was no difference in infarc or noninfarc collagen conen beween anerior and inferior infarcion subgroups. -emodynamic changes. The 2-day baseline hemodynamie changes were similar for all reamen groups and subgroups for all 36 dogs (hear rae beas/min; mean arerial pressure 111 _+ 15 mm Hg; lef arial pressure 15 mm Hg). On day 2, capopril and enalapril produced a marked decrease in lef arial pressure (20% o 40%), a mild decrease in mean arerial pressure (5% o 10%) bu no change in hear rae compared wih ha during placebo. Alhough hese variables decreased in all groups beween 2 days and 6 weeks, lef arial and arerial pressures remained lower wih angioensinconvering enzyme inhibiion han wih placebo, and only he decrease in mean arerial pressure wih capopril was saisically significan (Table 1). Alhough he overall decrease in mean arerial pressure was slighly greaer wih capopril han enalapril (-14 vs. -7%), and he overall decrease in mean lef arial pressure was slighly less wih capopril han wih enalapril (-34 vs. -49%), hese differences were no saisically significan (p < 0.2 and p < 0.1, respecively). Afer drug wihdrawal a 6 weeks, arerial and lef arial pressures increased in he capopril and enalapril groups, such ha he changes in arerial (-4% vs. -1% vs. -1%) and arial (-31% vs. -26% vs. -28%) pressures from baseline were similar in he capopril, enalapril and placebo groups, respecively. There was no difference in hemodynamic changes beween he anerior and inferior infarcion subgroups. Lef venricular geomery. The effecs on geomery are depiced in Figures 2 o 4. Compared wih placebo, capopril and enalapril decreased regional infarc expansion (Fig. 2), infarc hinning (Fig. 3) and lef venricular diasolic volumes (Fig. 4). The placebo subgroup wih anerior infarcion showed greaer elongaion of he infarc-conaining segmen and greaer increase in expansion index (Fig. 2), noninfarc wall hickness (Fig. 3), end-diasolic and end-sysolic volumes and diasolic endocardial surface area (Fig. 4) han he placebo subgroup wih inferior infarcion. n addiion, he aniremodeling effecs on infarc expansion and venricular enlargemen ended o be greaer wih capopril han enalapril, especially beween 3 and 6 weeks (Fig. 2 o 4). Lef venricular funcion. Compared wih placebo, capopril and enalapril decreased regional lef venricular asynergy, bu he effec was more marked in he anerior infarcion subgroup (Fig. 5). The decrease in oal lef venricular asynergy was less pronounced (Fig. 5). The improvemen in global volume ejecion fracion was greaer wih capopril han wih enalapril in boh anerior and inferior infarcion subgroups Table 1. Percen Changes in Hemodynamic Variables From Two-Day Baseline Value* Hear Rae (beas/min) Mean Arerial Pressure (mm Hg) Mean Lef Arial Pressure (mm Hg) Group 1 wk 3 wk 6 wk 1 wk 3 wk 6 wk 1 wk 3 wk 6 wk Placebo (n = 12) _ _ _ _+ 22 Capopril (n = 12) -22 _ _ _+ 13"~ -15 _+ 11:~ _ Enalapril (n = 12) _ _ L-_ 24 *Decreases (minus sign) are significan versus he wihin-group 2-day value (p <_ 0.05). P < 0.05, :~p < 0,001, p < 0.005, capopril or enalapril groups versus placebo group. Daa presened are mean value _+ SD.

4 JACC Vol. 25, No. 7 JUGDUTr 1721 CAPTOPRL VERSUS ENALAPRL AFTER NFARCTON m 6O 40 rv < 20 er 0 O,,- ~-20 O < -4o ~g 2o c~ cc 0 < m -20 _o rr,uj -40 _z NFARCT CONTANNG NON-NFARCT EXPANSON SEGMENT LENGTH CONTANNG NDEX SEGMENT LENGTH 25 ; / 1" :[: $ 1` 1" x 1` 1" 1" $ * $ ~; 2lol wl 2lo l l l 2 W l l 3W 6 pdw 3W 6W pdw D 3 6W pdw Figure 2. Effec of herapy on in vivo changes in infarc expansion. Resuls are mean value +- SEM; poins are offse around ime lines for clariy. D = day; pdw = pos drug wihdrawal; W - week. *p <_ 0.05, anerior versus inferior infarcion subgroups. ~'p _< 0.05, enalapril (T) or capopril (&) versus placebo (e). ~p _< 0.05, capopril versus enalapril. (Fig. 5). The frequency of lef venricular aneurysm a 6 weeks was lower in he inferior han anerior placebo subgroup (3 of 6 vs. 6 of 6, p < 0.1), he anerior capopril han anerior placebo subgroup (2 of 8 vs. 6 of 6, p < 0.01) and he combined capopril han placebo groups (3 of 12 vs. 9 of 12, p < 0.025). The frequency of lef vcnricular aneurysm was no significanly differen for placebo versus enalapril or capopril versus enalapril. Figure 3. Effec of herapy on in vivo changes in infarc hinning. Resuls are mean value _+ SEM; poins are offse around ime lines for clariy. *p _< 0.05, anerior versus inferior infarcion subgroups.?p < 0.05, enalapril or capopril versus placebo. ~p _< 0.05, capopril versus enalapril. Abbreviaions and symbols as in Figure 2. g 2O 10,,< o (~ ' F Ol- _o -2ol- NFARCT WALL NON-NFARCT WALL THNNNG RATO THCKNESS THCKNESS 1 1 ; i 1 21D r i ; i i D 3W 6W pdw 3W 6W pdw D 3W 6W pdw Lef venricular mass. Compared wih placebo, boh capopril (-2% vs. +2%, p = 0.5) and enalapril (-10% vs. +2%, p = 0.2) lowered lef venricular mass, bu only enalapril achieved saisical significance in he anerior infarcion subgroup (-11% + 17% vs. +12% +_ 14%, p < 0.05). Posmorem opography. Topographic maps in he shoraxis view a 6 weeks confirmed less caviy area, infarc wall hinning, noninfarc wall hickness and infarc zone bulging wih inferior han anerior infarcion and wih capopril or enalapril han wih placebo (Table 2). The caviy area was larger wih enalapril han capopril for boh anerior and inferior infarcion (Table 2), supporing he in vivo finding in Figure 4. Discussion There were four major findings in his sudy: 1) furher infarc expansion, infarc hinning and venricular enlargemen occurred beween 2 days and 6 weeks wih infarcs a boh anerior and inferior locaions in he placebo group. Alhough here was no difference in exen of infarc hinning a he wo infarc locaions, he exen infarc expansion and venricular enlargemen was greaer in anerior han inferior infarcion. 2) Capopril and enalapril herapy improved lef venricular geomery and funcion beween 2 days and 6 weeks afer boh anerior and inferior infarcion. However, he magniude of he effecs on expansion and venricular enlargemen were greaer in anerior han inferior infarcion. n addiion, he effecs on expansion, volumes and global funcion ended o be greaer wih capopril han enalapril. 3) Capopril and enalapril decreased lef venricular mass in anerior and inferior infarcion, bu only he decrease wih enalapril in anerior infarcion was saisically significan. 4) Capopril and enalapril decreased infarc collagen conen, bu he effec was more marked wih enalapril. Enalapril also produced a mild decrease in noninfarc collagen conen. Mechanisms. Boh capopril and enalapril decreased lef arial (index of preload) and mean arerial pressures (index of aferload), lef venricular volumes and lef venricular and infarc collagen conen in anerior and inferior infarcion. Four main mechanisms explain he effecs common o he wo angioensin-convering enzyme inhibiors: 1) Angioensinconvering enzyme inhibiors mediae vasodilaion by inhibiion of angioensin formaion and bradykinin breakdown and increased bradykinin, niric oxide (21), prosaglandin E 2 and prosacyclin (22). Vasodilaion, in urn, leads o lef venricular unloading, less regional bulging, smaller chamber size and lower diasolic wall sress (by virue of he Laplace law), less wall srech, less gene expression of conracile and nonconracile proeins and less hyperrophy (23,24). 2) These agens inhibi issue angioensin-convering enzyme and inramyocardial conversion of angioensin o angioensin, hereby decreasing local angioensin ; aciviies of myocye, fibroblas and ransforming-growh facors (25-27); myocye hyperrophy; and collagen deposiion. Release of niric oxide secondary o increased bradykinin migh also inhibi myocye

5 1722 JUGDUTT JACC Vol. 25, No. 7 CAPTOPRL VERSUS ENALAPRL AFTER NFARCTON Figure 4. Effec of herapy on in vivo changes in lef venricular enlargemen. Resuls are mean value -+ SEM; poins are ~_ offse around ime lines for clariy. *p < 0.05, anerior versus o inferior infarcion subgroups, p <- 0.05, enalapril or capopril ~- 7 versus placebo. ~p -< 0.05, capopril versus enalapril. Abbreviaions and symbols as in Figure 2. rr z 40 o_ o 20 la. _z o_ -20 o < -40 4O 2o END- DASTOLC END-SYSTOLC ENDOCARDAL VOLUME VOLUME SURFACE AREA $ $ $ o n- -20 _z -40 " -J 2D 3W 6W pdw 2D 3W 6W pdw 2D 3W 6W pdw hyperrophy (28). 3) Angioensin-convering enzyme inhibiors improve nurien flow hrough bradykinin and niric oxidemediaed dilaion of coronary areries and collaeral vessels as well as reduced endocardial compression secondary o decreased diasolic wall sress (3,4). 4) Because high myocardial wall sress and low nurien flow cause marix disrupion (29,30), lowering diasolic wall sress and increasing flow wih angioensin-convering enzyme inhibiion would end o preserve he supporing marix, improve he mechanical coupling beween collagen fibrils a infarc scar borders and live myocyes (31), limi remodeling and preserve funcion. Figure 5. Effec of herapy on in vivo changes in regional and global lef venricular funcion. Resuls are mean value _+ SEM; poins are offse around ime lines for clariy. *p _< 0.05, anerior versus inferior infarcion subgroups.?p < 0.05, enalapril or capopril versus placebo. ~p _< 0.05, capopril versus enalapril. Abbreviaions and symbols as in Figure 2. 4o,~ ~- -2o - o ~: 40 aj o o."='~ 20 cc 0 _z ee -20 O r7-40 _z -60 REGONAL ASYNERGY TOTAL LV ASYNERGY 21D 31W 61W p(lw 21D 31W 61W pdw EJECTON FRACTON $ 61W 2D 3W pdw Several differences beween he effecs of he wo angioensinconvering enzyme inhibiors in his sudy migh relae o differences in heir chemisry and pharmacology (32). 1) Capopril, unlike enalapril, has a sulfhydryl group ha addiionally causes direc vasodilaion (10) and increases vasodilaory prosaglandins. These effecs migh explain he slighly greaer decrease in blood pressure wih capopril. Alhough he oxygen-free radical scavenging aciviy of he sulfhydryl group is proecive afer reperfusion (11), is role in his permanen occlusion model is no clear. 2) Alhough capopril is iself he acive drug, enalapril has o undergo hepaic deeserificaion o he acive form, enalaprila. Also, whereas capopril Undergoes meabolism o disulfides and primarily urinary excreion, enalaprila is excreed in urine (61%) and feces (33%) wihou furher meabolism. Enalapril herefore has a slower onse (2 vs. 0.5 h), laer peak (6 vs. 1 h) and longer duraion (24 vs. 6 h) of acion han capopril, and he eliminaion half-life is longer (>30 vs. 1.7 h). Alhough he finding of a greaer decrease in venricular mass wih enalapril despie a lesser decrease in blood pressure suggess an exaggeraed response wih his drug, i is also possible ha venricular unloading was susained for a longer period beween doses wih enalapril. Because boh drugs produced unloading a he doses used and have fla doseresponse curves, i is unlikely ha doses used played a major role in he differences. 3) Enalapril possesses greaer angioensin-convering enzyme inhibiory poency and more binding sies (seven vs. five) han capopril (32). migh produce greaer inhibiion of angioensin, fibroblas growh facor and ransforminggrowh facor-bea 1 han capopril. This migh explain why enalapril (bu no capopril) produced a decrease in noninfarc collagen and why enalapril decreased infarc scar collagen more han capopril. The finding ha boh agens produced marked lowering of collagen in he infarc scar region bu lile

6 JACC Vol. 25, No. 7 JUGDUTT 1723 CAPTOPRL VERSUS ENALAPRL AFFER NFARCTON Table 2. Mean (-+SD) Posmorem Measuremens a Low Papillary Level on Shor-Axis Topographic Maps Placebo Capopril Enalapril Anerior infarcion subgroup No. of dogs Angular exen of infarc (0 ) 121 _ _+ 9* 90 _+ 5* nfarc wall hickness (mm) ' 9 _+ 1' Noninfarc wall hickness (mm) 15 _ _+ 1' " LV caviy area (cm 2) _+ 0.6* 3.5 _+ 0.5* Area of endocardial bulge (cm 2) 1.3 _ " 0.5 _+ 0.1' nferior infarcion subgroup No. of dogs Angular exen of infarc (0 ) 105 _ * 80 _+ 3* nfarc wall hickness (ram) _+ 1" 9 _+ 1" Noninfarc wall hickness (mm) 14 _ _+ 1' " LV caviy area (cm 2) 4.6 _ * 3.2 _+ 0.4* Area of endocardial bulge (cm 2) 1.0 _ _+ 0* 0.3 _+ 0* *p _< 0.05, capopril or enalapril versus placebo, P < 0.05, enalapril versus capopril. LV = lef venricular. decrease in collagen in he nonscar region also suggess ha angioensin-convering enzyme inhibiion migh preferenially block collagen deposiion in areas where i acively occurs, as in he healing infarc scar. The greaer inhibiion of infarc collagen wih enalapril migh explain why infarc sreching and venricular enlargemen were greaer and why here was less improvemen in global ejecion fracion han wih capopril. is possible ha low infarc collagen conen migh weaken he scar and be poenially harmful by allowing greaer remodeling under he effec of mechanical forces (33) and by causing defecive mechanical coupling a he infarc borders. Wheher increased collagenase aciviy migh have played a role is no known. However, no marked deleerious effec was found wih he small infarcs in his sudy. To our knowledge, a decrease in infarc collagen wih long-erm angioensin-convering enzyme inhibiion has no been repored previously. Alhough regression of fibrous issue and decreased deposiion or increased degradaion of collagen wih angioensin-convering enzyme inhibiors is hough o be beneficial in pressure overload hyperrophy (34), a similar effec on noninfarc collagen in "volume overload hyperrophy" afer infarcion (13-17,25) was hough o be harmful (15), n he ra infarcion model, which is associaed wih exensive necrosis of he lef venricular free wall, marked chamber dilaion, hyperrophy and fibrosis of he sepum, early (14) bu no lae (16), capopril herapy inhibied deoxyribonucleic acid synhesis, fibroblas proliferaion and collagen deposiion in noninfarc regions. n he same model, a similar effec was demonsraed wih perindopril (13), and nearly complee inhibiion of noninfarc collagen was produced by he angioensin ype recepor blocker losaran (17). n conras, he dog infarcion model in his sudy was associaed wih only mild hyperrophy and very lile increase in noninfarc collagen. Meris and limiaions. The dog model allowed in vivo quaniaion of major remodeling variables during healing over 6 weeks as well as posmorem mapping of opography and quaniaion of infarc and noninfarc collagen conen in he same animals. However, he infarcs were small, and 83% were ransmural. As repored previously (19,20), infarcs shrink during healing from -20% of he lef venricle on day 1 o 10% a 6 weeks. Marix disrupion (18) and remodeling (19) would probably have been more severe if he infarcs were large and 100% ransmural. Alhough echo-opaque beads were implaned for consisen serial imaging (3,4,18,19), we could no deec adverse effecs on in vivo bulging or aneurysm wih eiher angioensin-convering enzyme inhibior. Alhough posmorem measuremens were made on hears ha were arresed in diasole and fixed in disension, no significan differences in regional bulging or hinning were deeced beween capopril and enalapril. n conras o previous sudies wih capopril (3,4), where ransmural samples were used and no significan decrease in infarc collagen was deeced, he infarc scar issue in he presen sudy was carefully excised for he collagen assays o minimize admixure wih normal issue. Marix ulrasrucure, collagenase aciviy or mechanical properies of he scar were no sudied. mplicaions. The goal of aniremodeling herapy during infarc healing is o preserve lef venricular geomery, preven dilaion and preserve funcion. A shor, hick and srong scar migh be desirable. The overall resuls of he presen sudy sugges ha he final oucome wih angioensin-convering enzyme inhibior herapy represens a balance of posiive and negaive effecs on facors involved in healing and remodeling afer infarcion (33). The resuls also sugges ha anihyperrophic and collagen-lowering effecs migh be more poen wih enalapril han capopril. Alhough reduced infarc collagen did no seem o have a marked negaive impac on he small nonransmural infarcs in his sudy, one migh expec a differen oucome wih large ransmural infarcs, as was found in he ra model (15). Because paiens in clinical rials of angioensin-convering enzyme inhibiors afer infarcion received oher early herapies, and because he rials included hrombolysis in -30% o 70% of paiens, he infarcs were

7 1724 JUGDUTT JACC Vol. 25, No. 7 CAPTOPRL VERSUS ENALAPRL AFTER NFARCTON June 1995: mos likely also small and subendocardial. The finding of a survival benefi in mos of hese sudies (33) suppors he concep ha final oucome represens a balance of effecs. However, he curren daa do no favor one angioensinconvering enzyme inhibior over anoher. Alhough capopril was associaed wih decreased moraliy in he Survival and Venricular Enlargemen (SAVE) (6) and nernaional Sudy of nfarc Survival (SS-4) (35) rials and wih aenuaion of venricular enlargemen in a SAVE subsudy (7) and oher remodeling sudies (5,36-38), survival benefi was also found wih ramipril in he Acue nfarcion Ramipril Eficacy (ARE) rial (39) and wih lisinopril in he Gruppo aliano per lo Sudio della Sopravvivenza nell'nfaro Miocardico (GSS) rial (40). Alhough no survival benefi was found wih enalapril in he Sudies of Lef Venricular Dysfuncion (SOLVD) (41) and Cooperaive Norh Scandinavian Enalapril Survival Sudy (CONSENSUS ) (42) rials, he recen "Pracical" sudy (43) ha compared capopril and enalapril afer infarcion showed ha boh agens aenuaed lef venricular dilaion and improved ejecion fracion, bu only enalapril improved survival. Conclusions. n he presen sudy, herapy wih capopril or enalapril during healing of relaively small nonransmural anerior and inferior myocardial infarcions limied remodeling, improved sysolic funcion and preserved lef venricular geomery a 6 weeks despie a marked decrease in infarc collagen conen. The beneficial effecs on remodeling and funcion were greaer in anerior han inferior infarcion. Alhough he greaer enalapril-induced lowering of infarc collagen migh explain he lesser improvemen in global sysolic funcion han ha induced by capopril, i did no seem o have a marked negaive impac on in vivo remodeling variables. Wheher he infarc-collagen lowering effec of angioensinconvering enzyme inhibiion migh be poenially harmful during early healing of large ransmural infarcions needs furher sudy. am graeful o Dr. Mohammad. Khan for assisance wih analysis of echocardiograms and Caherine Graham for yping he manuscrip. References 1. Pfeffer JM, Pfeffer MA, Braunwald E. nfluence of chronic capopril herapy on he infarced lef venricle of he ra. Circ Res 1985;57: Pfeffcr MA, Pfeffer JM, Seinberg C, Finn P. Survival afer an experimenal myocardial infarcion: beneficial effecs of long-erm herapy wih capopril. Circulaion 1985;72: Jugdu B, Schwarz-Michorowski BL, Khan M. Effec of long-erm capopril herapy on lef venricular remodeling and funcion during healing and canine myocardial infarcion. J Am Coll Cardiol 1992;19: Jugdu B, Humen DP, Khan M, Schwarz-Michorowski BL. Effec of lef venricular unloading wih capopril on remodelling and funcion during healing of anerior ransmural myocardial infarcion in he dog. Can J Cardiol 1992;8: Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effec of capopril on progressive venricnlar dilaaion afer anerior myocardial infarcion. N Engl J Med 1988;319: Pfeffer MA, Braunwald E, Moy6 LA, e al. on behalf of he SAVE nvesigaors. Effec of capopril on moraliy and morbidiy in paiens wih lef venricular dysfuncion afer myocardial infarcion. N Engl J Med 1992;327: S. John Suon M, Pfeffer MA, Plapper T, e al. Quaniaive wodimensional echocardiographic measuremens are major predicors of adverse cardiovascular evens afer acue myocardial infarcion: he proecive effecs of capopril. Circulaion 1994;89: Pfeffer MA, Braunwald E. Venricnlar remodeling afer myocardial infarcion: experimenal observaions and clinical implicaions. Circulaion 1990; 81: Li K, Cher X. Proecive effecs of capopril and enalapril on myocardial ischemia and reperfusion damage of ra. J Mol Cell Cardiol 1987;19: van Gris WH, Seholens E, de Graeff PA, de Langen CD, Wesseling H. Differenial influences of angioensin-convering enzyme inhibiors on he coronary circulaion. Circulaion 1988;77 Suppl : Weslin W, Mullane K. Does capopril aenuae reperfusion-induced myocardial dysfmcion by scavenging free radicals? Circulaion 1988;77 Suppl : van Wijngaarden J, Pino YM, van Gils WH, de Graeff PA, De Langen CDJ, Wesseling H. Convering enzyme inhibiion afer experimenal myocardial infarcion in ras: comparaive sudy beween spirapril and zofenopril. Cardiovasc Res 1991;25: Michel JB, Laion AL, Salzmann JL, e al. Hormonal and cardiac effecs of convering enzyme inhibiion in ra myocardial infarcion. Circ Res 1988;62: van Krimpen C, Schoemaker RG, Cleujens JPM, e al. Angioensin convering enzyme inhibiors and cardiac remodeling. Basic Res Cardiol 1991;86: Schoemaker RG, Debcs JJM, Sruyker-Boudier HAJ, Smis JFM. Delayed bu no immediae capopril herapy improved cardiac funcion in conscious ras, following myocardial infarcion. J Mol Cell Cardiol 1991;23: Liwin SE, Liwin CM, Raya TE, Warner AL, Goldman S. Conraciliy and siffness of non-infarced myocardium afer coronary ligaion in ras. Effecs of chronic angioensin convering enzyme inhibiion. Circulaion. 1991;83: Sairs JFM, van Krimpen C, Schoemaker RG, Cleujens JPM, Daemen MJAP. Angioensin recepor blockade afer myocardial infarcion in ras: effecs on hemodynamics, myocardial DNA synhesis, and inersiial collagen conen. J Cardiovasc Pharmacol 1992;20: Jugdu B, Tang S-B, Khan M, Basualdo CA. Funcional impac of remodeling during healing afer non-q wave versus Q wave anerior myocardial infarcion in he dog. J Am Coil Cardiol 1992;20: Jugdn B, Khan M. Effec of prolonged nirae herapy on lef venricular remodeling afer canine acue myocardial infarcion. Circulaion 1994;89: Jugdu B, Amy RWM. Healing afer myocardial infarcion in he dog: changes in infarc hydroxyproline and opography. J Am Coil Cardiol 1986;7: Palmer RMJ, Ferrige AG, Moncada S. Niric oxide release accouns for he biological aciviy of endohelium-derived relaxing facor. Naure 1987;327: Needleman P, Marshall GR, Sobel BE. Hormone ineracions in he isolaed rabbi hear: synhesis and coronary vasomoor effecs of prosaglandins, angioensin and bradykinin. Circ Res 1975;37: Schneider MD, Parker TG. Cardiac myocyes as arges for he acion of growh facors. Circulaion 1990;81: Chien KR, Knowlon KU, Zhu H, Chien S. Regulaion of cardiac gene expression during myocardial growh and hyperrophy: molecular sudies of an adapive physiologic response. FASEB J 1991;5: Hirsch AT, Talsness CE, Schunker H, Paul M, Dzau VJ. Tissue specific acivaion of cardiac angioensin convering enzyme in experimenal hear failure. Circ Res 1991;69: Sadoshima J, zumo S. Molecular characerizaion of angioensin -induced hyperrophy of cardiac myocyes and hyperplasia of cardiac fibroblass: criical role of he AT 1 recepor subype. Circ Res 1993;73: Thompson NL, Bazoberry F, Speir EH, e al. Transforming growh facor beaa in acue myocardial infarcion in ras. Growh Facors 1988;1: Garg UC, Hassid A. Niric oxide-generaing vasodilaors and 8-bromocyclic guanosine monophosphae inhibi miogenesis and proliferaion of culured ra vascular smooh muscle cells. J Clin nves 1989;83: Fujiwara H, Ashraf M, Sao S, Millard R. Transmural cellular damage and blood flow disribuion in early ischemia in pig hear. Circ Res 1982;51:

8 JACC Vol. 25, No. 7 JUGDUTT 1725 CAPTOPRL VERSUS ENALAPRL AFTER NFARCTON 30. Zhao M, Zhang H, Robinson TF, e al. Profound srucural aleraions of he exracellular collagen marix in posischemic dysfuncional ("sunned") bu viable myocardium. J Am Coll Cardiol 1987;10: Whiaker P, Boughner DR, Kloner RA. Analysis of healing afer myocardial infarcion using polarized ligh microscopy. Am J Pahol 1989;34: Raia JJ, Barone JA, Byerly WG, Lacy CR. Angioensin-convering enzyme inhibiors: a comparaive review. DCP Ann Pharmacoher 1990; 24: Jugdu B. Prevenion ofvenricuar remodelling pos myocardial infarcion: iming and duraion of herapy. Can J Cardiol 1993;9: Weber KT, Brilla CG. Pahological hyperrophy and cardiac inersiium. Fibrosis and renin-angioensin-aldoserone sysem. Circulaion 1991;83: SS Collaboraive Group. SS-4: randomizaion of oral isosorbide mononirae in over 50,000 paiens wih suspeced acue myocardial infarcion [absrac]. Circulaion 1993;88 Suppl : Sharpe N, Smih H, Murphy J, e al. Early prevenion of lef venricuar dysfuncion afer myocardial infarcion wih angioensin-convering enzyme inhibiion. Lance 1991;337: Oldroyd KG, Pye MP, Ray SG, e al. Effecs of early capopril adminisraion on infarc expansion, lef venricular remodelling and exercise capaciy afer acue myocardial infarcion. Am J Cardiol 1991;68: Nabel EG, Topoi EJ, Galaena A, e al. A placebo-conrolled rial of combined early inravenous capopril and recombinan issue-ype plasminogen acivaor in acue myocardial infarcion. J Am Coil Cardiol 1991;17: Ball SG. The acue infarcion ramipri efficacy (ARE) sudy invesigaors. Effec of ramipril on moraliy and morbidiy of acue myocardial infarcion wih clinical evidence of hear failure. Lance 1993;342: Gruppo aliano per lo Sudio della Sopravvivenza nell'fnfarco Miocardico. GSS-3: effecs of lisinopril and ransdermal glyceryl rinirae singly and ogeher on 6-week moraliy and venricular funcion afer acue myocardial infarcion. Lance 1994;343: Yusuf S. The SOLVD nvesigaors. Effec of enalapril on moraliy and he developmen of hear failure in asympomaic paiens wih reduced lef venricular ejecion fracions. N Engl J Med 1992;327: Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H, for he CONSENSUS Sudy Group. Effecs of early adminisraion of enaapril on moraliy in paiens wih acue myocardial infarcion: resuls of he cooperaive Norh Scandinavian Enalapril Survival Sudy (CONSENSUS ). N Engl J Med 1992;327: Foy SG, Crozier G, Turner JG, e al. Comparison of enalapril versus capopril on lef venricular funcion and survival hree monhs afer acue myocardial infarcion (he "Pracical" Sudy). Am J Cardio11994;73: