Ventricular

Remodeling Following Infarction Norman Sharpe,

Ventricular remodeling denotes structural changes that occur in ventricular chamber size, wall thickness, and composition followi~ myocardial damage. Following acute coronary occlusion, there are various factors to consider at different times that may contribute to subsequent ventricular dilation. Early infarct expansion and later healing may be accompanied by compensatory hypertrophy in the noninfarcted region and progressive global dilation, that may progress long term, the major stimulus being increased wall stress. The 2 major factors influencing ventricular remodeling followi~ myocardial infarctin are infarct artery patency and the ventricular loadi* condttions. Thrombolytic therapy may produce coronary reperfusion and limit infarct size. Patency of the infarct-related artery may also provide later benefii for ventricular remodeling. Following infarct evolution, pharmacologic itiervention provides the potential to minimize the sequelae of infarct expansion and ventricular dilation. Clinical studies indicate that treatment of symptomless left ventricular dysfunction with anglotensin-converti@ enzyme inhibition at L 1 week following myocardial infarctiin may prevent further ventricular dilation and reduce the probabilii of progression to heart failure. Earlier intervention, at 24-46 hours following Q-wave myocardial infarction, is also practicable and effectiie. Even earlier intervention, in combination with or immediately following thrombolysii, is being assessed in other studies. The timing of treatment is of considerable importance because btockade of compensatory mechanisms activated at the time of infarction may not be desirable immediately, even though these mechanisms may be deleterious later. The results of large-scale mortality studios are awaited to indi-

From the Department of Medicine, University of Auckland School of Medicine, Auckland, New Zealand. Address for reprints: Norman Sharpe, MD, Department of Medicine, Auckland Hospital, Park Road, Auckland 1, New Zealand.

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cate the benefit of this type of treatment in terms of heart failure prevention and survival long term. (Am J Cardiol199&70:2OG26C)

T

he structural and functional changes that occur in heart failure have long been studied. However, it is only relatively recently that the term “cardiac remodeling” has been introduced, as the complexity and importance of the regional and global changes in ventricular size, shape, and composition that occur in heart failure have become better understood.Cardiac or ventricular remodeling denotes structural changes that occur in ventricular chamber size, wall thickness, and composition following myocardial damage. The regional and global topographic changes that occur following myocardial infarction have been the subject of most studies on this subject, but it is also relevant to consider myocardial changes that occur in other forms of heart failure with pressure or volume overload. Whatever the underlying cause of heart failure, there is commonly a prolonged period prior to the occurrence of clinically manifest congestive heart failure (CHF) during which ventricular remodeling occurs, initially as an adaptive compensatory process with varying degrees of ventricular dilation and hypertrophy, but leading to progressive ventricular dysfunction. The poor prognosis of advanced clinical CHF has recently led to consideration of earlier intervention, during the phase of symptomless ventricular dysfunction, and treatment directed at modifying the process of ventricular remodeling. Infarct expansion and healing: At different times following acute coronary occlusion in the clinical setting, there are various factors to consider that may contribute to subsequent ventricular dilation. Thrombolytic therapy may produce coronary reperfusion and limit infarct size. Early infarct expansion and later healing may be accompanied by compensatory hypertrophy in the noninfarcted region and progressive global dilation, which may

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progress long term, the major stimulus being increased wall stress. A sequential 2-dimensional echocardiographic study of patients after acute transmural myocardial infarction demonstrated disproportionate dilation and transmural thinning of the infarcted zone in 8 of the 28 patients studied.i This regional expansion was first observed as early as 3 days after infarction and was progressive during the 2 weeks of study. Infarct segment length increased 50%, producing a total left ventricular circumferential dilation of 25%. Patients showing infarct expansion all had anterior infarcts and significantly greater g-week mortality compared with the patients without expansion. A distinction is required between infarct expansion and extension, i.e., between disproportionate dilation and thinning of the area of infarction not explained by additional or new myocardial necrosis.2 Infarct extension appears to be a much less frequent event than expansion and generally will not compromise cardiac function further.2 Infarct expansion can mimic or possibly cause extension and commonly worsens cardiac function through ventricular dilation. Various cellular mechanisms for infarct expansion have been suggested, including myocyte necrosis and rupture, reduction in intercellular space, and stretching or slippage of myocytes.3 Detailed histologic study of rat hearts with infarct expansion, complemented by study of human hearts, indicates that rearrangement of groups or bundles of myocytes with a decreased number of cells across the wall accounts for most of the wall thinning in the infarct zone and all the thinning of noninfarcted regions.3 In noninfarcted regions, cell slippage accounts for wall thinning, whereas cell stretch and loss of intercellular space are confined to the infarct zone and contribute less to wall thinning than does cell slippage. The association of infarct expansion with larger, more transmural infarcts noted experimentally has been confirmed in a large patient autopsy analysis.“ Infarcts with greater expansion had significantly more endocardial thrombus and endocardial fibroelastosis. Left ventricular hypertrophy and increased heart weight had a significant negative correlation with infarct expansion, which occurred ‘more frequently in left anterior descending coronary artery distribution compared with the right coronary artery. From these findings, it can be postulated that differences in the degree of normal segmental wall thickness related to radius of curva-

TABLE

I Ventricular

Dilation

Following

Myocardial

Acute transmural infarction Early infarct expansion Regional Continued Increased General

L Days

ventricular dilation expansion vs healing wall stress ventricular

Infarction

i Weeks 1 Months

dilation

ture and intramural tension explain the increased tendency for infarct expansion in the distribution of the left anterior descending coronary artery.4 With left ventricular hypertrophy and increased wall thickness, infarcts tend to be less transmural and the apparent protection from expansion in the presence of hypertrophy may be due to relatively smaller infarct size. Global ventricular dilation: Early infarct expansion and regional ventricular dilation after myocardial infarction may be accompanied or followed by a phase of global ventricular dilation occurring over subsequent months and involving both infarcted and noninfarcted segments (Table I). This has been demonstrated from serial 2-dimensional echocardiographic early studies in a group of patients after transmural anterior myocardial infarction.5 Patients with early infarct expansion showed significant continuing dilation during longterm observation up to 30 months in the infarcted anterior and noninfarcted posterior segments. In contrast, the patients without initial infarct expansion showed no significant later change in anterior or posterior segment length. Remodeling of the entire left ventricle with volume overload hypertrophy of noninfarcted segments may also occur during the early convalescent period and accompany infarct expansion. An angiographic study on admission and at 2 weeks in a group of patients with their first acute transmural anterior myocardial infarct treated successfully with thrombolytic therapy showed a significant increase in left ventricular volume over the 2-week period but a significant decrease in left ventricular filling pressure. 6 The volume increase correlated with infarct size as assessed by the extent of wall motion abnormality present acutely. Increased endocardial perimeter lengths were present in both infarcted and noninfarcted segments at 2 weeks. Lengthening of the endocardial perimeter in the ventricular wall without regional wall motion abnormality and wall thinning suggests a volume overload hypertrophy with a net increase in myocardial mass of these segments and is analogous to the

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and increased wall stress may be matched by adequate hypertrophy, with the tendency to progressive dilation, eventually mismatch occurs and Process Intervention heart failure becomes clinically manifest.1°J3 Coronary occlusion Restore infarct artery patency The pattern of left ventricular dilation following Restore infarct artery patency Myocardial infarction myocardial infarction can be quite variable. In a Size Optimize oxygen supply:demand Reduce regional wall stress group of 57 patients with myocardial infarction, Transmural extent Reperfusion injury Attenuate reperfusion injury none of whom had undergone thrombolysis, radioMyocardial infarct expansion Reduce regional wall stress nuclide evaluation showed approximately half of Early/late the patients to have > 20% increase in left ventricGlobal ventricular dilation and Reduce wall stress and hyperular end-diastolic volume index from 2 weeks to 1 compensatory hypertrophy trophy year following infarction.14 A similar study with Progressive ventricular Ventricular unloading serial evaluation of left ventricular volume changes dysfunction in 50 patients who did not receive thrombolysis Recurrent ischemialinfarction Optimize oxygen supply:demand showed >20% increase in left ventricular endArrhythmias diastolic volume from day 2 to day 10 in 11 patients, Clinical congestive heart failure Relieve congestion Block neurohormonal activation and similar left ventricular dilation from day 10 to 6 Improve myocardial contractility months in 10 other patients.15 Among these 21 patients, progressive dilation with serial volume increases on 22 occasions occurred in 8 patients, compensatory hypertrophy demonstrated early fol- all of whom had large anterior infarcts. Thus, lowing acute myocardial infarction in experimental approximately 40% of infarct survivors demonanimal studies.7-9Such volume overload hypertro- strated significant ventricular dilation within 6 phy results from series addition of sarcomeres, in months of infarction. Progressive dilation was assocontrast to pressure overload hypertrophy where ciated with deterioration in left ventricular funcnew myofibrils are added in parallel. It has been tion and increased 2-year mortality, in contrast to postulated that increased diastolic pressure and patients with dilation that stabilized, who had a wall stress from volume overload leads to sarco- better clinical outcome. mere replication in series with resultant chamber enlargement. lo Such chamber enlargement accommodates the volume overload, returning diastolic MODIFICATION OF LEFC VENTRICULAR pressure to normal. The chamber enlargement also REMODELING causesan increase in systolic wall stress that results Various processes may contribute to ventricular in slight wall thickening. remodeling at different stages from the time of The demonstration of early significant left ven- coronary occlusion until the possible development tricular diastolic dysfunction assessedby radionu- of progressive ventricular dysfunction and clinical elide angiography within 24 hours of acute myocar- heart failure (Table II). These processes are amedial infarction, which occurred even in patients nable to intervention at different times, the overall with preserved systolic function, further supports aim being to prevent significant ventricular dysfuncthe suggestion that left ventricular dilation and tion and heart failure and improve the long-term increased diastolic wall stress act as the primary prognosis. The loading conditions of the ventricle stimuli for continued ventricular remode1ing.l’ An and infarct artery patency are of central imporincrease in wall stress in infarcted and ischemic tance in influencing ventricular remodeling and segments has also been demonstrated in patients eventual outcome. with coronary artery disease studied by cardiac Infarct artery patency: Infarct artery patency catheterization.12 End-systolic wall stress was in- may confer a beneficial effect on ventricular remodcreased in infarcted and ischemic segments com- eling and long-term survival through mechanisms pared with normal matched segments. Residual other than early limitation of infarct size. The wall stress at the end of isovolumic relaxation was relation between perfusion of the infarct-related increased both in infarcted areas and in nonin- artery and changes in left ventricular volume and farcted areas perfused by stenosed arteries. How- function during the month after a first myocardial ever, whereas the rate of decrease in local stressin infarct has been examined in a clinical study of 40 infarcted areas paralleled the rate of decrease in patients who did not receive thrombolysis.l’j Sponpressure, in ischemic areas the rate of decrease in taneous perfusion of the infarct artery was docustresswas slower. Although initial volume overload mented at predischarge angiography and left venI

TABLE II Ventricular Infarction

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tricular volumes assessed from radionuclide angiography within 48 hours of infarction and at 1 month. Left ventricular dilation ( > 20% increase in volume) occurred in all 14 patients without perfusion of the infarct-related artery compared with only 2 of 26 with perfusion due to subtotal occlusion or collateral vessels. All 5 patients with a decrease in left ventricular volume had a perfused infarct artery. The degree of perfusion was a more important predictor of volume change than was infarct size, assessed by peak creatine kinase or electrocardiographic QRS score. Thus, perfusion of the infarct-related artery may be important in preventing continuing infarct expansion and left ventricular dilation. Reperfusion may preserve endocardial tissue, and it is also possible that reperfused infarcts with contraction band necrosis may have higher tensile strength and reduced propensity to expansion than nonperfused infarcts.17 A further study of the time course of left ventricular dilation after myocardial infarction that confirmed variable patterns of early, later, and progressive dilation-and showed greater dilation in those with left anterior descending coronary artery occlusion-did not show any relation of volume changes to reperfusion.18 This was attributed to relatively late thrombolysis, with delay between onset of symptoms and reestablishment of collateral flow. Various other studies of thrombolysis and left ventricular function have clearly demonstrated benefit from myocardial reperfusion with reduced infarct size and associated improvement in regional and global ventricular function.1g-22 Reperfusion and patency of the infarct-related artery may thus determine not only a reduction in infarct size and propensity to early infarct expansion, but also possible later benefits for ventricular remodeling and long-term survival. Pharmacologic intervention: Improved understanding of the process of ventricular remodeling and the prognostic importance of ventricular dilation following myocardial infarction23 have led to experimental and clinical studies of pharmacologic intervention for treatment of left ventricular dysfunction in the postinfarct period. As previously mentioned, thrombolysis and other measures are of proven value in the acute phase in which the primary objective is limitation of infarct size and salvage of ischemic myocardium. Once infarct evolution has occurred, however, there is potential for intervention to minimize the sequelae of infarct expansion and ventricular dilation and thus improve the long-term prognosis. Intravenous nitroglycerin has been shown to

limit infarct size, infarct expansion, other infarctrelated complications, and mortality up to 1 year.24 The beneficial effect of nitroglycerin on limiting infarct expansion was apparent from serial echocardiographic study during the first 2-3 days, suggesting early remodeling. Decreased preload and afterload were considered important contributing factors to this, although reduced infarct size and improved collateral flow may also have played a role. There has been considerable interest in the effects of angiotensin-converting enzyme (ACE) inhibition on left ventricular remodeling. In rats studied 3-4 months after myocardial infarction, ventricular dilation and depression of cardiac performance were demonstrated to be a function of infarct size.2s A continuum of heart failure was observed, with progressive increase in left ventricular filling pressure and decrease in maximal forward output and ejection fraction as infarct size increased. Compensatory dilation of the left ventricle allowed preservation of forward output at any filling pressure. Infarction of moderate-to-larger size reduced overall chamber stiffness. Treatment with the ACE inhibitor captopril improved forward output and reduced ventricular dilation and the change in ventricular chamber stiffness. Longer term studies in the same model showed survival was inversely related to infarct size but improved with captopril treatment, particularly in animals with infarcts of moderate size.26 Clinical studies have also been carried out to study the effects of ACE inhibition following myocardial infarction. In a randomized, double-blind trial, the effects of captopril, a diuretic (furosemide), and placebo were studied in patients with asymptomatic left ventricular dysfunction (ejection fraction < 45%) 1 week following Q-wave myocardial infarction.27,28 Left ventricular volume and function were assessed at intervals during the subsequent year, using 2-dimensional echocardiography. The furosemide and placebo groups showed significant increases in ventricular volumes with stroke volume index unchanged and ejection fraction slightly reduced, whereas the captopril group showed a significant reduction in left ventricular end-systolic volume index, with stroke volume index and ejection fraction increased. At 12 months, the difference in the change in ejection fraction from baseline between the captopril and other groups was about 10%. Another study randomized patients to captopril or placebo after a mean of 18 days following a first myocardial infarction. 2g As in the former study, no patient had overt heart failure and all had ejection A SYMPOSIUM:

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fraction < 45%. End-diastolic volume increased in the placebo group, during the year of treatment but not in the captopril group although there was no significant difference between the groups. Dilation was more evident in the placebo patients with an extensive wall motion abnormality or with an occluded infarct-related artery. In a subgroup of patients from this study,3othe importance of left ventricular shape in determining exercise capacity was assessed and the interaction between left ventricular shape and captopril therapy evaluated. A greater shape distortion, indicated by increasing left ventricular sphericity was associated with increased left ventricular volumes, decreased ejection fraction, and a larger abnormally contracting segment. Left ventricular sphericity index was the only independent predictor of exercise duration in the placebo group. Placebo-treated patients in the tercile with the most spherical ventricles had the lowest exercise capacity and highest heart failure and specific activity scores. Captopril-treated patients with the same baseline distortion of left ventricular shape did not show these shapedependent changes in functional capacity. It has been speculated that, despite the expected decrease in equatorial wall stress with changes in radius of curvature as the dilating ventricle assumes a more spherical shape, altered myocardial fiber orientation may be associated with increased stress per myocardial fiber.31 The motion of endocardial landmarks in a normally contracting ventricle follows a pattern maximizing systolic mechanical advantage.32 This pattern may be changed with apical distortion, which leads to lossof the mechanical advantage of orderly contraction of myocardial segments and compromises global ventricular function more than expected from the extent of the infarct alone. These observations may explain the importance of left ventricular shape as a descriptor of left ventricular structure and function as well as outcome. Although left ventricular dysfunction can be improved with ACE inhibition commenced r 1 week following myocardial infarction, earlier intervention appears to provide greater benefit. In a double-blind study in patients with Q-wave myocardial infarction but without clinical heart failure, treatment with captopril or placebo was commenced 24-48 hours following the onset of symptoms.33During 3 months of treatment, the placebo group showed significant increases in left ventricular volumes, with ejection fraction unchanged. In contrast, the captopril group showed no change in left ventricular end-diastolic volume index and a 24C

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significant reduction in left ventricular end-systolic volume index with ejection fraction increased significantly. Most of the treatment benefit was evident during the first month. Comparison of the results of this study with those from the study where treatment was commenced 1 week following myocardial infarction27l28 indicates a greater benefit from earlier treatment. These clinical results are somewhat at variance from those of an experimental study in rats with myocardial infarction, 34where there was no difference in benefit when oral treatment commenced immediately, 2 hours after coronary ligation, compared with delayed treatment started at 21 days, when the animals’ left ventricular performance, weight, and volumes were assessedafter 4 months’ treatment. Also, blockade of compensatory mechanisms activated at the time of infarction may not be desirable in the immediate postinfarct period even though these mechanisms may be deleterious later. This possibility is supported by further experimental data that indicate that captopril therapy in chronically infarcted conscious rats improved cardiac function when treatment was started after completion of the healing process, but that early treatment had an adverse effect on function.35 When captopril was given from 1-21 days during the healing period, cardiac output with volume loading was the same as in the untreated infarct control animals, but with heart rate increased and stroke volume reduced. Although the rat model is useful for studies of left ventricular remodeling after myocardial infarction, patients with coronary artery disease may respond differently to converting enzyme inhibition. Nevertheless, the timing of this treatment is obviously important clinically. Although intervention > 24 hours after infarction appears practical and beneficial, more immediate treatment, < 24 hours after infarction may increase the risk of hypotension with thrombolytic treatment and possibly compromise coronary perfusion. Immediate intervention may produce blockade of mechanisms, which, although disadvantageous in the long term, are initially truly compensatory and beneficial. The mechanism of improvement with ACE inhibition is probably related principally to the peripheral vasodilating effect and ventricular unloading and in this respect both preload and afterload reduction appear to be important.36 There may also be additional beneficial effects on the coronary circulation,37p38which are advantageous for remodeling. However, while coronary hemodynamic data have suggested a balanced effect of

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converting enzyme inhibition on the coronary circulation, a recent clinical study in patients with heart failure and ischemia has indicated that such treatment may worsen ischemia as a result of hypotension and presumably compromised coronary perfusion.39 Finally, converting enzyme inhibition may have an important direct effect on myocardial tissue,40-42 preventing inappropriate growth and hypertrophy stimulated by angiotensin II and other growth factors. REMAINING

QUESTIONS

The process of left ventricular remodeling has now been extensively studied, but a number of important questions remain to be answered. Although the progression from initial compensatory hypertrophy to pathologic hypertrophy has been studied experimentally, this aspect of remodeling is not easily amenable to clinical study and remains poorly understood. Studies of laboratory models of heart failure must be complemented by clinical investigation of the role of cardiac growth and hypertrophy in heart failure for a better understanding to be obtained. With the gradual change of the myocardial infarction paradigm during the past decade from considerations of infarct size to infarct artery patency, and further to early and late ventricular remodeling, there are now a number of therapeutic interventions that may be applied. The benefits of early and late ventricular unloading and reduced wall stress have been demonstrated in terms of improved ventricular size and function, but it remains to be determined whether this is translated into clinical benefit in terms of heart failure prevention and improved survival. Large-scale studies currently in progress should provide information on this most important aspect during the next several years. Further clinical studies are also required to confirm the optimal timing of this type of intervention and particularly the value of treatment in combination with, or immediately after, thrombolysis. Assessment of the comparative and possibly additive effects of converting enzyme inhibition, nitrates, and P-blockade in the postinfarction period is also required. REFERENCES L Eaton LW, Weiss JL, Bulkley BH, Garrison JB, Weisfeldt ML. Regional cardiac dilatation after acute myocardial infarction. N Enql J Med 1979;300:5762. 2. Hutchins GM, Bulkley BH. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am J Cardiol 1978;41:1127-1132. 3. Weisman HF, Bush DE, Mannisi JA, Weisfeldt ML, Healy B. Cellular mechanisms of myocardial infarct expansion. Circulation 1988;78:18&201.

4. Pirolo JS, Hutchins GM, Moore GW. Infarct expansion: pathologic analysis of 204 patients with a single myocardial infarct. JAm Co11 Cardiol1986;7:349354. 5. Erlebacher JA, Weiss JL, Eaton LW, Kallman C, Weisfeldt ML, Bulkley BH. Late effects of acute infarct dilatation on heart size. A two dimensional echocardiographic study. Am .I Curdiol1982;49:1121&1126. 6. McKay RG, Pfeffer MA, Pastern& RC, Markis JE, Come PC, Nakao S, Alderman JD, Ferguson JJ, Safian RD, Grossman W. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation 1986;74:693-702. 7. Anversa P, Loud AV, Levicky V, Guideri G. Left ventricular failure induced by myocardial infarction. 1. Myocyte hypertension. Am .I Physiol 1985;17:H87& H882. 8. Rubin SA, Fishbein MC, Swan HJC, Rabines A. Compensatory hypertmphy in the heart after mywxrdial infarction in the rat. JAm Co11 Cardtil1983;1:14351441. 9. Anversa P, Loud AV, Leticky V, Guideri G. Left ventricular failure indeed by myocardial infarction. II. Tissue morphometry. Am J @siul 1985;17:H883H889. 10. Grossman W. Cardiac hypertrophy: useful adaptation or pathologic p;;lcess? Am .I Med 1980;69:57&584. 1L Seals AA, Pratt CM, Mahmarian JJ, Tadros S, Kleiman N, Koberis K, Verani MS. Relation of left ventricular dilatation during acute myocardial infarction to systolic performance, diastolic dysfunction, infarct size and loca tion. Am J Cardiol 1988;61:224-229. l2. Pouleur H, Rousseau MF, Van Eyll C, Charlier AA. Assessment of regional left ventricular relaxation in patients with coronary artery diseacz importance of geometric factors and changes in wall thickness. Cixx&zti~~ 1984;69:69&702. 13. Katz AM. Cardiomyopathy of overload. A mzajor determinant of progosis in congestive heart failure. N Engl JMed 1990;322:lC&llO. 14. Gadsboll N, Hoilund-Carlsen PF, Badsberg JH, Stage P, Mawing J, L@nberg-Jensen H, Jensen BH. Late ventricular dilatation in survivors of acute my-dial infarction. Am .I Cardiol1989;64:961-966. 15. Jeremy RW, Alhnan KC, Bautovitch G, Harris PJ. Patterns of left ventricular dilatation during the six months after myocardial infarction. J Am Co11 Cur&l 1989;13:304-310. 16. Jeremy RW, Hackworthy RA, Bautovitch G, Hutton BF, Harris PJ. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. JAm Co11 Curdioi 1987;9:98%995. 17.Connelly CM, Vogel WM, \Neigner AW. Effects of reperfusion after coronary artery occlusion on post-infarction scar tissue. Circ Res 1985;57:56”577. is. Warren SE, Royal HD, Markis JE, Grossman W, McKay RG. Time course of left ventricular dilatation after myocardial infarction: influence of infarct-related artery and sxcess of coronary thrombolysis. J Am Co11 Cardiol 1988;11:12-19. 19. Sermys PW, Simoons ML, Smyapranata H, Vermeer F\ Wijns W, Van den Brand M, Bar F, Zwaan C, Krauss H, Remme WJ, Res J, Verheugt FWA, van Domburg R, Lubsen J, Hugenholtz PG. Preservation of global and regional left ventricular function after early thrombolysis in acute myocardial infarction. JAm Co11 Cardiol 1986;1:729-742. 20. Sheehan FH, Doeer R, Schmidt WG, Bolson EL, Uebis R, Von Essen R, Effert S, Dodge HT. Early recovery of left ventricular function after thrombolytic therapy for acute myocardial infarction: an important determinant of survival. JAm CON Cardbl1988;12:28~300. 23. Touchstone DA Belier GA, Nygaard TW, Tedesco C, Kaul S. Effects of successful intravenous reperfusion therapy on regional myocardial function and geometry in humans: a topographic assessment using two-dimensional echocardiography. JAm Co11 Cardio11989;13:150&1513. 22. Marina P, Zanolla L, Zardini P. Effect of streptokinase on left ventricular modeling and function after myocardial infarction: the GISSI Trial. JAm Co11 Cardiol1989;14:1149-1158. 23. White Hd, Norris RM, Brown MA, Brandt PW, Whitlock RML, Wild CJ. I.& ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44-51. 24. Jugdutt BI, Warnica W. Intravenous nitroglycerin therapy to limit myocardial infarct size expansion and complications. Circulation 1988;78:906-919. 26. Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:84-95. 26. Pfeffer MA, Pfeffer JM, Steinberg C, Fii P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Cireukztion 1985;72:406-412. 27. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with

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J, Smith H, Hannan S. Preventive treatment of asymptomatic left ventricular dysfunction following myocardial infarction. Etq Heart J 199q;ll:S147-S156. 29. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captoprii on progressive ventricular dilatation after anterior myocardial infarction. N EngI J Med 1988;319:80-86. 30. Lamas GA, Vaughan DE, Parisi AF, Pfeffer MA. Effects of left ventricular shape and captopril therapy on exercise capacity after anterior wall acute myocardial infarctiondm j Car&l 1989;63:1167-1173. 3iGould KL, Lipscomb K, Hamilton GW, Kennedy JW. Relation of left ventricular shape, function and wall stress in man. Am J Cardiol 1974;34:627634. 32. Slager Cl, Hcoghoudt

TEH, Serruys,P, Schuurbiers JCH, Reiber JHC, Mbester GT, Verdouw PD, Hugenholtz PG. &mtitative assessment of regional left ventricular motion using eddocardial landmarks. J km Coil Cardiol 1986;7:317-326. 33.Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G. Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting enzyme inhibition. Lancer 1991;337:872-876. 34. Gay RG. Early and late effects of captopril treatment after large myocardial infarction in rats. JAm Co11 Cardiol1990,16:967-977.

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35. Schoemaker RG, Debets JJM, Stnryker-Boudier HAJ, Smits JFM. Delayed but not immediate captopril therapy improves cardiac function in conscious rats, following myocardial infarction. J Mel Cell Cardiol1991;23:187-197. 36. Raya TE, Gay RG, Goldman S: The importance of venodilatation in the prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine. Circ Res 1989;64:33b-337. 37. Daly P, Mettauer B, Romeau JL, Cousineau D, Burgess JH. Lack of reflex increase in myocardial sympathetic tone after captopril: potential antianginal effect. Circulation i985;71:317-32.5. 38. Magrini F, Shii M, Roberts N, Fouad FM, Tarazi RC, Zanchetti A. Converting-enzyme inhibition and coronaii blood flow. CLculrfion 198775: s1168-S1174. 39. Cleland JGF, Henderson E, McLenachen J, Fmdlay IN, Dargie HJ. Effect of captopiii, an angiotensin-converting enzyme inhibitor, in patients with angina pectoris and heart failure. JAm Co11 i7ardio11991;17:733-739. 40. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. C@&ion 1991;83:1849-1865. 4l.Dzau VJ, Re RN. Evidence for the existence of renin in the heart. %@xlation 1987;75:S1134-S1136. 42. Lindpaintner K, Jin M, Wilhelm MJ, Suzuki F, Lii W, Schoelkens BA, Ganten D. Intracardiac generation of angiotensin and its physiologic role. Cirrulatin 1988;77:118-I.23

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