Static and dynamic abnormalities in electromechanical and autonomic cardiac function characterize the proarrhythmic substrate in the long-QT syndrome

Arrhythmogenesis in long-QT syndrome (LQTS) is driven by electrical instabilities, proarrhythmic electromechanical reciprocity, and swift autonomic nervous system (ANS) fluctuations.

Characterizing the proarrhythmic electromechanical and autonomic substrate in LQTS patients without and with previous ventricular tachyarrhythmia (VT).

LQTS patients prospectively underwent simultaneous non-invasive ECG imaging (ECGi), echocardiography, provocation testing with epinephrine (Epi; Mayo Clinic protocol), and 24h-Holter. Electromechanical window (EMW) was calculated by subtracting the QT time from the aortic-valve closure time. Data were either assessed longitudinally, compared to an ECGi (n=22) or an echocardiography control cohort (n=24). Data are shown as mean±SD or median (25th to 75th percentile).

23 LQTS patients (n=17 female, 47±14 years old, 9/23 symptomatic (=previous VT)) were included, of which 16 underwent provocation testing. LQTS genotypes were LQT1 (n=4), LQT2 (n=5), LQT3 (n=10), and LQT7 (n=4), with a mean QTc of 472±51 ms. 19/23 patients were treated with β-blockers, which were interrupted in 84%. At baseline, a negative EMW was found in LQTS patients when compared to controls (-45 (-60 to -30) vs. 20 (10 to 38) ms, p<0.0001), confirming an abnormal electromechanical sequence in LQTS. ECGi-derived epicardial recovery time (RT) was longer in LQTS patients compared to controls (313±49 vs. 266±30 ms, p=0.002). While RT (258±38 vs. 272±28 ms, p=0.02) and RT gradients (24±11 vs. 33±11 ms/cm, p=0.03) increased from apex to base in controls, this apex-to-base change in RT (324±64 vs. 310±42 ms, p=0.29) and RT gradients (30±16 vs. 33±16 ms/cm, p=0.88) was absent in LQTS. During 0.1 mcg/kg Epi provocation, the EMW was rendered more negative in LQTS (-104 (-165 to -65) ms, p=0.02 , Fig. 1).

Symptomatic LQTS patients had longer baseline QTc (504±52 vs. 450±39 ms, p=0.01), higher diurnal maximal QTc (550±39 vs. 512±31 ms, p=0.02), and lower EMW (-82±59 vs. -34±28 ms, p=0.02) in comparison to asymptomatic patients. Moreover, a lower sympathetic tone (low/high frequency ratio: 2.1±1.2 vs. 4.1±2.6, p<0.05) was found in the 24h-Holter of symptomatic patients. At Epi 0.1 mcg/kg, EMW was more negative in symptomatic patients (-177±92 vs. -84±51 ms, p=0.03). ECGi revealed numerically higher RTs in symptomatic compared to asymptomatic patients (335±54 vs. 292±34 ms, p=0.13), with significantly higher mean (46±15 vs. 22±8 ms/cm, p=0.006) and maximum RT gradients (186±64 vs. 90±32 ms/cm, p=0.008), and considerable dynamic changes in RT (gradient) patterns exposed upon Epi (Fig. 2).

Dynamic spatiotemporal alterations in repolarization, electromechanical sequence and ANS function differentiate symptomatic from asymptomatic LQTS patients. Multimodality imaging enables characterizing LQTS as a complex electromechanical disease and holds great potential to improve arrhythmia-risk stratification.Figure 1  Figure 2