Decreased inward rectifying K+ current and increased ryanodine receptor sensitivity synergistically contribute to sustained focal arrhythmia in the intact rabbit heart

Heart failure leads to dramatic electrophysiological remodelling as a result of numerous cellular and tissue‐level changes. Important cellular changes include increased sensitivity of ryanodine receptors (RyRs) to Ca2+ release and down‐regulation of the inward rectifying K+ current (IK1), both of which contribute to triggered action potentials in isolated cells. We studied the role of increased RyR sensitivity and decreased IK1 in contributing to focal arrhythmia in the intact non‐failing rabbit heart using optical mapping and pharmacological manipulation of RyRs and IK1. Neither increased RyR sensitivity or decreased IK1 alone led to significant increases in arrhythmia following local sympathetic stimulation; however, in combination, these two factors led to a significant increase in premature ventricular complexes and focal ventricular tachycardia. These results suggest synergism between increased RyR sensitivity and decreased IK1 in contributing to focal arrhythmia in the intact heart and may provide important insights into novel anti‐arrhythmic treatments in heart failure.

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