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Protein kinase C induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism

Center for Cardiovascular Research, ¹Department of Medicine, Section of Cardiology, and ²Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Submitted 5 May 2005 ; accepted in final form 8 June 2005

Myofilament dysfunction is a common point of convergence for many forms of heart failure. Recently, we showed that cardiac overexpression of PKC initially depresses myofilament activity and then leads to a progression of changes characteristic of human heart failure. Here, we examined the effects of PKC on contractile reserve, Starling mechanism, and myofilament activation in this model of end-stage dilated cardiomyopathy. Pressure-volume loop analysis and echocardiography showed that the PKC mice have markedly compromised systolic function and increased end-diastolic volumes. Dobutamine challenge resulted in a small increase in contractility in PKC mice but failed to enhance cardiac output. The PKC mice showed a normal length-dependent tension development in skinned cardiac muscle preparations, although Frank-Starling mechanism appeared to be compromised in the intact animal. Simultaneous measurement of tension and ATPase demonstrated that the maximum tension and ATPase were markedly lower in the PKC mice at any length or Ca²⁺ concentration. However, the tension cost was also lower indicating less energy expenditure. We conclude 1) that prolonged overexpression of PKC ultimately leads to a dilated cardiomyopathy marked by exhausted contractile reserve, 2) that PKC does not compromise the Frank-Starling mechanism at the myofilament level, and 3) that the Starling curve excursion is limited by the inotropic state of the heart. These results reflect the significance of the primary myofilament contractilopathy induced by phosphorylation and imply a role for PKC-mediated phosphorylation in myofilament physiology and the pathophysiology of decompensated cardiac failure.

pressure-volume loops; cardiac myofilaments

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