Recognizing that a shortage of donor organs limits the availability of cardiac transplantation, the broad objective of this proposal is to explore whether myocardial recovery is possible in some patients with advanced heart failure awaiting transplantation. The hypothesis of the proposed studies is that mechanical circulatory support with a left ventricular assist device promotes improvements in electromechanical function in cardiac myocytes from patients with end-stage heart failure. Employing recent advances in myocyte isolation techniques, studies are proposed in freshly isolated human cardiac myocytes obtained at the time of cardiac transplantation.
The specific aims of this proposal are: 1) To determine if LVAD support causes normalization of the action potential duration and wave shape and define the membrane bases of these changes and 2) To determine if LVAD support causes normalization of myocyte contractions and define the cellular and molecular bases for these changes. Specific experiments for Aim 1 will examine changes in calcium (Ca2+) currents, potassium currents and Na+/Ca2+ exchange in the presence and absence of antecedent LVAD support using standard single cell voltage clamp techniques and pharmacologic probes. Specific experiments for Aim 2 will determine if contractile improvement is related to changes in cellular Ca2+ regulation or myofibrillar Ca2+ sensitivity. Specialized techniques will be used to identify the respective roles of sarcoplasmic reticulum Ca2+-ATPase, Na+/Ca2+ exchange and Ca2+ currents on the changes in the Ca2+ transient observed following LVAD support. The molecular basis of changes in Ca2+ regulation will be determined by paired measurements of mRNA and protein levels of sarcoplasmic reticulum Ca2+-ATPase and phospholamban. The applicant is a physician-scientist who is dedicated to becoming an independent investigator elucidating basic mechanisms of heart failure pathophysiology. This application represents a plan for expanding the applicant's knowledge and technical expertise in cellular physiology and applied molecular biology which are essential tools for future studies examining cardiac adaptations during evolving heart failure. The applicant's institution is the nation's largest adult cardiac transplant program which performed over 60 transplants in each of the past four years. This large clinical experience, the sponsor's expertise and record of mentorship in cellular physiology, and a strong institutional commitment to the applicant make this setting uniquely well-suited for successful completion of the proposed studies and advancement of the applicant's career development.
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