Arrhythmogenesis and contractile dysfunction in heart failure - Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness

Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these s ame aspects of human HF, we demonstrate that a 2-fold functional upregulati on of Na+-Ca2+ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca2+ st ores, reducing Ca2+ transients and contractile function, Whereas beta -adre nergic receptors (beta -ARs) are progressively downregulated in I-IF, resid ual beta -AR responsiveness at this critical HF stage allows SR Ca2+ load t o increase, causing spontaneous SR Ca2+ release and transient inward curren t carried by NaCaX. A given Ca2+ release produces greater arrhythmogenic in ward current in HF las a result of NaCaX upregulation), and approximate to 50% less Ca2+ release is required to trigger an action potential in HF. The inward rectifier potassium current (I-K1) is reduced by 49% in HF, and thi s allows greater depolarization for a given NaCaX current. partially blocki ng I-K1 in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a no vel. paradigm in which changes in NaCaX and I-K1 and residual beta -AR resp onsiveness, conspire to greatly increase the propensity for triggered arrhy thmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.