The Time Course of Left Ventricular Remodeling After Acute Myocardial Infarction

Abstract

Myocardial infarction (MI) is a leading cause of heart failure. MI is associated with a 7- to 10-fold greater risk of developing heart failure compared with a normal population. Left ventricular dysfunction and subsequent mortality are highly correlated, with the principal determinants of survival after MI being left ventricular end-diastolic and end-systolic (and particularly the latter) volume. Acute MI results in progressive myocardial cell necrosis and is associated (over the next hours to days) with infarct expansion (thinning and elongation of the necrotic myocardium). The residual normal myocardium also undergoes structural changes, including dilation and hypertrophy (assumed to be a compensatory mechanism in an attempt to maintain stroke volume), a process that occurs over a period of days to months, and one that can lead to progressive left ventricular dysfunction. The development of heart failure after MI results in impaired ventricular function, and consequently potentially adverse neurohumoral activation. These processes of remodeling and neurohumoral activation have taken on increasing importance with the recognition that angiotensin-converting enzyme (ACE) inhibitors could favorably affect the remodeling process and thereby reduce cardiovascular morbidity and mortality when administered in the postinfarction period. 1‐3 The question of how ACE inhibitors prolong survival, however, is not fully answered. The left ventricular structural remodeling following MI is a time-dependent process, but the time course, particularly the early time course, has not been completely elucidated. The time course of remodeling has certain therapeutic implications, including the earliest time at which therapy should be initiated, the latest time at which therapy would have no benefit, and the ultimate duration of therapy. Early experiments in a rat model initiated ACE inhibitor therapy as soon as 2 days after infarction, and demonstrated a benefit in remodeling compared with untreated controls. 4 In subsequent human studies ACE inhibitor therapy was initiated 12 days and then as early as 7 days after infarction, leading up to the Survival and Ventricular Enlargement (SAVE) trial in which therapy was initiated as early as 3 days after infarction. 1,5,6 Questions were already being asked about the risk benefit of earlier ACE inhibitor therapy, but in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS) II trial, enalapril was begun intravenously within the first 24 hours after infarction (followed by oral therapy). 7 CONSENSUS II was terminated prematurely at 6 months when no benefit (and a slight trend toward worsening) was observed in the treated group. However, subsequent studies with oral ACE inhibitor therapy begun within 6 to 24 hours of infarction have demonstrated a benefit in remodeling and morbidity and mortality. 8 ‐11 The disparate results between these 3 trials and CONSENSUS II might be the result of the abrupt hypotensive effects of intravenous enalapril. The zofenopril trial 11 demonstrated that lives were saved within 24 hours of randomization to treatment, which also serves to allay the concern that early treatment could precipitate symptomatic hypotension, a situation that could certainly be problematic in the setting of acute infarction. This further indicates that there should be no unnecessary delay in initiating oral ACE inhibitor therapy follow