Aging is the major independent risk factor of chronic heart failure and the leading cause of death in the elderly, which constitutes a significant segment of the US population predicted to increase in the next decades. Thus, identification of factors involved in the origin and progression of aging myopathy together with the development of preventive and therapeutic strategies for elderly patients are necessary to counteract the projected growing incidence of cardiovascular diseases. The central hypothesis of this proposal is that increased late Na+ current (INaL) with age is a major determinant of the electrophysiological and functional defects of senescent myocytes and ventricles. The increase in intracellular Na+ secondary to the enhancement of the late Na+ current in aged cardiomyocytes may influence Ca2+ cycling and provide inotropic support to the aged myocardium. However, imbalance of the process may result into a vicious positive feedback loop comprising the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation and operation of Na+ channels and ryanodine receptors. Thus, aberrant Na+ and Ca2+ homeostasis are viewed as major components of the delayed electromechanical coupling and diastolic dysfunction in the senescent heart. To test these possibilities, initially we will establish whether INaL is enhanced in myocytes of aged human heart, employing donor organ declined for transplantation. Subsequently, we will use engineered genetic gain- and loss-of-function mouse lines to modulate INaL in cardiomyocytes. The effects of INaL increase or failure to enhance INaL on Ca2+ cycling, electromechanical coupling, and diastolic function in vivo will be established in mice at different age, to dissect the contribution of enhanced late Na+ currents on the manifestation of the aging myopathy. Moreover, modulation of CaMKII activity, intracellular Na+ load, and ryanodine receptor function will be induced experimentally to gain mechanistic information on the cascade of events linking INaL, incidence of arrhythmias, and diastolic dysfunction. Whether components of the vicious feedback loop are critically altered with aging will also be established. Collectively, our work will define the contributions of electrophysiological remodeling of ventricular myocytes on the defective performance of the aged myocardium. Also proposed studies have the potential to identify therapeutic targets of pharmacological intervention to prevent or delay the progressive functional deterioration of the aging heart.
Studies proposed in this application are directed to the identification of mechanisms responsible for the development of cardiac dysfunction and exercise intolerance with aging. Results to be collected will provide information on novel therapeutic drug targets for the elderly population.
