Abstracts & Commentary
Since aldosterone is extracted by the heart following acute myocardial infarction (MI), this group of investigators from Japan hypothesized that blocking its action may attenuate postinfarction remodeling. Thus, they studied 150 patients admitted for their first acute MI who were successfully treated by percutaneous coronary interventions. They were randomized to receive the mineralocorticoid receptor blocker canrenoate intravenously early after catheterization followed by spironolactone 25 mg/d or no aldosterone blocker. All patients were given enalapril 2.5 mg/d, which was up-titrated to a final mean dose of 9 mg/d, and aspirin. Beta blockers and other cardiovascular drugs were given as needed. Patients who developed creatinine > 2.0 mg/dL or potassium > 5.5 mEq/dL were excluded. At 1 month, all patients underwent repeat cardiac catheterization. Patients who developed significant culprit vessel restenosis were excluded. At the initial catheterization and the subsequent one, blood samples for aldosterone were taken from the aortic root and coronary sinus. Blood samples to measure a procollagen substance were taken from the coronary sinus as a marker of myocardial collagen formation. After the various exclusions, 134 of the initial 150 patients finished the protocol. Exclusions for heart failure, lethal arrhythmias, and restenosis were similar for both groups, but only the aldosterone antagonist group had 2 exclusions for renal failure and 2 for gynecomastia. Left ventricular ejection fraction increased in both groups after 1 month, but the increase was greater in the spironolactone group (7.2% vs 4.5%, P < .05). Left ventricular end-diastolic volume (LVEDVI) also increased at 1 month in both groups, but the increase was less in the spironolactone group (4 vs 19 mL/m2; P < .001). After 1 month, aldosterone extraction by the myocardium was significantly reduced in both groups vs baseline but was suppressed more in the spironolactone group (7 vs 18 pg/mL; P < .0001). The procollagen marker was increased in both groups at 1 month but was significantly less in the spironolactone group. Also, the change in this marker was correlated with the change in LVEDVI, r = .685. Hayashi and colleagues concluded that spironolactone plus enalapril can prevent left ventricular remodeling better than angiotensin converting enzyme inhibitor alone (Hayashi M, et al. Circulation 2003;107:2559-1565; Pitt B. Circulation. 2003;107:2525-2527).
Comment by Michael H. Crawford, MD
This study from Japan extends our knowledge regarding aldosterone antagonists following acute MI. The recent EPHESUS study1 showed beneficial effects of eplerenone in post-MI heart failure patients, but due to fears of compromising hemodynamics early, it was not started until 3-14 days postinfarction. The modest gains in mortality (15% reduction) and a combined mortality/morbidity end point (13% reduction) in EPHESUS may have been better had eplerenone been started earlier. The Japanese study suggests that aldosterone blockade can be started acutely with an intravenous drug without adverse hemodynamic effects and with demonstrated improvement in left ventricular function at 1 month. The question now is whether we should start giving aldosterone blocking drugs early to all post-MI patients as we do with beta blockers and angiotensin converting enzyme inhibitors.
The first consideration in answering this question is what the patients who were selected by the Japanese study were like. Clearly, they were a sick group. Despite the fact that the average ejection fraction was 46%, 20% were on catecholamine infusions, and 10% had intraaortic balloon pumping. This raises the question of when percutaneous revascularization was done, which is not stated in the paper. What was the symptom onset or door to balloon time? Also, the patients were undertreated by our standards. Only 31% were on beta blockers, and the average dose of carvedilol was 6 mg/d. The average enalapril dose was 9 mg/d. In addition, 70% of the patients were on oral nitrates for unclear reasons: persistent pain, heart failure? Thus, the question becomes, if the patients were revascularized in < 6 hours from symptom onset and were treated with standard doses of beta blockers and ACE inhibitors, what would have been the additive effect of spironolactone? So, at this point, until a larger randomized trial is done with state-of-the-art care, I am reserving aldosterone antagonist usage to severe heart failure patients (classes III-IV).
This study does provide important information concerning the potential mechanism of any beneficial effect of aldosterone antagonists, in that biochemical markers of myocardial fibrosis are suppressed. This may explain the positive effects on remodeling observed. However, other treatments that reduced fibrosis formation in acute myocardial infarction, such as steroids, have led to increased cardiac rupture. So we must be cautious about applauding reduced collagen formation in the infarcted heart. Some is necessary to keep the myocardial wall intact.
Dr. Crawford is Professor of Medicine, Mayo Medical School; Consultant in Cardiovascular Diseases, and Director of Research, Mayo Clinic, Scottsdale, AZ.
Reference
1. Pitt B, et al. N Engl J Med. 2003;348:1309-1321.
Since aldosterone is extracted by the heart following acute myocardial infarction (MI), this group of investigators from Japan hypothesized that blocking its action may attenuate postinfarction remodeling.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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