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

Abstract Background Expression and phosphorylation of the cardiac Na + -Ca 2+ 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 was determined by Western blotting. Phosphorylated NCX-1 (P-NCX) was 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 dogs, 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 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.