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Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction

¹Departments of Surgery, ²Pediatrics, and ³Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109

Submitted 1 December 2003 ; accepted in final form 26 January 2004

Diastolic dysfunction results from impaired ventricular relaxation and is an important component of human heart failure. Genetic modification of intracellular calcium-handling proteins may hold promise to redress diastolic dysfunction; however, it is unclear whether other important aspects of myocyte function would be compromised by this approach. Accordingly, a large animal model of humanlike diastolic dysfunction was established through 1 yr of left ventricular (LV) pressure overload by descending thoracic aortic coarctation in canines. Serial echocardiography documented a progressive increase in LV mass. Diastolic dysfunction with preserved systolic function was evident at the whole organ and myocyte levels in this model, as determined by hemispheric sonomicrometric piezoelectric crystals, pressure transducer catheterization, and isolated myocyte studies. Gene transfer of the sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a) and parvalbumin (Parv), a fast-twitch skeletal muscle Ca²⁺ buffer, restored cardiac myocyte relaxation in a dose-dependent manner under baseline conditions. At high Parv concentrations, sarcomere shortening was depressed. In contrast, during -adrenergic stimulation, the expected enhancement of myocyte contraction (inotropy) was abrogated by SERCA2a but not by Parv. The mechanism of this effect is unknown, but it could relate to the uncoupling of SERCA2a/phospholamban in SERCA2a myocytes. Considering that inotropy is vital to overall cardiac performance, the divergent effects of SERCA2a and Parv reported here could impact potential therapeutic strategies for human heart failure.

heart failure; calcium; contraction; inotropy; sarco(endo)plasmic reticulum Ca²⁺-ATPase 2a; canine

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