JACC Vol. 19, No.3 March I, 1992:722-3
722
Editorial Comment
Geometric Adaptation to Afterload Reduction: Understanding Left Ventricular Remodeling After Myocardial Infarction * THOMAS J. DONOHUE, MD, MORTONJ.KERN,MD,FACC Saint Louis, Missouri
Infarct expansion, a localized distortion in cardiac geometry affecting both the adjacent and remote areas to myocardial necrosis, is dependent on both the infarct size and the types of healing (1,2). Thinning ofthe ventricular wall and lengthening of infarcted endocardial segments appear functionally to increase the infarct size in the absence of further loss of viable myocardium (1). In addition, a series of compensatory mechanisms to maintain cardiac output evoke enhanced sympathetic tone, activation of the renin-angiotensin endocrine axis, increased contractility of the remaining functional myocardium, and use of preload reserve by ventricular dilation (3). Although these mechanisms serve to, at least temporarily, restore near normal systolic function, they do so at the expense of increasing ventricular wall stress, often leading to the deleterious clinical consequences of left ventricular dilation. These dynamic changes that occur in left ventricular geometry after myocardial infarction are among important factors previously illustrated to influence patient survival (4). Angiotensin-converting enzyme inhibitors, as well as calcium channel blocking agents and prostacyclin, in a variety of experimental animal and human studies (5,6) favorably affect ventricular remodeling through afterload reduction and logically should favorably influence long-term patient survival. The present study. The study by Jugdutt et al. (7) in this issue of the Journal provides a detailed time sequence analysis of the effects of an angiotensin-converting enzyme inhibitor on left ventricular remodeling. This study contributes to our understanding of an important addition to treatment of the patient with acute myocardial infarction. *Editorials published in Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of lACC or the American College of Cardiology. From the Cardiac Catheterization Laboratory, Saint Louis University Hospital, Saint Louis, Missouri. Address for reprints: Morton J. Kern, MD, Cardiac Catheterization Laboratory, Saint Louis University Hospital, 3635 Vista Avenue at Grand, Saint Louis, Missouri 63110. ~1992
by the American College of Cardiology
Changes in left ventricular geometry were examined over a 6-week period after an experimentally induced anterior wall myocardial infarction, produced by ligation of the anterior descending artery distal to the first diagonal branch in a canine model. Dogs were randomized after 2days to receive either oral captopril (50 mg twice daily) or placebo. At 6 weeks, captopril treatment was associated with a significant decrease in the infarct expansion index, degree of ventricular wall thinning in the infarct zone, endocardial segment length of the infarcted region, systolic and diastolic volumes, and left atrial pressure. Unique to this study were findings of similar infarct scar mass, transmurality, and collagen content in the control and treated dogs, information not previously available in the landmark study of Pfeffer et al. (3). This well executed, precise study (7) adds to earlier findings (3,5,8), and emphasizes that the healing of the infarcted ventricle can be influenced by various manipulations resulting in vastly different and clinically important end points. This healing is always associated with geometric changes that either improve filling pressures and volumes or become maladaptive with chamber dilation and increased left ventricular end-diastolic pressure and wall stress. The maladaptively remodeled ventricle is often forced into a cycle of expansion, thinning and increasing wall stress with resultant decreasing pump function and eventually clinical congestive heart failure. Study limitations. The limitations of this study (7) are few. Questions about changes in the noninfarct segment and adaptive responses in the uninvolved myocardium are as important, if not more so, than changes seen in the infarct zone. Postinfarction compensatory hypertrophy of noninfarcted tissue may occur either in an eccentric pattern from volume overload or in a concentric pattern from pressure overload (9,10). From earlier experiments in Jugdutt's laboratory (11), infarcts of approximately 9% of left ventricular weight at 6 weeks corresponded to 20% infarcts at 1day. In untreated animals these infarcts produced dramatic left ventricular asynergy, increased end-systolic and diastolic volumes, a pronounced increase in left atrial pressure and increases in the noninfarct segment length. These changes, reflecting elevated left ventricular wall stress, would be expected to increase left ventricular mass by the addition of sarcomeric units, either in parallel or in series. The absence of compensatory hypertrophy, although somewhat puzzling, may be due to the time course of the study. It has been demonstrated that healing is slower in this model (11) than in others previously studied and, therefore, grossly demonstrable changes of compensatory hypertrophy may not occur in the time course studied. The extent of hypertrophy would have been addressed by histologic measurement of cell size, which could have confirmed the early changes of compensatory hypertrophy previously described (9). This information (i.e., the type and degree of compensatory hypertrophy) has prognostic implications and may be useful in differenti0735-1097/92/$5.00
JACC Vol. 19. No.3 March I. 1992:722-3
ating neurohumoral from mechanical effects on cellular changes and late sequelae of left ventricular remodeling. Implications. The degree of left ventricular asynergy and aneurysm formation in the placebo-treated groups is also striking, with 75% of the animals developing an aneurysm with extreme thinning and expansion. It is impressive that none did so in the captopril-treated group. The initial stages of infarct healing are notable for myocardial edema and inflammatory infiltrates. The extent of coagulation or contraction band necrosis and the degree of edema or inflammatory infiltrate, or both, may have independent effects on both the qualitative and quantitative healing process (12). The characteristics of the infarction scar in both treated and untreated groups might provide data on whether increased cellularity occurs independent of the degree of collagen deposition and the influence of angiotensin. Angiotensin II is a potent growth factor that, if produced and activated at the tissue level, could have significant effects on healing and muscle growth and function (13). While the authors (7) have demonstrated systemic inhibition of the renin-angiotensin endocrine axis, future studies must examine whether the local, tissue level, system is activated in an important manner in this clinical setting, and whether systemic angiotensin-converting enzyme inhibition will produce an additional favorable tissue response. Finally, in current cardiology practice, an increasing number of patients presenting with acute myocardial infarction are benefiting from early reperfusion with thrombolysis or emergency percutaneous transluminal coronary angioplasty, or both. The possibility of ischemic reperfused myocardium that can be salvaged adds fervor to recent emphasis placed on achieving patency of the infarct-related artery and the attendant improvement in mortality (14). For extrapolation of this study (7) to the clinical setting, results of a late reperfusion group and demonstration of persistent beneficial changes would support the universal inclusion of angiotensin-converting enzyme inhibitors in the pharmacotherapy of patients after myocardial infarction. Clinical significance. Jugdutt et al. (7) have presented a well conceived and impressive study. Their results document that captopril has profound advantageous functional and structural effects during the critical early postinfarction
DONAHUE AND KERN EDITORIAL COMMENT
723
period during which left ventricular remodeling is initiated. Few can argue against the data indicating that the addition of captopril early after myocardial infarction is associated with favorable geometric adaptive and clinical responses. The only lacking datum is the anticipated reduced mortality rates that should accompany the improvement in left ventricular function.
References 1. Healy B. Weisman HF. Myocardial infarct expansion. infarct extension. and reinfarction: pathophysiologic concepts. Prog Cardiovasc Dis 1987; 30:73-109. 2. Eaton LW. Bulkley BH. Expansion of acute myocardial infarction: Its relationship to infarct morphology in a canine model. Circ Res 1981;49: 80-8. 3. Pfeifer JM. Pfeifer MA. Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:84-95. 4. Kannel WB. Sorlie p. McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J CardioI1979;44:53-9. 5. Raya TE. Gay RG. Aguirre M. Goldman S. Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine. Circ Res 1989;64:330-7. 6. Jugdutt BI. Delayed effects of early infarct-limiting therapies on healing after myocardial infarction. Circulation 1985;72:907-14. 7. Jugdutt B1. Schwarz-Michorowski BL. Khan MI. Effect of long-term captopril therapy on left ventricular remodeling and function during healing of canine myocardial infarction. J Am Coli CardioI1992;19:71321. 8. Pfeffer MA. Lamas GA. Vaughan DE. Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80-6. 9. McKay RG. Pfeffer MA. Pasternak RC. et al. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation 1986;74:693-702. 10. Rubin SA. Fishbein MC. Swan HJC. Compensatory hypertrophy in the heart after myocardial infarction in the rat. J Am Coli Cardiol 1983; I: 1435-41. 11. Jugdutt B1. Any RWM. Healing after myocardial infarction in the dog: changes in infarct hydoxyproline and topography. J Am Coli Cardiol 1986;7:91-102. 12. Hanmerman H. Schoen FJ. Braunwald E. et al. Drug-induced expansion of infarct: morphologic and functional correlations. Circulation 1984;69: 611-7. 13. Frohlich ED. Iwata T. Sasaki O. Clinical and physiologic significance of local tissue renin-angiotensin systems. Am J Med 1989;87(suppI6Bj: 19523S. 14. Cigarroa RG. Lange RA. Hillis LD. Prognosis after acute myocardial infarction in patients with and without residual anterograde coronary blood flow. Am J CardioI1989;64:155-60.
722
Editorial Comment
Geometric Adaptation to Afterload Reduction: Understanding Left Ventricular Remodeling After Myocardial Infarction * THOMAS J. DONOHUE, MD, MORTONJ.KERN,MD,FACC Saint Louis, Missouri
Infarct expansion, a localized distortion in cardiac geometry affecting both the adjacent and remote areas to myocardial necrosis, is dependent on both the infarct size and the types of healing (1,2). Thinning ofthe ventricular wall and lengthening of infarcted endocardial segments appear functionally to increase the infarct size in the absence of further loss of viable myocardium (1). In addition, a series of compensatory mechanisms to maintain cardiac output evoke enhanced sympathetic tone, activation of the renin-angiotensin endocrine axis, increased contractility of the remaining functional myocardium, and use of preload reserve by ventricular dilation (3). Although these mechanisms serve to, at least temporarily, restore near normal systolic function, they do so at the expense of increasing ventricular wall stress, often leading to the deleterious clinical consequences of left ventricular dilation. These dynamic changes that occur in left ventricular geometry after myocardial infarction are among important factors previously illustrated to influence patient survival (4). Angiotensin-converting enzyme inhibitors, as well as calcium channel blocking agents and prostacyclin, in a variety of experimental animal and human studies (5,6) favorably affect ventricular remodeling through afterload reduction and logically should favorably influence long-term patient survival. The present study. The study by Jugdutt et al. (7) in this issue of the Journal provides a detailed time sequence analysis of the effects of an angiotensin-converting enzyme inhibitor on left ventricular remodeling. This study contributes to our understanding of an important addition to treatment of the patient with acute myocardial infarction. *Editorials published in Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of lACC or the American College of Cardiology. From the Cardiac Catheterization Laboratory, Saint Louis University Hospital, Saint Louis, Missouri. Address for reprints: Morton J. Kern, MD, Cardiac Catheterization Laboratory, Saint Louis University Hospital, 3635 Vista Avenue at Grand, Saint Louis, Missouri 63110. ~1992
by the American College of Cardiology
Changes in left ventricular geometry were examined over a 6-week period after an experimentally induced anterior wall myocardial infarction, produced by ligation of the anterior descending artery distal to the first diagonal branch in a canine model. Dogs were randomized after 2days to receive either oral captopril (50 mg twice daily) or placebo. At 6 weeks, captopril treatment was associated with a significant decrease in the infarct expansion index, degree of ventricular wall thinning in the infarct zone, endocardial segment length of the infarcted region, systolic and diastolic volumes, and left atrial pressure. Unique to this study were findings of similar infarct scar mass, transmurality, and collagen content in the control and treated dogs, information not previously available in the landmark study of Pfeffer et al. (3). This well executed, precise study (7) adds to earlier findings (3,5,8), and emphasizes that the healing of the infarcted ventricle can be influenced by various manipulations resulting in vastly different and clinically important end points. This healing is always associated with geometric changes that either improve filling pressures and volumes or become maladaptive with chamber dilation and increased left ventricular end-diastolic pressure and wall stress. The maladaptively remodeled ventricle is often forced into a cycle of expansion, thinning and increasing wall stress with resultant decreasing pump function and eventually clinical congestive heart failure. Study limitations. The limitations of this study (7) are few. Questions about changes in the noninfarct segment and adaptive responses in the uninvolved myocardium are as important, if not more so, than changes seen in the infarct zone. Postinfarction compensatory hypertrophy of noninfarcted tissue may occur either in an eccentric pattern from volume overload or in a concentric pattern from pressure overload (9,10). From earlier experiments in Jugdutt's laboratory (11), infarcts of approximately 9% of left ventricular weight at 6 weeks corresponded to 20% infarcts at 1day. In untreated animals these infarcts produced dramatic left ventricular asynergy, increased end-systolic and diastolic volumes, a pronounced increase in left atrial pressure and increases in the noninfarct segment length. These changes, reflecting elevated left ventricular wall stress, would be expected to increase left ventricular mass by the addition of sarcomeric units, either in parallel or in series. The absence of compensatory hypertrophy, although somewhat puzzling, may be due to the time course of the study. It has been demonstrated that healing is slower in this model (11) than in others previously studied and, therefore, grossly demonstrable changes of compensatory hypertrophy may not occur in the time course studied. The extent of hypertrophy would have been addressed by histologic measurement of cell size, which could have confirmed the early changes of compensatory hypertrophy previously described (9). This information (i.e., the type and degree of compensatory hypertrophy) has prognostic implications and may be useful in differenti0735-1097/92/$5.00
JACC Vol. 19. No.3 March I. 1992:722-3
ating neurohumoral from mechanical effects on cellular changes and late sequelae of left ventricular remodeling. Implications. The degree of left ventricular asynergy and aneurysm formation in the placebo-treated groups is also striking, with 75% of the animals developing an aneurysm with extreme thinning and expansion. It is impressive that none did so in the captopril-treated group. The initial stages of infarct healing are notable for myocardial edema and inflammatory infiltrates. The extent of coagulation or contraction band necrosis and the degree of edema or inflammatory infiltrate, or both, may have independent effects on both the qualitative and quantitative healing process (12). The characteristics of the infarction scar in both treated and untreated groups might provide data on whether increased cellularity occurs independent of the degree of collagen deposition and the influence of angiotensin. Angiotensin II is a potent growth factor that, if produced and activated at the tissue level, could have significant effects on healing and muscle growth and function (13). While the authors (7) have demonstrated systemic inhibition of the renin-angiotensin endocrine axis, future studies must examine whether the local, tissue level, system is activated in an important manner in this clinical setting, and whether systemic angiotensin-converting enzyme inhibition will produce an additional favorable tissue response. Finally, in current cardiology practice, an increasing number of patients presenting with acute myocardial infarction are benefiting from early reperfusion with thrombolysis or emergency percutaneous transluminal coronary angioplasty, or both. The possibility of ischemic reperfused myocardium that can be salvaged adds fervor to recent emphasis placed on achieving patency of the infarct-related artery and the attendant improvement in mortality (14). For extrapolation of this study (7) to the clinical setting, results of a late reperfusion group and demonstration of persistent beneficial changes would support the universal inclusion of angiotensin-converting enzyme inhibitors in the pharmacotherapy of patients after myocardial infarction. Clinical significance. Jugdutt et al. (7) have presented a well conceived and impressive study. Their results document that captopril has profound advantageous functional and structural effects during the critical early postinfarction
DONAHUE AND KERN EDITORIAL COMMENT
723
period during which left ventricular remodeling is initiated. Few can argue against the data indicating that the addition of captopril early after myocardial infarction is associated with favorable geometric adaptive and clinical responses. The only lacking datum is the anticipated reduced mortality rates that should accompany the improvement in left ventricular function.
References 1. Healy B. Weisman HF. Myocardial infarct expansion. infarct extension. and reinfarction: pathophysiologic concepts. Prog Cardiovasc Dis 1987; 30:73-109. 2. Eaton LW. Bulkley BH. Expansion of acute myocardial infarction: Its relationship to infarct morphology in a canine model. Circ Res 1981;49: 80-8. 3. Pfeifer JM. Pfeifer MA. Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:84-95. 4. Kannel WB. Sorlie p. McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J CardioI1979;44:53-9. 5. Raya TE. Gay RG. Aguirre M. Goldman S. Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine. Circ Res 1989;64:330-7. 6. Jugdutt BI. Delayed effects of early infarct-limiting therapies on healing after myocardial infarction. Circulation 1985;72:907-14. 7. Jugdutt B1. Schwarz-Michorowski BL. Khan MI. Effect of long-term captopril therapy on left ventricular remodeling and function during healing of canine myocardial infarction. J Am Coli CardioI1992;19:71321. 8. Pfeffer MA. Lamas GA. Vaughan DE. Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80-6. 9. McKay RG. Pfeffer MA. Pasternak RC. et al. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation 1986;74:693-702. 10. Rubin SA. Fishbein MC. Swan HJC. Compensatory hypertrophy in the heart after myocardial infarction in the rat. J Am Coli Cardiol 1983; I: 1435-41. 11. Jugdutt B1. Any RWM. Healing after myocardial infarction in the dog: changes in infarct hydoxyproline and topography. J Am Coli Cardiol 1986;7:91-102. 12. Hanmerman H. Schoen FJ. Braunwald E. et al. Drug-induced expansion of infarct: morphologic and functional correlations. Circulation 1984;69: 611-7. 13. Frohlich ED. Iwata T. Sasaki O. Clinical and physiologic significance of local tissue renin-angiotensin systems. Am J Med 1989;87(suppI6Bj: 19523S. 14. Cigarroa RG. Lange RA. Hillis LD. Prognosis after acute myocardial infarction in patients with and without residual anterograde coronary blood flow. Am J CardioI1989;64:155-60.
