In addition to relieving symptoms and reducing morbidity and mortality, postinfarction therapy also aims at preventing heart failure progression by slowing or reversing postinfarction remodeling. Kawai et al showed longer 5-year survival in recipients of pharmacologically induced reverse remodeling than in their nonrecipient controls.
Angiotensin-converting enzyme inhibition.
Effects, and the attenuation of ventricular dilation. There may be additional benefits for the coronary circulation and intrinsic plasminogen-activating system.
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ACE inhibitors may act directly on myocardial tissue, preventing the inappropriate growth and hypertrophy stimulated by angiotensin II. They may also reduce the number of ischemic events, as suggested by the Studies Of Left Ventricular Dysfunction (SOLVD) And Survival And Ventricular Enlargement (SAVE) data.
A recent systematic overview of data from five long-term randomized trials showed an overall 28% reduction in death, myocardial infarction, and hospital admission for heart failure in patients with postinfarction left ventricular dysfunction treated with angiotensin-converting enzyme (ACE) inhibitors. There was a correlation between the degree of baseline left ventricular dysfunction and the response to ACE inhibitors. The lower the ejection fraction, the lower the mortality and rehospitalization rates for heart failure. ACE inhibitors appeared most beneficial after large infarcts, which tend to cause ventricular dilation.
Activation of the renin-angiotensin system in the first few days after acute myocardial infarction can increase the heart rate and systemic vascular resistance, and decrease coronary artery perfusion, thus leading to infarct expansion. This could account for the early (first week) benefits of ACE inhibitors observed in the Grup-po Italiano per lo Studio della Soprawivenza nell'Infar-to miocardico (GISSI-3) study and Fourth International Study of Infarct Survival (ISIS-4).
The mechanism of ACE-inhibitor action is due in part to peripheral vasodilation, neurohumoral.
Patients with postinfarction left ventricular dysfunction or heart failure should be treated with ACE inhibitors without delay. Alternatively, all patients should be treated with ACE inhibitors initially, and therapy continued depending on subsequent assessment of left ventricular function. Gaudron et al showed that ACE inhibition prevents further progression of asymptomatic left ventricular dilation and remodeling after remote myocardial infarction, possibly due to attenuation of an exercise-induced increase in left ventricular filling pressure. In this study, ACE-inhibitor therapy arrested the ongoing process of progressive left ventricular dilation even in cases in which it had begun years after infarction in asymptomatic patients.
In a study by Sutton et al of left ventricular dilation in a large cohort of SAVE patients, late left ventricular dysfunction beyond 1 year appeared refractory to continued captopril therapy. Patients may therefore escape from the attenuating effect of ACE inhibitor therapy on left ventricular dilation. Markers of particularly high risk for progressive dilation and adverse cardiovascular events include a history of prior myocardial infarction, low ejection fraction, early heart failure, older age, and continuing changes in the echocardiographic indices of left ventricular geometry and function. Optimization of antiremodeling therapy in these patients requires further clinical research.
According to the results of the Val-HeFT Trial, the combination of valsartan, an angiotensin II receptor blocker, with an ACE inhibitor can favorably influence left ventricular modeling.
The mechanism behind the ability of p-blockade to decrease mortality in chronic heart failure is thought to involve the combination of an antiarrhythmic effect and improved hemodynamic function of the left ventricle, itself caused by a slower heart rate and inhibition of the detrimental neurohumoral activation virtually always present in chronic heart failure. It has been suggested that p-blockade benefits patients with a wide range of resting baseline heart rates, and not only those with evidence of sympathetic hyperactivation. It has also been suggested that long-term p-blockade in heart failure improves left ventricular contractility and mechanical work without increasing myocardial oxygen consumption. Other mechanisms include improved diastolic function, direct protection of myocytes against excess catecholamines, and improved regional wall motion. P-Blockers may also have a favorable effect on hibernating myocardium caused by imbalance between myocardial oxygen supply and demand.
Interestingly, it appears that the improvement in function precedes the antiremodeling effect. Once intrinsic myocardial function improves, a larger end-diastolic volume is no longer needed to maintain stroke volume, so that remodeling then adaptively reverses.
The left ventricular ejection fraction is the parameter that has shown the most consistent improvement on p-blocker therapy (a 20% to 30% relative increase, exceeding that observed with any other agent in heart failure therapy).
Carvedilol, metoprolol, and bisoprolol added to standard therapy including an ACE inhibitor have reduced mortality and morbidity in large-scale studies of ischemic and nonischemic heart failure. Metoprolol and bisoprolol are selective P,-adrenoceptor blockers. Carvedilol is a nonselective, P-adrenergic receptor antagonist that also blocks a [-adrenoceptors, providing more comprehensive neurohumoral antagonism. It is also a potent antioxidant, and thus may prevent the loss of cardiac myocytes that occurs in heart failure as a result of oxidative stress.
Studies with carvedilol and metoprolol have shown significant decreases in left ventricular end-diastolic and end-systolic volumes and increases in the left ventricular ejection fraction. These effects seem dose-dependent with carvedilol. The increase in the ejection fraction was apparent after 6 months and still preserved at 12 months.
In patients on long-term treatment after acute myocardial infarction complicated by left ventricular systolic dysfunction, carvedilol reduced the rates of all-cause and cardiovascular mortality, and recurrent nonfatal myocardial infarctions. The reduction in all-cause mortality was additional to the effects of ACE inhibitors and reperfusion therapy. Thus the effects of ACE inhibition and P~ blockade appear complementary. Both decrease mortality from progressive heart failure. ACE inhibition also controls remodeling while P-blockade improves myocardial performance and lowers the risk of sudden death. In summary, in significant left ventricular dysfunction or heart failure after myocardial infarction, combined neuroendocrine blockade may be optimal, although occasionally limited by hypotension.
The future challenge must be the primary prevention of myocardial infarction in patients at high risk for coronary disease. In addition, we must aim at new antiremodeling strategies which modulate the molecular and cellular factors involved in tissue repair, including hypertrophy, fibrosis, and microcirculation.