Multiple Alterations in Ca2+ Handling Determine the Negative Staircase in a Cellular Heart Failure Model

PALOMEQUE, JULIETA; MARTIN GERARDO VILA PETROFF; LUCIANA SAPIA; CECILIA MUNDIÑA-WEILENMANN; OSCAR GENDE; ALICIA MATTIAZZI

JOURNAL OF CARDIAC FAILURE

Elsevier

Año: 2007 vol. 13 p. 143 - 154

1071-9164

The flat or negative force frequency relationship (FFR) is a hallmark in heart failure. Either decreases in SERCA2a expression, increases in Na+/Ca2+ exchanger (NCX) expression or elevated Na+i, have been independently proposed as mediators of the negative FFR. Objective:  To determine if each one of these mechanisms is sufficient to account for the negative FFR of the failing heart or on the contrary, various mechanisms, acting in concert are required. Methods: SERCA2a was inhibited with thapsigargin (TG) and/or cyclopiazonic acid (CPA), Na+i was increased with ouabain (Oua) or Monensin and NCX protein was overexpressed by gene transfer (Ad.NCX), to mimic in non-failing cat myocytes, the phenotype of the failing heart and examine their effect on the FFR.  Results: The positive FFR of healthy myocytes could not be significantly modified by either SERCA2a inhibition, Na+i elevation or NCX overexpression. However, the combination of TG + Oua, Oua + Ad.NCX or TG + Ad.NCX, converted the positive FFR to negative. Moreover, the FFR became negative at lower frequencies, when the three interventions were combined.