Alteration of the Frank-Starling law in heart failure relates to titin

Abstract

Alterations of the Frank-Starling relationship under pathological conditions is still a matter of controversy. We investigated this property in perfused whole hearts and in single cells isolated from normal and post-myocardium infarcted (PMI) rats. A balloon connected to a pressure sensor was implanted in the left ventricle, and the intraventricular pressure was monitored following changes in volume. A first group of rats with a very low level of remodeling had a preserved Frank-Starling relationship. The second group, in heart failure, was characterized by tremendous fibrosis and ventricle dilatation, and presented an alteration of the Frank-Starling relationship. ‘Ihe passive and contractile properties of single chemically skinned ventricular cells were measured as well as their length-dependent Ca2’ sensitivity. Cells from failing hearts exhibited a lower stiffness and abnormal tension-pCa properties characterized by a decrease (from 0.4 pCa Unit in control to below 0.2) in the shift of pCa50 induced by a stretch from 1.9 pm to 2.3 nm sarcomere length. Biochemical analysis of contractile proteins was performed. Polyacrylamide gel electrophoresis (2.5-12%) revealed an altered form of titin in the pathological conditions. Based on a previous report showing that the degradation of titin by a mild trypsin digestion resulted in an alteration of the contractility of normal cells (Cazorla et al. 1999), we conclude that the inability of failing hearts to use the Frank-Starling relationship is, in part, attributable to titin alteration.