Alterations in cardiac myocyte function during the progression of volume overload-induced heart failure

A major hallmark of heart failure is a decreased function of the cardiac myocyte, the contractile unit of the heart. Little is known about the cellular mechanisms that lead to the progression of heart failure. Cardiomyocyte dysfunction could result from intrinsic abnormalities in sarcomere structure, calcium (Ca2+) homeostasis, and intercellular gap junctions or may result from altered regulation by the neurohormonal milieu.; In this dissertation, we utilized an animal model of volume overload created by an aortocaval fistula (ACF). Our data showed dynamic changes in single myocyte function during different phases of the volume overload model, with a decrease in myocyte shortening during late, decompensated heart failure. Isolated myocytes exhibited preserved responsiveness to β-adrenergic agonist stimulation in the late stages of the volume overload. This study is unique because we studied rat myocyte contractility and [Ca2+]i transients during different stages over the development of heart failure due to volume overload and correlated these results with in vivo measurements of chamber function by echocardiogram. Additionally, we also showed a low dose reactive oxygen species-induced myocyte contractile dysfunction and Ca2+ overload, which is partially mediated by Na +/H+ exchanger-1 (NHE-1) activation secondary to phosphorylation of NHE-1 by the extracellular recognition kinase-1/2 mitogen activated protein kinase pathway.; By investigating intrinsic myocyte function during the progression of volume overload and the factors in the interstitial milieu that may alter myocyte function, we have gained a better understanding of the dynamic changes at the level of the cardiomyocyte in the development and progression of heart failure.