Action Potential Dynamics Explain Arrhythmic Vulnerability in Human Heart Failure: A Clinical and Modeling Study Implicating Abnormal Calcium Handling Original Research Article

Objectives The purpose of this study was to determine whether abnormalities of calcium cycling explain ventricular action potential (AP) oscillations and cause electrocardiogram T-wave alternans (TWA). Background Mechanisms explaining why heart failure patients are at risk for malignant ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) are unclear. We studied whether oscillations in human ventricular AP explain TWA and predict VT/VF, and used computer modeling to suggest potential cellular mechanisms. Methods We studied 53 patients with left ventricular ejection fraction 28 ± 8% and 18 control subjects. Monophasic APs were recorded in the right ventricle (n = 62) and/or left ventricle (n = 9) at 109 beats/min. Results Alternans of AP amplitude, computed spectrally, had higher magnitude in study patients than in controls (p = 0.03), particularly in AP phase II (p = 0.02) rather than phase III (p = 0.10). The AP duration and activation restitution (n = 11 patients) were flat at 109 beats/min and did not explain TWA. In computer simulations, only reduced sarcoplasmic reticulum calcium uptake explained our results, causing calcium oscillations, AP amplitude alternans, and TWA that were all abolished by calcium clamping. On prospective follow-up for 949 ± 553 days, 17 patients had VT/VF. The AP amplitude alternans predicted VT/VF (p = 0.04), and was 78% concordant with simultaneous TWA (p = 0.003). Conclusions Patients with systolic dysfunction show ventricular AP amplitude alternans that prospectively predicted VT/VF. Alternans in AP amplitude, but not variations in AP duration or conduction, explained TWA at ≤109 beats/min. In computer models, these findings were best explained by reduced sarcoplasmic reticulum calcium uptake. Thus, in heart failure patients, in vivo AP alternans may reflect cellular calcium abnormalities and provide a mechanistic link with VT/VF.