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Induces Systolic Cardiac Failure Marked by Exhausted Inotropic Reserve and Intact Frank-Starling Mechanism
1 Section of Cardiology, University of Illinois at Chicago, Chicago, IL, USA; Northwestern University Feinberg School of Medicine, Chicago, IL, USA
2 Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
3 Section of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
4 Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA; Section of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
5 Section of Cardiology, University of Illinois at Chicago, Chicago, IL, USA; Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: buttrick{at}uic.edu.
Myofilament dysfunction is a common point of convergence for many forms of heart failure. Recently, we showed that cardiac over-expression of PKC
initially depresses myofilament activity 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 over-expression 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 patho-physiology of decompensated cardiac failure.
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