Dissection of the Mechanisms Underlying the Negative Staircase Using a Cellular Heart Failure Model

PALOMEQUE, JULIETA; VILA PETROFF, MARTÍN G; LUCIANA SAPIA; MATTIAZZI, ALICIA

Dallas, USA

Congreso; American Heart Association (AHA). Scientific Sessions 2005,; 2005

AHA

The flat or negative force frequency relationship (FFR) is a hallmark of the failing heart (FH), which prevent it from satisfying even minimal metabolic requirements. Either decreases in SERCA2a expression, increases in Na+/Ca2+ exchanger (NCX) expression or elevated Na+i, have been separately proposed as mediators for the negative FFR. Whether these results indicate that each one of these mechanisms is sufficient to account for the negative FFR of the FH or on the contrary, they suggest a more complex scenario, where various mechanisms, acting in concert, are required, is still undefined. To dissect among these possibilities, we mimicked in non-failing adult cat myocytes, the three major alterations of the FH, and examined their effect on the FFR. The positive FFR of healthy myocytes could not be significantly modified by either inhibition of SERCA2a, [1 mM thapsigargin (TG), 10 mM CPA or both combined], elevation of Na+i, [10 mM ouabain (Oua)], or of NCX protein (adenoviral gene transfer, Ad.NCX), to similar levels than those observed in the FH. 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 stimulation rates, when the three interventions were combined (Fig). The results indicate that Ca2+ handling has to be altered at several levels to explain the negative FFR of the FH and that these anomalies in Ca2+ homeostasis acting in synergy, have additive effects.