Objective
To determine whether abnormalities of calcium cycling explain ventricular action potential (AP) oscillations and cause ECG T-wave Alternans (TWA).
Background
Mechanisms explaining why heart failure patients are at risk for malignant ventricular arrhythmias (VT/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 LV ejection fraction 28±8% and 18 control subjects. Monophasic AP were recorded in the right (RV, n=62) and/or left (LV, n=9) ventricle at 109 beats/min.
Results
Alternans of AP amplitude, computed spectrally, had higher magnitude in study patients than controls (p=0.03), particularly in AP phase II (p=0.02) rather than phase III (p=0.10). APD 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 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 suffered VT/VF. 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 APD or conduction, explained TWA at ≤109 beats/min. In computer models, these findings were best explained by reduced sarcoplasmic reticulum calcium uptake. In heart failure patients, in vivo AP alternans may reflect cellular calcium abnormalities and provide a mechanistic link with VT/VF.