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

Steven M. Pogwizd, Klaus Schlotthauer, Li Li, Weilong Yuan, Donald M Bers

Research output: Contribution to journalArticle

610 Scopus citations

Abstract

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 β-adrenergic receptors (β-ARs) are progressively downregulated in HF, residual β-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 ≈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 β-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.

Original languageEnglish (US)
Pages (from-to)1159-1167
Number of pages9
JournalCirculation Research
Volume88
Issue number11
StatePublished - Jun 8 2001
Externally publishedYes

Keywords

  • Ca transport
  • Excitation-contraction coupling
  • Heart failure
  • K currents
  • Na -Ca exchange

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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