Angiotensin converting enzyme inhibitors in acute myocardial infarction: Mechanisms of action
- Guy S Reeder, MD
Guy S Reeder, MD
- Section Editor — Coronary Disease
- Professor of Medicine
- Mayo Medical School
- Section Editor
- Juan Carlos Kaski, MD, DM, DSc, FRCP, FESC, FACC, FAHA
Juan Carlos Kaski, MD, DM, DSc, FRCP, FESC, FACC, FAHA
- Section Editor — Coronary Heart Disease
- Professor of Cardiovascular Science
- Head, Cardiovascular Sciences Research Centre
- St. George's, University of London
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 unstable angina and non-ST elevation myocardial infarction".)
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) . 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 . 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 .
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 .
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 . There is no increase in interstitial fibrosis in the noninfarcted tissue remote from the scar ; this tissue retains normal contractility even though it is involved in the remodeling process. (See "Cardiac remodeling: Clinical assessment and therapy".)
- Flather MD, Yusuf S, Køber L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355:1575.
- Korup E, Dalsgaard D, Nyvad O, et al. Comparison of degrees of left ventricular dilation within three hours and up to six days after onset of first acute myocardial infarction. Am J Cardiol 1997; 80:449.
- Hutchins GM, Bulkley BH. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am J Cardiol 1978; 41:1127.
- Kelley ST, Malekan R, Gorman JH 3rd, et al. Restraining infarct expansion preserves left ventricular geometry and function after acute anteroapical infarction. Circulation 1999; 99:135.
- Gaudron P, Eilles C, Kugler I, Ertl G. Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential mechanisms and early predictors. Circulation 1993; 87:755.
- Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990; 81:1161.
- Pfeffer MA, Pfeffer JM, Lamas GA. Development and prevention of congestive heart failure following myocardial infarction. Circulation 1993; 87:IV120.
- Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000; 101:2981.
- Gerber BL, Rochitte CE, Melin JA, et al. Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation 2000; 101:2734.
- Marijianowski MM, Teeling P, Becker AE. Remodeling after myocardial infarction in humans is not associated with interstitial fibrosis of noninfarcted myocardium. J Am Coll Cardiol 1997; 30:76.
- Yousef ZR, Redwood SR, Marber MS. Postinfarction left ventricular remodelling: where are the theories and trials leading us? Heart 2000; 83:76.
- Konstam MA, Kronenberg MW, Rousseau MF, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. SOLVD (Studies of Left Ventricular Dysfunction) Investigators. Circulation 1993; 88:2277.
- Greenberg B, Quinones MA, Koilpillai C, et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation 1995; 91:2573.
- Pfeffer MA, Lamas GA, Vaughan DE, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319:80.
- Pfeffer MA, Greaves SC, Arnold JM, et al. Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial. Circulation 1997; 95:2643.
- Mankad S, d'Amato TA, Reichek N, et al. Combined angiotensin II receptor antagonism and angiotensin-converting enzyme inhibition further attenuates postinfarction left ventricular remodeling. Circulation 2001; 103:2845.
- Hokimoto S, Yasue H, Fujimoto K, et al. Expression of angiotensin-converting enzyme in remaining viable myocytes of human ventricles after myocardial infarction. Circulation 1996; 94:1513.
- Oosterga M, Voors AA, de Kam PJ, et al. Plasma angiotensin-converting enzyme activity and left ventricular dilation after myocardial infarction. Circulation 1997; 95:2607.
- Li K, Chen X. Protective effects of captopril and enalapril on myocardial ischemia and reperfusion damage of rat. J Mol Cell Cardiol 1987; 19:909.
- Piana RN, Wang SY, Friedman M, Sellke FW. Angiotensin-converting enzyme inhibition preserves endothelium-dependent coronary microvascular responses during short-term ischemia-reperfusion. Circulation 1996; 93:544.
- Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998; 97:2202.
- Miki T, Miura T, Tsuchida A, et al. Cardioprotective mechanism of ischemic preconditioning is impaired by postinfarct ventricular remodeling through angiotensin II type 1 receptor activation. Circulation 2000; 102:458.
- Vantrimpont P, Rouleau JL, Wun CC, et al. Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol 1997; 29:229.
- MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol 2000; 36:438.
- Schneider CA, Voth E, Moka D, et al. Improvement of myocardial blood flow to ischemic regions by angiotensin-converting enzyme inhibition with quinaprilat IV: a study using [15O] water dobutamine stress positron emission tomography. J Am Coll Cardiol 1999; 34:1005.
- Willenheimer R, Rydberg E, Oberg L, et al. ACE inhibition with ramipril improves left ventricular function at rest and post exercise in patients with stable ischaemic heart disease and preserved left ventricular systolic function. Eur Heart J 1999; 20:1647.
- Mancini GB, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 1996; 94:258.
- Prasad A, Husain S, Quyyumi AA. Effect of enalaprilat on nitric oxide activity in coronary artery disease. Am J Cardiol 1999; 84:1.
- Vaughan DE, Rouleau JL, Ridker PM, et al. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation 1997; 96:442.
- Brown NJ, Abbas A, Byrne D, et al. Comparative effects of estrogen and angiotensin-converting enzyme inhibition on plasminogen activator inhibitor-1 in healthy postmenopausal women. Circulation 2002; 105:304.
- Ridker PM, Gaboury CL, Conlin PR, et al. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 1993; 87:1969.
- Soejima H, Ogawa H, Yasue H, et al. Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction. J Am Coll Cardiol 1999; 34:983.
- Minai K, Matsumoto T, Horie H, et al. Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2001; 37:1565.
- Pretorius M, Rosenbaum D, Vaughan DE, Brown NJ. Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin. Circulation 2003; 107:579.
- van den Heuvel AF, Dunselman PH, Kingma T, et al. Reduction of exercise-induced myocardial ischemia during add-on treatment with the angiotensin-converting enzyme inhibitor enalapril in patients with normal left ventricular function and optimal beta blockade. J Am Coll Cardiol 2001; 37:470.
- Pepine CJ, Rouleau JL, Annis K, et al. Effects of angiotensin-converting enzyme inhibition on transient ischemia: the Quinapril Anti-Ischemia and Symptoms of Angina Reduction (QUASAR) trial. J Am Coll Cardiol 2003; 42:2049.
- Domanski MJ, Exner DV, Borkowf CB, et al. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 1999; 33:598.
- Hikosaka M, Yuasa F, Yuyama R, et al. Effect of angiotensin-converting enzyme inhibitor on cardiopulmonary baroreflex sensitivity in patients with acute myocardial infarction. Am J Cardiol 2000; 86:1241.