The most common stimulus for myocardial hypertrophy and remodeling is hemodynamic overload. Abnormal mechanical stresses on cardiac myocytes may be a direct stimulus for myocardial remodeling. A positive long-term correlation has been found between increased left ventricular end-diastolic pressure and infarct size. The change in pressure combined with the increase in chamber diameter results in a marked elevation of diastolic wall stress that parallels infarct dimension. The two structural mechanisms that have been identified in the genesis of ventricular remodeling after myocardial infarction are side-to-side slippage of cells within the nonviable and viable ventricular tissue and the pattern of cellular hypertrophic response in the surviving myocardium.
Numerous studies have demonstrated marked alterations in diastolic behavior in the early stages of coronary occlusion, with impaired ventricular relaxation and greatly elevated myocardial stiffness. These abnormalities are followed by elevation of the ventricular end-diastolic pressure. Bolognese et al recently showed that a restrictive filling pattern was the most powerful predictor of left ventricular remodeling, even after controlling for infarct size, and that the degree of left ventricular dilation was related to the severity of impairment of left ventricular filling.
A gradual decrease in neurohumoral activation after myocardial infarction was recently found in patients with a good prognosis. In contrast, patients who went on to experience a further event within 3 months of myocardial infarction had markedly elevated neurohumoral levels (ANP, aldosterone, norepinephrine, renin) when asymptomatic a mean 10 days after infarction. Occasionally, positive feedback causes additional chamber dilation in response to increased wall stress and myocardial oxygen demand, and this can compromise further myocardium through ischemia or infarction. Without therapy to reduce ventricular dilation, decrease wall stress, promote favorable neurohumoral patterns, or develop appropriate ventricular
Pathophysiology hypertrophy, this process will spiral over months or years into chronic heart failure.
Left ventricular remodeling does not result only from myocardial necrosis. It can also be initiated by regional dysfunctional myocardium, consequent to severe coronary stenosis. In such cases, early revascularization is required not only to promote functional recovery but also to prevent left ventricular remodeling and ischemic cardiomyopathy.
In addition to improving symptoms and reducing morbidity and mortality, therapy must also seek to prevent the progression of heart failure by slowing or reversing the remodeling process. Multivariate analysis has identified higher systolic blood pressure and lower pulmonary arterial wedge pressure at diagnosis as independent predictors of reverse remodeling. Kawai et al found 5-year survival better in recipients of drug-induced reverse remodeling than in nonrecipients.
A recent systematic overview of data from five longterm 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 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 dilatation.
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 Gruppo Italiano per lo Studio della Soprawivenza nel-l’lnfarto 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 effects, and the attenuation of ventricular dilation. There may be additional benefits for the coronary circulation and intrinsic plasminogen-activating system. 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 data from the Studies Of Left Ventricular Dysfunction (SOLVD) and Survival And Ventricular Enlargement (SAVE). 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.
(3-Blockade The mechanism behind the ability of (3-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 [3-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 [3-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. [3-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
Pathophysiology that has shown the most consistent improvement on (3-blocker therapy (a mean 29% increase, exceeding that observed with any component of heart failure therapy). It was recently suggested that patients with nonischemic cardiomyopathy with higher left ventricular inotropic reserve (evaluated using dobutamine radionuclide ventriculography) and a normal right ventricular ejection fraction respond to [3-blockade with a greater increase in the left ventricular ejection fraction.
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 pj-adrenoceptor blockers. Carvedilol is a nonselective, (3-adrenergic receptor antagonist that also blocks (Xj-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 present at review after 12 months. Another recent study suggested that in patients with dilated cardiomyopathy who were poor responders to chronic metoprolol, carvedilol had favorable effects on left ventricular systolic function and remodeling as well as on ventricular arrhythmias.
In patients on long-term treatment after acute myocardial infarction complicated by left ventricular systolic dysfunction, carvedilol reduced the frequencies 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.
Eichhorn et al showed that patients with the highest peak systolic pressure, highest left ventricular end-diastolic pressure, and longest isovolumetric relaxation interval at baseline responded best to metoprolol. Perkan et al reported a close relationship between heart rate and the response to chronic metoprolol in patients with dilated cardiomyopathy.
Thus, the effects of ACE inhibition and P-blockade appear complementary and 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 neurohumoral blockade may be optimal, although occasionally limited by hypotension.
The 35% reduction in the risk of hospitalization for worsening heart failure in the Randomized ALdactone Evaluation Study (RALES) can probably be ascribed to the ability of spironolactone to reduce myocardial and vascular fibrosis. Similar results were seen in the recently reported data from the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and Survival Study (EPHESUS)
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 that modulate the molecular and cellular factors involved in tissue repair, including hypertrophy, fibrosis, and microcirculation.
pathophysiology; postinfarction ventricular remodeling; neuroendocrine factor; neurohumoral activation; cytokine; treatment; ACE-inhibition; j3-blocker; antialdosterone drug
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