Basic Science and Experimental Study Induced Overexpression of Na D /Ca 2D Exchanger Does Not Aggravate Myocardial Dysfunction Induced by Transverse Aortic Constriction

Background: Alterations i Q1 n expression and activity of cardiac Na þ /Ca 2þ exchanger (NCX1) have been implicated in the pathogenesis of heart failure. Methods and Results: Using transgenic mice in which expression of rat NCX1 was induced at 5 weeks of age, we performed transverse aortic constriction (TAC) at 8 weeks and examined cardiac and myocyte function at 15e18 weeks after TAC (age 23e26 weeks). TAC induced left ventricular (LV) and myocyte hypertrophy and increased myocardial fibrosis in both wild-type (WT) and NCX1-overexpressed mice. NCX1 and phosphorylated ryanodine receptor expression was increased by TAC, whereas sarco(endo) plasmic reticulum Ca 2þ -ATPase levels were decreased by TAC. Action potential duration was prolonged by TAC, but to a greater extent in NCX1 myocytes. Na þ /Ca 2þ exchange current was similar between WT-TAC and WT-sham myocytes, but was higher in NCX1-TAC myocytes. Both myocyte contraction and [Ca 2þ ]i transient amplitudes were reduced in WT-TAC myocytes, but restored to WT-sham levels in NCX1-TAC myocytes. Despite improvement in single myocyte contractility and Ca 2þ dynamics, induced NCX1 overexpression in TAC animals did not ameliorate LV hypertrophy, increase ejection fraction, or enhance inotropic (maximal first derivative of LV pressure rise, þdP/dt) responses to isoproterenol. Conclusions: In pressure-overload hypertrophy, induced overexpression of NCX1 corrected myocyte contractile and [Ca 2þ ]i transient abnormalities but did not aggravate or improve myocardial dysfunction.