Calcium dynamics, beta-adrenergic receptor blockade, and cardiac function in failing and non-failing hearts

Heart failure manifests as impaired systolic and/or diastolic dysfunction associated with defects in Ca2+ cycling within cardiomyocytes. β-adrenergic signaling is a short term stress response mechanism that enhances Ca2+ cycling and cardiac contractility, but chronic β-adrenergic stimulation contributes to heart failure. The mechanism of chronic β-adrenergic signaling leading to altered Ca 2+ handling and ensuing heart failure is unclear. The relationship between β-adrenergic signaling and myocardial Ca2+ dynamics was investigated in this dissertation using a murine model of heart failure treated with β-blockers in order to analyze effects upon Ca2+ handling and cardiac function. Calcium dynamics were assessed using real-time line scan confocal microscopy, calcium handling protein expression was measured by immunoblot analyses, and hemodynamic parameters were evaluated by echocardiography. Short-term treatment for two weeks with β-blockers normalized Ca2+ handling without concomitant improvement in cardiac function, demonstrating a dissociation between Ca2+ dynamics and cardiac function. Longer treatment for ten weeks with β-blockers produced significant improvement in cardiac function. Related studies showed additional beneficial effects of β-blockade including reduction of apoptosis and prevention of remodeling associated with development of heart failure, indicating a central role for the β-signaling cascade in development of heart failure. These results demonstrate the significant contributory role that chronic β-adrenergic signaling plays in the pathogenesis of heart failure by altering myocardial Ca2+ dynamics and provides novel insights regarding cellular and molecular mechanism(s) responsible for beneficial effect of long-term β-blockade therapy.