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Abstract: Objective: Diastolic dysfunction is a characteristic finding of the aged mammalian heart. Parvalbumin acts as a Ca2+ sink and enhances relaxation in skeletal muscle, and overexpression of parvalbumin in myocardium increased cardiac relaxation in vitro as well as in vivo. Therefore, the objective of this study is to test the hypothesis that in vivo gene transfer of parvalbumin will improve diastolic dysfunction in aged rat heart. Methods: We used adenovirus to transfer parvalbumin into two different rat models of aging: the Fischer 344 (F344) and the Fischer 344×Brown Norway F1 hybrid (F344×BN). Cardiac function was measured and compared after gene transfer. Results: In vivo overexpression of parvalbumin in both rat aging models had no effect on systolic parameters but reduced left ventricular diastolic pressure and the time course of pressure decline. Overexpression of parvalbumin also improved the force frequency relationship in senescent rats. Conclusion: In vivo overexpression of parvalbumin improves diastolic dysfunction in two rat models of senescence, and this effect is independent of the rat strain investigated. The results show promise that gene therapy of parvalbumin may address the impaired Ca2+ homeostasis and diastolic dysfunction without an increase in energy expenditure. [Copyright &y& Elsevier]