Calcium mishandling in diastolic dysfunction: Mechanisms and potential therapies

Michelle L. Asp, Joshua J. Martindale, Frazer I. Heinis, Wang Wang, Joseph M. Metzger

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Diastolic dysfunction is characterized by slow or incomplete relaxation of the ventricles during diastole, and is an important contributor to heart failure pathophysiology. Clinical symptoms include fatigue, shortness of breath, and pulmonary and peripheral edema, all contributing to decreased quality of life and poor prognosis. There are currently no therapies available that directly target the heart pump defects in diastolic function. Calcium mishandling is a hallmark of heart disease and has been the subject of a large body of research. Efforts are ongoing in a number of gene therapy approaches to normalize the function of calcium handling proteins such as sarcoplasmic reticulum calcium ATPase. An alternative approach to address calcium mishandling in diastolic dysfunction is to introduce calcium buffers to facilitate relaxation of the heart. Parvalbumin is a calcium binding protein found in fast-twitch skeletal muscle and not normally expressed in the heart. Gene transfer of parvalbumin into normal and diseased cardiac myocytes increases relaxation rate but also markedly decreases contraction amplitude. Although parvalbumin binds calcium in a delayed manner, it is not delayed enough to preserve full contractility. Factors contributing to the temporal nature of calcium buffering by parvalbumin are discussed in relation to remediation of diastolic dysfunction. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

Original languageEnglish (US)
Pages (from-to)895-900
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number4
DOIs
StatePublished - Apr 1 2013

Keywords

  • Calcium
  • Diastolic dysfunction
  • Gene therapy
  • Heart failure
  • Parvalbumin

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