Pathophysiological targets for beta-blocker therapy in congestive heart failure.

The treatment of congestive heart failure has seen considerable changes: while treatment with diuretics, digitalis glycosides and vasodilators has remained the mainstay of therapy, recently neurohumeral inhibition has been developed as an important principle: ACE-inhibitors have been shown to significantly improve quality of life and exercise performance and to substantially reduce mortality. Beta-blockers have been employed with increasing success mainly in congestive heart failure due to dilated idiopathic cardiomyopathy, in which a significant improvement in symptoms and life expectancy has been demonstrated. However, the precise mechanisms by which beta-blockade improves congestive heart failure remain to be elucidated. In addition to direct sympathoadrenal inhibition, reduction of heart rate may also play a major role in the therapeutic efficacy of beta-blockade in congestive heart failure. In the normal human heart increase in heart rate is accompanied by an increase in myocardial contractile performance (Bowditch-Treppe phenomenon). In chronic heart failure the myocardium undergoes a phenotype change which includes alterations of the activity of enzymes regulating calcium homoeostasis. The sarcoplasmic reticulum calcium ATPase (SERCA) is depressed both in function, as well as in expression. At the same time the sarcolemmal sodium-calcium exchanger is increased both in function and in expression. The result is a characteristic change in calcium homoeostasis with decreased diastolic uptake of calcium into the sarcoplasmic reticulum with subsequently reduced calcium release during the next systole, resulting in reduced contractile performance. At the same time increased capacity of the sodium-calcium exchanger extrudes intracellular calcium ions to the extra-cellular space, thereby rendering these ions unavailable for the contractile cycle. A result of these, seemingly specific, phenotype changes is an alteration of the force/frequency relationship. Instead of increasing force of contraction with increasing heart rates, in the chronically failing myocardium the contractile performance declines with increasing heart rates and only improves with decreasing rates. Optimal performance can be seen at heart rates as low as 30 beats.min. Studies employing photoluminescence markers of free cytosolic calcium, such as aequorin, have shown that there is a direct correlation between free cytosolic calcium and contractile performance at different levels of heart rate. It is likely, therefore, that the heart rate reduction with beta-blockade may provide the major explanation for the therapeutic benefits of beta-blockade in chronic congestive heart failure.