Molecular basis of diastolic dysfunction

Abstract

Diastolic dysfunction is characterized by prolonged relaxation, increased filling pressure, decreased contraction velocity, and reduced cardiac output. Phenotypical features of diastolic dysfunction can be observed at the level of the isolated myocyte. This article reviews the cellular mechanisms that control relaxation at the level of the myocyte in the healthy situation and discusses the alterations that can affect physiologic function during disease. It focuses specifically on the mechanisms that regulate intracellular calcium handling, and the response of the myofilaments to calcium, including the changes in these components that can contribute to diastolic dysfunction.

Figure 1

Potential contributors to Ca²⁺ dysregulation in failing heart muscle. A decreased expression and activity of SERCA pump could explain slowed rate of Ca²⁺ uptake and prolongation of muscle relaxation. Enhanced NCX expression and activity could increase Ca²⁺ efflux and compete with SERCA pump, reducing SR Ca²⁺ stores. RyR2 phosphorylation by PKA or CaMKII causes increased opening and Ca²⁺ leak, further contributing to loss of Ca²⁺. A net loss of Ca²⁺ could contribute to both systolic and diastolic dysfunction.