Mechanisms linking electrical alternans and clinical ventricular arrhythmia in human heart failure

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.

Keywords: Alternans; Arrhythmia; Computational modeling; Heart failure; Simulation.

Figure 1

Rate-dependent distribution of alternans in the failing HVM colored according to their respective HVM location (orange=basal endocardium, red=basal epicardium, blue=apical endocardium, cyan=apical epicardium).

Figure 2. Action potential (AP) and calcium transient (CaT) dynamics underlying RT-ALT in the failing HVM

Odd (red) and even (blue) beats for AP and CaT duration and activation sampled from the endocardial apex and base. Control HVM traces are plotted with dashed lines.

Figure 3. Arrhythmogenesis in the failing HVM

(A) Repolarization, activation (50ms isochrone line spacing), and transmembrane voltage (V_m) maps corresponding to (B), the pseudo-ECG resembling VF in precordial lead V1. (C) APD, activation time (AT), and repolarization time (RT) at the highlighted location in (A) for the 9 beats prior arrhythmia initiation.

Figure 4. Discordant RT-ALT in the failing HVM

Activation (50ms isochrone lines spacing), Rdiff, and Rmap maps revealing apicobasal rate-dependent conduction slowing, discordant RT-ALT, and steepening of repolarization, respectively, during endocardial LV apex (A) and epicardial RV (B) pacing.

Figure 5. Complex APD oscillations and APV-ALT predict VT/VF in HF patients

(A) 26 year old male with cardiomyopathy and VT/VF on follow-up showing complex, non-alternating, APD oscillations constituting 5.1% of mean APD during pacing with CL=600ms. The frequency spectrum showed a broad peak at 0.2–0.35 cycles/beat (non-alternating periodicity) even greater than the significant alternans peak at 0.5 cycles/beat (k-score>13.27). (B) 72 year old male with cardiomyopathy and VT/VF during follow-up showing minimal complex APD oscillations (2.4%) and a broad peak at 0.3–0.45 cycles/beat, yet a modest alternans peak (k-score 1.78). (C) 61 year old male with cardiomyopathy and no events during follow-up free of complex APD oscillations (1.3%) and APV-ALT (k-score=−1.03).

Figure 6. Complex APD oscillations in the failing HVM

For the Rdiff(b32) at the pacing CL=500ms, complex APD oscillations were detected only near RT-ALT nodal lines. As in HF patients, the presence of complex APD oscillations broadened spectral alternans frequency to <0.5 cycles/beat.

Figure 7. Pseudo-ECG for the failing HVM during apical pacing with CLs of 400 and 500ms

The pseudo-ECG was computed by taking the basal extracellular voltage subtracted from the apical extracellular voltage (electrodes in magenta). Beat-to-beat alternans and complex oscillations in the pseudo-ECGs are shown by superimposing the odd (Red) and even (Blue) beats during the last 8 of 32 beats for the two pacing CLs. Transmembrane voltage maps are shown for the HVM at three different time points for the first of the last 8 superimposed beats.