Cardiac Contractility Modulation Electrical Signals Normalize Activity, Expression, and Phosphorylation of the Na+-Ca2+ Exchanger in Heart Failure

Background: Expression and phosphorylation of the cardiac Na+-Ca2+ exchanger-1 (NCX-1) are up-regulated in heart failure (HF). We examined the effects of chronic cardiac contractility modulation (CCM) therapy on the expression and phosphorylation of NCX-1 and its regulators GATA-4 and FOG-2 in HF dogs. Methods and Results: Studies were performed in LV tissue from 7 CCM-treated HF dogs, 7 untreated HF dogs, and 6 normal (NL) dogs. mRNA expression of NCX-1, GATA-4, and FOG-2 was measured using reverse transcriptase polymerase chain reaction, and protein level wits determined by Western blotting. Phosphorylated NCX-1 (P-NCX) wits determined using a phosphoprotein enrichment kit. Compared with NL dogs, NCX-1 mRNA and protein expression and GATA-4 mRNA and protein expression increased in untreated HF dos, whereas FOG-2 expression decreased. Compared with NL dogs, the level of P-NCX-1 normalized to total NCX-1 increased in untreated HF dogs (0.80 +/- 0.10 vs 0.37 +/- 0.04; P < .05). CCM therapy normalized NCX-1 expression, GATA-4, and FOG-2 expression, and the ratio of P-NCX-1 to total NCX-1 (0.62 +/- 0.10). Conclusion: Chronic monotherapy with CCM restores expression and phosphorylation of NCX-1. These It findings are consistent with previous observations of improved LV function and normalized sarcoplasmic reticulum calcium cycling in the left ventricles of HF dogs treated with CCM therapy. (J Cardiac Fail 2009:15.-48-56)