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Asian Cardiovasc Thorac Ann 2000;8:85-90
© 2000 Asia Publishing EXchange Pte Ltd

REVIEW PAPER

Angiotensin-Converting Enzyme Inhibition After Myocardial Infarction

Zhu Yi Zhun, MD, Lee How Sung, PhD

Department of Pharmacology
Faculty of Medicine
National University of Singapore
Singapore, Republic of Singapore
For reprint information contact: Zhu Yi Zhun, MD Tel: 65 874 3676 Fax: 65 773 0579 email: phczhuyz{at}nus.edu.sg, Department of Pharmacology, Faculty of Medicine, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Republic of Singapore.

   Abstract
TOP
 Abstract
Introduction
 ACE and ACE Inhibitors
 ACE Inhibition in Experimental...
 ACE Inhibition in Large-Scale...
 Conclusion
 References
 
Myocardial infarction was the underlying event in the majority of deaths from cardiovascular disease in Western countries in the past quarter-century. The introduction of angiotensin-converting enzyme inhibitors to the treatment of heart failure following myocardial infarction was a major advance in the last 10 years. However, the role of cardiac angiotensin-converting enzyme during postinfarction cardiac remodeling remains to be elucidated. Experimental studies demonstrated that angiotensin-converting enzyme inhibitors administered one week before myocardial infarction could limit infarct size, improve cardiac function, and prevent cardiac hypertrophy. Numerous large-scale clinical trials have shown that angiotensin-converting enzyme inhibitors are safe and can reduce mortality and the occurrence of severe left ventricular dysfunction after myocardial infarction. This review focuses on the effects of these inhibitors in experimental studies and in multicenter clinical trials.


   Introduction
TOP
 Abstract
 Introduction
ACE and ACE Inhibitors
 ACE Inhibition in Experimental...
 ACE Inhibition in Large-Scale...
 Conclusion
 References
 
Angiotensin-converting enzyme (ACE) inhibitors have become important drugs in the treatment of hypertension, congestive heart failure, myocardial infarction (MI), and diabetic nephropathy.1–6 ACE inhibitors have been shown to be cardioprotective in both experimental and clinical studies. They can induce myocardial capillary growth, improve the metabolic status of the myocardium, prevent cardiac hypertrophy, limit infarct size, and thus improve cardiac function after MI. The therapeutic success of these drugs is related to their unique pharmacological profile involving both a reduction of plasma and tissue angiotensin II concentrations and potentiation of endogenous kinins. Reduction of angiotensin II by ACE inhibitors exerts an antihypertensive action by lowering both vascular resistance and intravascular volume. In cardiac failure, this mechanism of action translates into the therapeutic goals of preload and afterload reduction. More recently, angiotensin II has been increasingly recognized as a growth-promoting factor contributing to vascular medial hypertrophy and hyperplasia, cardiac left ventricular hypertrophy and fibrosis, and nephrosclerosis. These angiotensin II-induced structural changes can be antagonized by ACE inhibitors in addition to their beneficial effects in blood pressure reduction. Thus, by their dual mode of action on two hormonal systems, ACE inhibitors can prevent or limit target-organ damage induced by hypertension, ischemia, and diabetes mellitus. These organ-protecting effects beyond blood pressure control, provide the basis for the reduction of mortality demonstrated in patients with congestive heart failure and MI under ACE inhibitor treatment.

However, the rapid onset of action of an intravenously administered ACE inhibitor within 24 hours following MI showed no beneficial effects and even displayed a trend towards increased mortality in comparison with placebo treatment.1 On the other hand, ACE inhibitors administered orally within 24 hours after myocardial infarction were able to exert beneficial actions, probably due to a smoother onset of action.2–4 Experimental studies showed that ACE inhibitors administered chronically before MI might limit myocardial infarct size, improve cardiac function, and prevent cardiac hypertrophy. All of these effects were attenuated by a bradykinin B2-receptor antagonist, suggesting a role of endogenous bradykinin in the cardioprotective actions of ACE inhibitors.5,6 In this review, the effects of ACE inhibition on cardiac function and structural parameters in MI are discussed.


   ACE and ACE Inhibitors
TOP
 Abstract
 Introduction
 ACE and ACE Inhibitors
ACE Inhibition in Experimental...
 ACE Inhibition in Large-Scale...
 Conclusion
 References
 
ACE, a monomeric zinc metallopeptidase consisting of two homologous domains with two zinc-containing binding sites as active centers, converts the inactive angiotensin I to the vasoconstrictor octapeptide angiotensin II by removing the dipeptide histidine-leutine from the C-terminal end of the angiotensin I molecule.7 In addition, ACE is identical to kininase II in that it also inactivates bradykinin by sequential removal of the dipeptides phenylalanine-arginine and serine-proline from the C-terminal end of the peptide, resulting in inactive meta-bolites.8 Thus, the same enzyme that produces a potent pressor substance also degrades a potent vasodepressor peptide. The enzyme is located mainly on the luminal surface of endothelial cells in various tissues and oriented so that the catalytic sites are exposed on the external surface of the cell. In addition to the endothelial location, ACE was also found in the brush borders of absorptive epithelia of kidney and small intestine, choroid plexus, prostate, male genital tract, mononuclear cells, and body fluids. ACE synthesis may be regulated by certain pathological conditions, for example, the gene expression of ACE was increased in hypertrophied noninfarcted myocardium following coronary artery ligation in rats.9 Consequently, cardiac ACE activation may enhance the conversion of angiotensin I to angiotensin II, which may induce inotropic and chronotropic effects, presynaptic facilitation of noradrenaline release from cardiac sympathetic nerve terminals, coronary vasoconstriction, myocyte hypertrophy, and stimulation of aldosterone release. Meanwhile, cardiac ACE activation may increase the rate of bradykinin degradation. ACE on the luminal surface of endothelial cells can be reached by ACE inhibitors from the circulation. In addition to the well-known conversion of angiotensin I to angiotensin II by endothelial ACE, there is also evidence in cultured endothelial cells from different species that the cells are then able to produce and release bradykinin into the extracellular space.10 Furthermore, components of the kallikrein-kinin system have been found in the heart and it has been shown that kinins can be released from ischemic hearts.11

ACE inhibitors were originally found in snake venom. Since the 1970s, many orally absorbable forms have been synthesized. These are competitive inhibitors with their negatively charged group (sulphydryl-, carboxyl-, or phosphorus-containing group) tightly bound to the zinc ions of the ACE molecule, preventing access of ACE substrates to the active sites of the enzyme.12 The demonstration of two zinc ions and two active sites on the ACE molecule gave rise to the idea that the two active sites may differ in their preference for various inhibitors and substrates, such as angiotensin II, bradykinin, substance P, and enkephalins.7 According to this theory, an ACE inhibitor may selectively inhibit angiotensin II synthesis or bradykinin degradation. It is noteworthy that the potency and duration of inhibition (including local action) of a particular ACE inhibitor depend on its binding characteristics rather than its tissue-penetrating property, since most of the physiologically important ACE in various tissues is localized on the luminal surface of endothelial cells with the two active sites accessible from the vascular lumen.13,14 When ACE inhibitors were first introduced into the treatment of hypertension, the antihypertensive actions of these drugs were generally ascribed to their property of reducing circulating angiotensin II. It was shown that the acute effects of ACE inhibitors on blood pressure were associated with decreased ACE activity, reduced angiotensin II levels, and augmented angiotensin I levels in blood. Plasma renin activity was increased because of the removal of negative feedback on renin release by angiotensin II.15,16


   ACE Inhibition in Experimental Myocardial Infarction
TOP
 Abstract
 Introduction
 ACE and ACE Inhibitors
 ACE Inhibition in Experimental...
ACE Inhibition in Large-Scale...
 Conclusion
 References
 
The beneficial effects of ACE inhibitors have been demonstrated in several experimental studies. In the rat model of coronary artery ligation, cardiac dilatation was attenuated and survival rate was improved.17,18 Schoemaker and colleagues19 reported that cardiac output was improved in rats treated with the ACE inhibitor captopril 3 to 5 weeks after MI, but rats treated 1 to 21 days after MI had poorer cardiac output. A similar finding was reported by Gay20 who showed that ACE inhibition with captopril initiated immediately after MI did not have a greater effect than treatment started 21 days post-infarction. In an in-vivo study in Wistar rats treated with the ACE inhibitor moexipril, cardiac mass and infarct size were significantly reduced.5 Since cardiac mass is taken as an indicator of cardiac hypertrophy, the reduction of cardiac mass with ACE-inhibitor treatment suggested possible clinical benefits of prevention of hypertrophy in high-risk patients. These experimental findings were partially in agreement with clinical observations in patients who survived MI. When administered to patients within 2 to 14 days after MI and continued for at least 3 months, ACE inhibitors limited left ventricular dilatation and improved ventricular function.21–24 When treatment was initiated early (within 24 hours), 6-month survival did not improve and the treatment had to be interrupted because of a trend indicating increased mortality in the ACE inhibitor-treated group; early hypotensive reactions were believed to be the reason.2 The mechanism of the beneficial effects of ACE inhibition on left ventricular failure after MI remains to be elucidated. Smits and colleagues25 found that the benefits of ACE inhibition with captopril on left ventricular failure following MI might not have been due to inhibition of angiotensin II synthesis because the angiotensin-receptor antagonist, losartan, did not improve cardiac function. This study gave rise to the idea that an ACE inhibitor-induced potentiation of bradykinin may contribute to the beneficial effects of ACE inhibition on heart failure following MI.

The development of cardiac hypertrophy was found to be impeded by an ACE inhibitor in a rat model of left anterior descending coronary artery ligation.5,6 This is in line with the findings of Gay20 who reported a reduction of left ventricular weight at 21 days and at 4 months after MI in rats treated with the ACE inhibitor, captopril. Smits and colleagues25 reported a reduction of cardiac mass and collagen content in rats treated with losartan from day 1 to 21 and in a different protocol, from day 21 to day 35 post-MI. However, coadministration with icatibant (a bradykinin B2-receptor antagonist) abolished the anti-hypertrophic action of moexipril, suggesting that the antihypertrophic effect of moexipril can be ascribed to ACE inhibitor-induced bradykinin potentiation rather than to angiotensin II synthesis inhibition.

ACE may also be involved in the process of tissue repair. It was reported that ACE expression in vascular smooth muscle cells was induced after intimal injury.26 In addition, ACE inhibitors are able to prevent myointimal pro-liferation.27 On the other hand, the antiproliferative action of ACE inhibitors could be partially blunted by co-administration of icatibant. Thus, bradykinin potentiation may also play a role in the antiproliferative action of ACE inhibitors.28 Over-expression of ACE was reported to be involved in the process of cardiac remodeling following MI.6,29,30 Increased ACE synthesis may lead to markedly enhanced angiotensin II formation. Angiotensin II-stimulated growth of myocytes and fibroblasts was suggested as a basis for compensatory ventricular remodeling.31 In cardiac fibroblasts, elevated angiotensin II levels were shown to increase both mRNA expression and protein synthesis of type-I collagen.31 Therefore, high angiotensin II concentrations in the scar tissue of infarcted hearts might activate fibroblast growth and collagen synthesis. This is in line with the study showing treatment with losartan resulted in a reduction of cardiac mass and collagen content following MI.25

It has recently been shown that ACE inhibition initiated one week before MI and continued for 6 weeks after MI could reduce myocardial infarct size in a rat model of left anterior descending coronary artery ligation; the limitation of infarct size by the ACE inhibitor moexipril was abolished by coadministration of the bradykinin B2-receptor antagonist.5 Similarly, in a rabbit model of MI, pretreatment with ramiprilat reduced infarct size from 40% to 20%, while coadministration of icatibant reversed this effect.32 In isolated perfused rat heart, the duration and incidence of postischemic reperfusion arrhythmias were reduced by bradykinin perfusion.33 Interestingly, the beneficial effects of bradykinin perfusion in the study of Linz and colleagues34 were almost identical to those induced by perfusion with the ACE inhibitor ramiprilat. All these effects of bradykinin and of the ACE inhibitor were attenuated by either icatibant or a nitric oxide synthase inhibitor, suggesting that the ACE inhibitor- induced bradykinin potentiation mediated most of the anti-ischemic actions of ACE inhibitors under these experimental conditions.34 In a recent study designed to investigate the mechanisms of the ACE inhibitor-induced reduction of MI size, tissue blood flow at the marginal zone of MI was measured by a laser Doppler flow meter in rats pretreated with the ACE inhibitor ramipril for one week. In ramipril-pretreated rats, tissue blood flow significantly increased after coronary artery ligation.5,6 In addition, infarct size evaluated 3 weeks after MI was also reduced by ramipril treatment in comparison with that of placebo-treated rats (Figure 1Go). Interestingly, long-term ACE inhibition was reported to double lifespan in the hypertensive rats. Ramipril was given to prehypertensive stroke-prone spontaneously hypertensive rats and agematched normotensive Wistar-Kyoto rats in an anti-hypertensive and sub-antihypertensive dose. Early-onset long-term ACE inhibition with a high dose of ramipril (1 mg•kg–1day–1) doubled lifespan to 30 months in spontaneously hypertensive rats and a low dose of ramipril (10 µg•kg–1day–1) prolonged lifespan from 15 to 18 months. The data suggest ACE inhibition may have a beneficial outcome on survival in high-risk patients with hypertension and associated cardiovascular disease.35



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  		Figure 1. Ramipril but not losartan reduced infarct size 3 weeks after MI. The effects of ramipril were abolished by the bradykinin B2-receptor antagonist, icatibant. *p < 0.05 compared with water-treated rats. {dagger}p < 0.05 compared with ramipril-treated rats. Rats (groups of 7 to 9) were treated prior to myocardial infarction, treatment was discontinued after infarction.1

 

   ACE Inhibition in Large-Scale Clinical Trials
TOP
 Abstract
 Introduction
 ACE and ACE Inhibitors
 ACE Inhibition in Experimental...
 ACE Inhibition in Large-Scale...
Conclusion
 References
 
The hypothesis of the Survival and Ventricular Enlarge-ment (SAVE) Study22 was that long-term administration of captopril to survivors of acute MI who had baseline ventricular dysfunction (ejection fraction of 40% or less) but no symptoms of overt heart failure or myocardial ischemia, would reduce mortality and improve clinical outcome. It was a large-scale double-blind randomized clinical trial performed in the USA and Canada. There were 2231 patients between the ages of 21 and 79 years, randomly divided into two groups (75 to 150 mg daily of captopril or placebo). The treatment began between 3 and 16 days (mean, 11 days) after MI on the basis of a radionuclide ejection fraction < 40% and no evidence of active ischemia. At the end of the study (mean follow-up, 42 months), a reduction of 19% in the risk of death from all causes was observed in the captopril group compared with the placebo group (Figure 2Go). The risk of death from cardiovascular causes was reduced by 21% for the captopril group. Within this group, a marked risk reduction of 37% in mortality due to progressive heart failure was found. The SAVE study demonstrated that in the group of patients with asymptomatic left ventricular dysfunction after MI, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. However, the SAVE study excluded patients who carried detectable ischemic risk and those with overt cardiac failure. Therefore, it is arguable how far the treatment benefit of captopril for the SAVE population can be extended to all patients suffering MI.36



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  		Figure 2. Risk reduction in clinical trials of angiotensin-converting enzyme inhibitors after myocardial infarction. SAVE22 showed a reduction of 19% in the risk of death from all causes in the captopril group compared with the placebo group. AIRE37 had an overall 27% reduction of deaths in ramipril-treated patients. FAMIS40 showed a 30% reduction in the incidence of death or moderate to severe congestive heart failure in fosinopril-treated patients. AIREX41 showed a relative risk reduction of 36% by ramipril and an absolute reduction in mortality of 11.4%.

 
The Acute Infarction Ramipril Efficacy (AIRE) Study37 was designed to determine whether administration of ramipril to patients with clinical evidence of heart failure after MI would improve survival. There were 2006 patients who had shown clinical evidence of heart failure at any time after an acute MI and were randomly allocated to double-blind treatment with either ramipril (1014 patients) or placebo (992 patients) on day 3 to 10 after MI. The patients were followed up for a minimum of 6 months (mean, 15 months). At the end of the study, the mortality was 17% in the ramipril group and 23% in the placebo group, with a 27% overall reduction in the risk of death; the data were highly significant statistically.

The second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II)1 was the first published early-intervention trial to examine the hypothesis that early ACE inhibition after MI improves long-term survival. CONSENSUS II was expected to reveal better preservation of ventricular function and therefore, survival benefits. Unfortunately, the trial was stopped after one year by the safety committee because of the high probability that enalapril was no better than placebo. The lack of beneficial effect could be due to the timing of administration of enalapril, which was initiated within 24 hours of onset of acute MI. However, in the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarcto Miocardio (GISSI-3)2 study, a small reduction in absolute mortality from 7.1% to 6.3% was found in the group treated with the ACE inhibitor lisinopril and nitrate (treatment began within 24 hours of MI). In an another study called Survival of Myocardial Infarction Long-term Evaluation (SMILE),38 the ACE inhibitor zofenopril was given within 24 hours after MI. An insignificant reduction was observed in the zofenopril-treated group but a significant relative reduction of 49% in the development of refractory heart failure at 6 weeks was found in the zofenopril group. The combined endpoint also showed a statistically significant benefit in the zofenopril group with a relative reduction of 33%. It remains to be elucidated when ACE inhibitors should be started after MI. When the onset of treatment is earlier (within 24 hours after acute MI), a fatal hypotensive reaction may be triggered. However, evidence from in-vivo animal studies suggests that pretreatment with ACE inhibitors before MI may limit infarct size by improving myocardial blood flow at the marginal zone of infarction.

To assess the clinical prevention of MI, stroke, or cardiovascular death by ACE inhibitors, a large and simple randomized trial, Heart Outcomes Prevention Evaluation Study (HOPE)39 is still running. HOPE could be one of the largest trials of two new interventions to prevent MI, stroke, or cardiovascular death in high-risk patients. The results of HOPE would have a direct public health impact with implications for clinical practice. The results of the HOPE study are expected to be published soon.

The Fosinopril in Acute Myocardial Infarction Study (FAMIS)40 aimed to investigate the hemodynamic and clinical effects of early (less then 9 hours from onset of symptoms) administration of the ACE inhibitor fosinopril in 285 patients with anterior acute MI undergoing thrombolysis within 6 hours of the onset of symptoms. After a 2-year randomized double-blind and placebocontrolled multicenter study, fosinopril-treated patients showed a 30% reduction in the incidence of death or moderate to severe congestive heart failure. This benefit of fosinopril was also confirmed in the subgroup of patients without congestive heart failure on admission who showed a 34.1% reduction in the occurrence of congestive heart failure. The FAMIS study demonstrated that early treatment with an ACE inhibitor in conjunction with thrombolysis, significantly delayed the development of congestive heart failure in acute MI.

The AIRE Extension (AIREX)41 study extended the follow-up time and assessed the long-term magnitude, duration, and reliability of the survival benefits observed after treatment with ramipril compared with placebo. The study investigated the mortality rate in all 603 patients recruited for the AIRE study. Three years after the AIRE study closed, death from all causes occurred in 117 (38.9%) of 301 placebo-treated patients and 83 (27.5%) of 302 ramipril-treated patients. The AIREX study showed a relative risk reduction of 36% and an absolute reduction in mortality of 11.4%. The data suggest that administration of ramipril to patients with clinically defined heart failure after acute MI results in a survival benefit that is not only large in magnitude but also sustained over many years.


   Conclusion
TOP
 Abstract
 Introduction
 ACE and ACE Inhibitors
 ACE Inhibition in Experimental...
 ACE Inhibition in Large-Scale...
 Conclusion
References
 
ACE inhibitors have been introduced into the treatment of hypertension, congestive heart failure, post-MI, and diabetic nephropathy for the past 15 years. Long-term treatment with ACE inhibitors in patients suffering from congestive heart failure following MI may reduce mortality and morbidity when treatment is initiated later than 24 hours after MI. ACE inhibitors are able to prevent cardiac hypertrophy, improve cardiac function, and limit infarct size. Under experimental conditions, various cardio-protective effects of ACE inhibitors appear to be due to the potentiation of endogenous kinins, including improved cardiac function, structural changes following myocardial ischemia, and induction of capillary growth in hypertension-induced left ventricular hypertrophy.


   References
TOP
 Abstract
 Introduction
 ACE and ACE Inhibitors
 ACE Inhibition in Experimental...
 ACE Inhibition in Large-Scale...
 Conclusion
 References
 

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