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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 33/3/312    most recent 00302.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Day, S. M. Articles by Metzger, J. M. Search for Related Content PubMed PubMed Citation Articles by Day, S. M. Articles by Metzger, J. M.

Cardiac-directed parvalbumin transgene expression in mice shows marked heart rate dependence of delayed Ca²⁺ buffering action

¹ Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
² Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan
³ Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan

Relaxation abnormalities are prevalent in heart failure and contribute to clinical outcomes. Disruption of Ca²⁺ homeostasis in heart failure delays relaxation by prolonging the intracellular Ca²⁺ transient. We sought to speed cardiac relaxation in vivo by cardiac-directed transgene expression of parvalbumin (Parv), a cytosolic Ca²⁺ buffer normally expressed in fast-twitch skeletal muscle. A key feature of Parv's function resides in its Ca²⁺/Mg²⁺ binding affinities that account for delayed Ca²⁺ buffering in response to the intracellular Ca²⁺ transient. Cardiac Parv expression decreased sarcoplasmic reticulum Ca²⁺ content without otherwise altering intracellular Ca²⁺ homeostasis. At high physiological mouse heart rates in vivo, Parv modestly accelerated relaxation without affecting cardiac morphology or systolic function. Ex vivo pacing of the isolated heart revealed a marked heart rate dependence of Parv's delayed Ca²⁺ buffering effects on myocardial performance. As the pacing frequency was lowered (7 to 2.5 Hz), the relaxation rates increased in Parv hearts. However, as pacing rates approached the dynamic range in humans, Parv hearts demonstrated decreased contractility, consistent with Parv buffering systolic Ca²⁺. Mathematical modeling and in vitro studies provide the underlying mechanism responsible for the frequency-dependent fractional Ca²⁺ buffering action of Parv. Future studies directed toward refining the dose and frequency-response relationships of Parv in the heart or engineering novel Parv-based Ca²⁺ buffers with modified Mg²⁺ and Ca²⁺ affinities to limit systolic Ca²⁺ buffering may hold promise for the development of new therapies to remediate relaxation abnormalities in heart failure.

heart failure; diastole; relaxation