Mechanisms of Improved Diastolic Function in Human Heart

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DESCRIPTION (provided by applicant): As an endpoint for many different types of cardiovascular disease, heart failure (HF) is a leading cause of mortality and morbidity in the U.S. Though some patients with HF have intact systolic function, virtually all patients with HF have abnormal diastolic function and an impaired ability to increase cardiac performance in response to physiologic stress, including exercise. During exercise, myocardial responses to increased heart rate and adrenergic stimulation normally involve augmentation of cardiac filling (requiring relaxation reserve) and enhanced ejection (requiring contractility reserve). At the cellular level, relaxation reserve, the focus of this application, requires faster decay of the intracellular calcium (Ca) transient and a decrease in myofilament Ca sensitivity. Ordinarily, both processes are enhanced by beta- adrenergic stimulation triggering PKA-mediated phosphorylation of key Ca regulatory and myofilament proteins. However, both relaxation reserved and adrenergic modulation of relaxation reserve are abnormal in failing hearts. Recognizing that Ca cycling dynamics are themselves abnormal in failing myocardium, the broad objective of the proposed studies is to examine beta-adrenergic/PKA-mediated modulation of relaxation reserve in failing human hearts in a manner that accounts for the defects in Ca cycling present in these hearts. Our working hypothesis is that adrenergic signaling defects result in an impaired beta-adrenergic augmentation of Ca uptake rates and a reduced ability to decrease myofilament Ca sensitivity. Mechanistically, we hypothesize that a reduced ability to phosphorylate phospholamban and troponin I cause an impaired ability of cAMP and PKA-dependent signaling to augment sarcoplasmic reticulum Ca uptake and reduce myofilament Ca sensitivity, respectively. Our specific aims are to: 1) examine beta-adrenergic modulation of relaxation reserve in patients with systolic an diastolic HF; 2) examine cAMP-induced modulation of relaxation reserve and Ca uptake in human myocardium; 3) examine PKA-dependent modulation of myofilament Ca sensitivity in human myocardium; and 4) determine whether Ca cycling defects or reduced targeting of PKA to troponin I limit PKA-dependent modulation of relaxation reserve. While defining mechanisms of impaired relaxation, these studies will help develop and validate dynamic noninvasive imaging strategies for clinical assessment of relation reserve in patients with HF.