Congestive hart failure is a common endpoint for many types of cardiovascular disease. With or without associated systolic dysfunction, virtually patients with heart failure have diastolic dysfunction. However, the cellular basis of impaired myocardial relaxation and diastolic filing abnormalities in patients with heart failure is poorly defined, and no specific therapies exist for diastolic dysfunction. The broad working hypothesis of this research is that recently observed improvements in myocardial relaxation at the cellular level following circulatory support provides a unique opportunity to identify pivotal mechanisms of diastolic dysfunction support in humans with heart failure. Our specific hypothesis is that changes in intracellular calcium homeostasis and its determinants represent primary mechanisms of improved cardiac and cellular relaxation following circulatory support. A major goal of this research is to establish relationships between Doppler-derived measures of diastolic function in vivo, cellular relaxation in isolated myocytes and changes in the decay of the calcium transient in failing human hearts. We will also define the extent to which changes in sarcoplasmic reticulum calcium ATPase and Na/Ca exchanges activity contribute to abnormal calcium homeostasis in advanced heart failure and improvements in cellular relaxation following circulatory assistance. Finally, we will examine whether alpha 1 adrenergic stimulation of interleukin 1beta stimulation in normal human cardiac myocytes can recapitulate the phenotype of impaired relaxation and calcium homeostasis observed in heart failure.
These aims will be accomplished using recent advances in myocyte isolation techniques and established methods of Doppler echo-cardiography, cell physiology, molecular biology and cell culture involving human cardiac myocytes. This project will involve close collaboration with other investigators include in this RNA application in that functional assessments at Temple will be complemented by quantitative analyses of the molecular determinants of myocardial relaxation by collaborators at UCSF. Defining the cellular and molecular basis for impaired myocardial relaxation in humans, will provide a foundation for the development of specific therapies for patients with diastolic dysfunction.
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