Background: Physiological electrical and mechanical (EM) heterogeneities and their interactions (electro-mechanical and mechano-electrical coupling; EMC and MEC) are essential for normal cardiac function. Alterations in these characteristics can result in increased arrhythmia formation. We have shown pronounced changes in electrical (prolonged and dispersed repolarization) and mechanical function (prolonged contraction duration and regional systolic and diastolic dysfunction) in the 'electrical' disease long QT syndrome (LQTS).

Objective: We aim to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological and pathological conditions to better understand their roles in arrhythmia development.

Methods: Multi-channel ECG and tissue phase mapping cardiac MRI were used to measure regional differences in electrical and mechanical function and EMC in healthy ('control') and I_Kr-blocker E4031 induced acute LQTS ('E4031') rabbit hearts in vivo.
MEC was studied in both groups by acutely changing mechanical function (increased preload by 6 ml/kg BW bolus of NaCl, warmed to body temperature).

Results: In acute LQTS hearts (E4031 10µg/kg bolus iv + 1µg/(kg*min) perfusion), cardiac repolarization was markedly prolonged (QTc (normalized to RR 250ms) [ms], all following data control vs. E4031,  153.0±11 vs. 274.1±39; p<0.0001; n=19), with increased spatial heterogeneity (QT dispersion Max-Min [ms], 14.4±4.2 vs. 30.4±9.7; p<0.001; n=13) compared to healthy controls.
Changing electrical function by E4031 resulted in changes of mechanical features (EMC): in acute LQTS hearts, systolic radial (Vr) and longitudinal (Vz) peak velocities were increased significantly in base, mid, and apex (p<0.05); diastolic longitudinal velocities (Vz) were reduced in all basal and mid-anterior and mid-anteroseptal segments (Vz_dia [cm/s] 5.5±1.2 vs. 4.6±0.9; p<0.01; n=19). Radial diastolic time-to-peak duration (TTP), a marker of contraction duration, was prolonged in two basal (inferoseptal, anterolateral; p<0.05) and three mid (anteroseptal, inferior, anterolateral; p<0.05) segments. Longitudinal diastolic TTP was prolonged by E4031 in 5 out of 6 basal and mid segments (p<0.05). These alterations led to an increased apicobasal heterogeneity of longitudinal contraction duration (basal-apical Vz_dia_TTP [ms], 2.2±11.8 vs. 21.7±24.1; p<0.02; n=8).
Increased preload acutely prolonged QTc [ms] in both 'control' (QT-increase: 20.6±7% vs. bsl, p<0.001, n=7) ) and 'E4031' hearts (QT-increase: 30.9±19%vs. E4031, p<0.05, n=7)) (MEC). This effect tended to be more pronounced in 'E4031' acute LQTS hearts in several leads (p=0.06). QT-dispersion Max-Min [ms], a marker for regional heterogeneity of repolarization, was also increased upon mechanical change - preferentially in 'E4031' (5 out of 7) compared to 'control' (3 out of 7) hearts by NaCl bolus.

Conclusion and Outlook: E4031-induced changes in electrical function resulted in marked alterations in mechanical features via EMC. Similarly, acute changes in mechanical function (increased preload) resulted in electrical changes via MEC. Importantly, QT-prolonging effects of acutely increased preload tended to be more pronounced in 'E4031' LQTS hearts, indicating that cardiac repolarization in LQTS may be more susceptible/vulnerable to acute MEC effects than in healthy individuals. Acute MEC effects may thus play an additional role in LQT-related arrhythmogenesis.