Action Potential Dynamics Explain Arrhythmic Vulnerability in Human Heart Failure

Abstract

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.

Multiple Defects in Intracellular Calcium Cycling in Whole Failing Rat Heart

“…22 Interestingly, there is also a recent report that AP amplitude alternans is associated with TWA and ventricular arrhythmias but not APD restitution, underscoring the link between Ca 2ϩ cycling defects and arrhythmias that are independent of APD restitution. 7 Finally, we found that defective Ca 2ϩ release in the form of both triggered and spontaneous waves is more prevalent in CHF. It is known that Ca 2ϩ waves promote triggered arrhythmias and we speculate that this occurs commonly in this patient population especially with their higher resting heart rates.…”

“…Interestingly, increased action potential (AP) amplitude alternans, T-wave alternans, and ventricular arrhythmias have been reported to be sensitive to altered Ca 2ϩ cycling and are unrelated to AP duration (APD) restitution. 7 …”

Sympathetic activity–associated periodic repolarization dynamics predict mortality following myocardial infarction

“…The complementary prognostic information provided by PRD and TWA implies that these 2 markers capture different aspects of repolarization instability. While PRD most probably reflects low-frequency oscillations related to sympathetic activity, TWA is mainly caused by high-frequency action potential oscillations provoked by abnormal calcium handling (34). TWA is an important predictor of cardiovascular mortality, including sudden death (6,27,35,36).…”

Three-Dimensional Impulse Propagation in Myocardium

“…Repolarization alternans (T-wave alternans) predicts sudden cardiac death in HF, 104 in particular at low heart rates when APD restitution slope is relatively flat. 105 There is also a strong association between the distribution or texture of fibrosis and risk of arrhythmia. 4,96,102 Figure 7.…”