It is important to differentiate the acute pharmacologic effects of (3-blockers from their chronic biological effects. Whereas the ejection fraction actually decreases by 1% to 2% over the very first days of treatment, the experimental and clinical evidence shows that it improves significantly, by up to 10%, during chronic heart failure therapy. Indeed, long-term use can reverse all the changes associated with left ventricular remodeling, with progressive reductions in myocardial mass, left ventricular volumes (the reduction in end-systolic volume exceeds that in end-diastolic volume), and left ventricular sphericity. These changes are associated with marked symptomatic and clinical improvement, reflected in a highly significant decrease in mortality from worsening heart failure. Improvement in the left ventricular ejection fraction is a (3-blocker class effect and, in the case of carvedilol at least, is dose-dependent.
It was recently suggested that shorter symptom duration, a history of hypertension, and a worse New York Heart Association class predict improvement in left ventricular systolic function, eg, in patients with idiopathic dilated cardiomyopathy, whose prognosis appears good once this improvement is achieved. Reduced left ventricular volumes, an increased ejection fraction, and delayed left ventricular dilatation have also been demonstrated in heart failure due to ischemic heart disease. Indeed, current evidence suggests that |3-blockers should be continued regardless of the ejection fraction response, provided they are clinically tolerated.
Several mechanisms account for the effects of (3-blockers on left ventricular systolic function:
â¢ Relative bradycardia seems particularly important in the dilated, failing heart where the energy balance is disrupted and an abnormal inverse relationship has become established between heart rate and contractile force. Selective and nonselective (3-blockers induce a similar decline in resting heart rate.
â¢ Recent in vitro studies have shown that norepinephrine promotes apoptosis, indicating that this effect is mediated by the (3, receptor and that activation of the (3, receptor may be protective in this regard. A reduced rate of apoptosis would be expected to delay the progressive loss of functional myocardium and could contribute to a net improvement in ejection fraction.
â¢ Restoration of adrenergic receptor adenyl cyclase system activity and downstream signaling pathways: Pj-selective agents are well known to upreg-ulate adrenergic receptor function, but presumably this would contribute little because these receptors would be inhibited by drug action. In contrast, carvedilol does not upregulate (3-receptor function, but may enhance signaling downstream from surface receptors.
â¢ Reduced preload: given that carvedilol induces a,-blockade, any additional improvement it produces in the ejection fraction could be due to a decrease in ventricular load rather than to an intrinsic improvement in contractility.