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Cytoskeletal Networks and the Regulation of Cardiac Contractility

Functional alterations after cardiac sodium-calcium exchanger overexpression in heart failure

Trigen GmbH, Martinsried, Germany

Submitted 16 December 2005 ; accepted in final form 20 March 2006

The sodium-calcium exchanger (NCX) is discussed as one of the key proteins involved in heart failure. However, the causal role and the extent to which NCX contributes to contractile dysfunction during heart failure are poorly understood. NCX overexpression was induced by infection with an adenovirus coding for NCX, which coexpressed green fluorescence protein (GFP) (AdNCX) by ex vivo gene transfer to nonfailing and failing rabbit cardiomyocytes. Myocardial gene transfer in rabbits in vivo was achieved by adenoviral delivery via aortic cross-clamping. Peak cell shortening of cardiomyocytes was determined photo-optically. Hemodynamic parameters in vivo were determined by echocardiography (fractional shortening) and tip catheter [maximal first derivative of left ventricular (LV) pressure (dP/dt_max); maximal negative derivative of LV pressure (–dP/dt_max)]. Peak cell shortening was depressed after NCX gene delivery in isolated nonfailing and in failing cardiomyocytes. In nonfailing rabbits in vivo, basal systolic contractility (fractional shortening and dP/dt_max) and maximum rate of LV relaxation (–dP/dt_max) in vivo were largely unaffected after NCX overexpression. However, during heart failure, long-term NCX overexpression over 2 wk significantly improved fractional shortening and dP/dt_max compared with AdGFP-infected rabbits, both without inotropic stimulation and after -adrenergic stimulation with isoproterenol. –dP/dt_max was also improved after NCX overexpression in the failing rabbits group. These results indicate that short-term effects of NCX overexpression impair contractility of isolated failing and nonfailing rabbit cardiomyocytes. NCX overexpression over 2 wk in vivo does not seem to affect myocardial contractility in nonfailing rabbits. Interestingly, in vivo overexpression of NCX decreased the progression of systolic and diastolic contractile dysfunction and improved -adrenoceptor-mediated contractile reserve in heart failure in rabbits in vivo.

gene transfer

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