Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness.
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Circ. Res. 88 (11): 1159--1167 (June 2001)

Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na$^+$-Ca$^2+$ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca$^2+$ stores, reducing Ca$^2+$ transients and contractile function. Whereas beta-adrenergic receptors (beta-ARs) are progressively downregulated in HF, residual beta-AR responsiveness at this critical HF stage allows SR Ca$^2+$ load to increase, causing spontaneous SR Ca$^2+$ release and transient inward current carried by NaCaX. A given Ca$^2+$ release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and approximately 50\% less Ca$^2+$ release is required to trigger an action potential in HF. The inward rectifier potassium current (I(K1)) is reduced by 49\% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking 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 novel paradigm in which changes in NaCaX and I(K1), and residual beta-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.
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