Congestive Heart Failure is the leading cause of death in much of the western world. A major hallmark of heart failure is diastolic dysfunction or the heart's inability to sufficiently relax between successive heartbeats. In order to ultimately treat, or even prevent, impaired relaxation, we need to understand the basic process of cardiac relaxation and determine what has gone wrong in pathological conditions, such as heart failure. Frequency-dependent activation and relaxation is a major physiological regulatory mechanism of cardiac contractile function, and it has been shown that the dynamic control of cardiac relaxation involves alterations in myofilament responsiveness. In particular, myofilament calcium sensitivity is modulated to accommodate the maintenance of adequate relaxation and a low diastolic force/filling pressure during frequency-induced changes in cardiac contractile output. Recent studies have demonstrated that in healthy rabbit right ventricular trabeculae, under near physiological conditions, myofilament calcium sensitivity decreases with frequency, which suggests frequency-induced desensitization to calcium. We believe these recent findings and clinical observations are ultimately functionally linked, and it is crucial we further elucidate the dynamic mechanisms governing myocardial relaxation in health and disease. Of late, it has been shown that staurosporine, a broad spectrum serine-threonine kinase inhibitor, inhibited the frequency-dependent myofilament calcium sensitivity modulations while the calcium handing remained unaltered. This finding indicates that the frequency-dependent modulation of calcium is regulated by a phosphorylation event located at the myofilament matrix. Based on this recently acquired data, we postulate the following central hypothesis: Dynamic control of diastolic function involves kinase-specific modulation of myofilament calcium sensitivity and is impaired in myocardial hypertrophy. In this proposal, we will address this central hypothesis by the following specific aims 1) To identify the kinase(s) and target(s) responsible for modification of frequency-dependent alterations of myofilament function, and 2) To dissect and quantify the mechanisms contributing to frequency-dependent impaired relaxation and elevated diastolic tension in hypertrophic myocardium.
|Program type||Predoctoral Fellowship|
|Effective start/end date||07/01/2009 → 06/30/2011|