Abstract
BACKGROUND: Mechanisms of ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with heart failure (HF) are undefined. OBJECTIVE: The purpose of this study was to elucidate VT/VF mechanisms in HF by using a computational-clinical approach. METHODS: In 53 patients with HF and 18 control patients, we established the relationship between low-amplitude action potential voltage alternans (APV-ALT) during ventricular pacing at near-resting heart rates and VT/VF on long-term follow-up. Mechanisms underlying the transition of APV-ALT to VT/VF, which cannot be ascertained in patients, were dissected with multiscale human ventricular models based on human electrophysiological and magnetic resonance imaging data (control and HF). RESULTS: For patients with APV-ALT k-score >1.7, complex action potential duration (APD) oscillations (≥2.3% of mean APD), rather than APD alternans, most accurately predicted VT/VF during long-term follow-up (+82%; -90% predictive values). In the failing human ventricular models, abnormal sarcoplasmic reticulum (SR) calcium handling caused APV-ALT (>1 mV) during pacing with a cycle length of 550 ms, which transitioned into large magnitude (>100 ms) discordant repolarization time alternans (RT-ALT) at faster rates. This initiated VT/VF (cycle length <400 ms) by steepening apicobasal repolarization (189 ms/mm) until unidirectional conduction block and reentry. Complex APD oscillations resulted from nonstationary discordant RT-ALT. Restoring SR calcium to control levels was antiarrhythmic by terminating electrical alternans. CONCLUSION: APV-ALT and complex APD oscillations at near-resting heart rates in patients with HF are linked to arrhythmogenic discordant RT-ALT. This may enable novel physiologically tailored, bioengineered indices to improve VT/VF risk stratification, where SR calcium handling and spatial apicobasal repolarization are potential therapeutic targets.