INTRODUCTION — A number of modalities may be beneficial in the management of the patient with acute myocardial infarction (MI), including direct angioplasty or fibrinolysis, aspirin, angiotensin converting enzyme (ACE) inhibitors, beta blockers, and nitrates. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".)
A meta-analysis concluded that administration of an ACE inhibitor within 3 to 16 days of infarction can slow the progression of cardiovascular disease and improve the survival rate (figure 1) [1]. The mechanisms by which ACE inhibitors improve survival after MI will be reviewed here, beginning with a discussion of infarct expansion. The clinical data supporting the use of ACE inhibitors in this setting are presented elsewhere. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".)
INFARCT EXPANSION AND REMODELING — Survivors of acute myocardial infarction (MI) have a significant risk of future cardiovascular events. Infarct expansion, due to thinning and stretching of the infarct zone, occurs within hours to days of a transmural MI and is an important prognostic determinant. Significant left ventricular dilation can begin within three hours from the onset of a first myocardial infarction, particularly among patients with anterior wall damage [2]. Patients who develop infarct expansion have a high risk of developing heart failure and sudden death. Pathologic evidence of infarct expansion has been found in up to 60 percent of patients dying from complications of an MI [3].
Ventricular dilatation itself may be deleterious, independent of the reduction in overall myocardial contractility induced by the infarct. Consistent with this hypothesis is the observation in an animal study that preventing left ventricular dilatation with a restraining mesh placed over the anticipated area of infarction preserved left ventricular geometry and function [4].
Following the initial insult in the area of infarction, ventricular remodeling can lead to progressive regional myocardial dysfunction [5-8]. The remodeling process begins with myocyte necrosis and the formation of fibrotic scar; it is followed by elongation of the infarcted segment and then dilatation and hypertrophy of the border zone ventricular myocardium (figure 2). The extent of microvascular obstruction within the infarcted area during the early healing phase after an infarction is indicative of absent blood flow and predicts left ventricular remodeling and dilatation, independent of infarct size [9]. There is no increase in interstitial fibrosis in the noninfarcted tissue remote from the scar [10]; this tissue retains normal contractility even though it is involved in the remodeling process. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Remodeling'.)
MECHANISM OF ACTION OF ACE INHIBITION — Attenuation of remodeling is thought to play an important role in the survival benefit associated with angiotensin converting enzyme (ACE) inhibitors after myocardial infarction. These drugs also may have favorable effects on ischemic preconditioning, recurrent myocardial infarction and ischemia, sudden death, and fibrinolysis (reduction in plasma plasminogen activator inhibitor-1). (See 'Reduction in recurrent myocardial infarction and ischemia' below.)
Attenuation of remodeling — In the early stages, ventricular dilatation can be considered beneficial, maintaining stroke volume through the Frank-Starling mechanism. However, over time, the dilating ventricle causes detrimental effects by exerting further demands on the surviving myocardium, a result of increases in wall tension (figure 3) [11].
ACE inhibitors have favorable effects on certain parameters of remodeling, slowing the rate of left ventricular dilatation over time [12-15]; the combination of an ACE inhibitor and an angiotensin II receptor blocker may be even more effective than an ACE inhibitor alone [16]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".) This effect is presumably mediated by inhibition of angiotensin II, which appears to play an important role in the remodeling process. In support of this hypothesis are the observations in humans that ACE is markedly increased at the edge of the infarct scar [17] and that the incidence of left ventricular (LV) dilatation after myocardial infarction (MI) is increased in patients with the ACE DD genotype (a genotype associated with increased ACE activity) [18]. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Neurohormonal activation'.)
The effect of ACE inhibitors on infarct expansion reflects a chronic benefit. There is also experimental evidence that ACE inhibitors have more acute benefits, limiting the following changes that can occur during acute ischemia: myocardial injury, degradation of high-energy phosphate stores, and impairment of endothelium-dependent arteriolar responses [19,20]. These observations constitute part of the rationale for the early administration of ACE inhibitors (within the first 24 hours) after the diagnosis of acute MI has been made [21]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".)
Effect on ischemic preconditioning — Ventricular remodeling after a myocardial infarction may interfere with ischemic preconditioning. This was examined in one animal study that found that the myocardium that was remodeled after an infarction was refractory to ischemic preconditioning; this was due to the interruption of cellular signaling of mitochondrial ATP-dependent potassium channels [22]. The angiotensin II receptor blocker valsartan was beneficial for suppressing remodeling and preserving ischemic preconditioning. (See "Myocardial ischemic conditioning: Pathogenesis".)
Reduction in recurrent myocardial infarction and ischemia — ACE inhibitors appear to reduce the incidence of recurrent myocardial infarction. As an example, the Survival and Ventricular Enlargement (SAVE) Trial of 2231 patients found that captopril was associated with a significant reduction in recurrent MI by 25 percent. This benefit was noted in all patient groups, including those who received other adjunctive therapies such as fibrinolysis, aspirin, and/or beta blockers [23].
The reduction in recurrent MI suggests that ACE inhibitor therapy has benefits beyond afterload reduction. How this might occur is not known; ACE inhibitors do not appear to reduce the degree of atherosclerosis [24]. The following factors may contribute:
●Improvement in the oxygen supply/demand ratio of the myocardium by reversing angiotensin II-induced vasoconstriction and inotropic activity. Among the clinical benefits that could be explained by this mechanism are increased myocardial blood flow to ischemic regions [25] and an improvement in resting left ventricular function and reduced diastolic dysfunction during exercise [26].
●Improvement in endothelial function [27]. This is probably related to inhibition of angiotensin II-related vasoconstriction and to diminished breakdown of bradykinin, which enhances endothelial release of nitric oxide [28]. (See "Coronary endothelial dysfunction: Clinical aspects".)
●Improvement in the hypercoagulable state after an MI by reducing plasma plasminogen activator inhibitor-1 (PAI-1) [29-31] and tissue factor levels [32] and increasing the release of tissue type plasminogen activator (tPA) by the endothelial cells within the coronary artery. Bradykinin stimulates the release of tPA, an effect that is enhanced by an ACE inhibitor, at least in women [33,34].
●Inhibition of the activation and accumulation of macrophages and monocytes by diminishing the levels of monocyte chemoattractant protein-1 [32].
There are conflicting data regarding a possible benefit of ACE inhibitor therapy in reducing exercise-induced ischemia. In one trial of 43 patients randomly assigned to either enalapril 10 mg twice daily or placebo, the exercise time to 1 mm ST segment depression was significantly increased by enalapril at 12 weeks, though not at three weeks [35]. In another trial of 336 patients randomly assigned to either quinapril 40 mg daily or placebo, there was no improvement in the exercise time to 1 mm ST segment depression at eight weeks [36]. The placebo group was then crossed over to 80 mg quinapril daily while the 40 mg group continued the same dose; again there was no difference eight weeks later.
Reduction in sudden death — ACE inhibitors reduce overall cardiovascular and sudden-death mortality [37]. There are several mechanisms that might contribute to the reduction in sudden death (see "Pathophysiology and etiology of sudden cardiac arrest"):
●Decrease in sympathetic activity along with an improvement in baroreceptor sensitivity which enhances vagal tone [38]
●Attenuation of ventricular remodeling and ventricular dilation, which are factors for arrhythmogenesis
●Decrease in the incidence of recurrent myocardial infarction, which increases electrical instability
SUMMARY — The addition of angiotensin converting enzyme (ACE) inhibitor or receptor blocker to standard medical therapy (including aspirin, thienopyridine, beta blocker, and statin) in patients with recent myocardial infarction improves cardiovascular outcomes. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Overview of the nonacute management of ST-elevation myocardial infarction" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction".)
Attenuation of remodeling is thought to play a critically important role in the survival benefit associated with ACE inhibitors after myocardial infarction. (See 'Attenuation of remodeling' above.)
Other possible mechanisms of benefits include:
●Preservation of ischemic preconditioning (see 'Effect on ischemic preconditioning' above)
●Reduction in recurrent myocardial infarction and ischemia (see 'Reduction in recurrent myocardial infarction and ischemia' above)
●Reduction in sudden death (see 'Reduction in sudden death' above)
