Abstract:

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

Objective: We aim to investigate cardiac EM heterogeneity and regional differences in EMC and MEC under physiological and pathological conditions to better understand their role in arrhythmia development.

Methods: In vivo, standard 12-lead ECG, 32-channel vest ECG and tissue phase mapping cardiac MRI are used to measure regional differences in electrical and mechanical function in healthy (‘control’) and I_Kr–blocker E4031 induced acute LQTS hearts (‘E4031’). Ex vivo, simultaneous Ca²⁺/voltage optical mapping (OM) and ultrasound-based visualization of mechanical deformation (strain ECHO) in Langendorff-perfused hearts are performed. Electro-mechano-electrical interactions (EMC and MEC) and their regional differences are studied by changing either electrical features (by E4031) or mechanical features (altered preload or contractility).

Results: Alterations in EM heterogeneities were assessed in vivo by applying E4031 (EMC). As expected, E4031 administration (10µg/kg bolus + 1µg/kg/min perfusion) resulted in marked prolongation of cardiac repolarization (QTc Fridericia, control: 248.5±16.2 vs. E4031: 410.3±38.9; p<0.01; n=14), and increased spatial heterogeneity in repolarization (QT dispersion Max-Min [ms] control: 14.4±4.2 vs. E4031: 30.4±9.7; p<0.01; n=13).

Electrical changes (E4031) resulted in changes of mechanical features: Systolic radial (Vr) and longitudinal (Vz) peak velocities were increased significantly in base, mid, and apex (p<0.05).

E4031 administration had no significant effect on diastolic radial velocity. In contrast, diastolic longitudinal velocity (Vz) was reduced in all basal and mid-anterior and mid-anteroseptal segments (Vz_dia [cm/s] Baseline: 5.5±1.2 vs. E4031: 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. In longitudinal direction, diastolic TTP duration was prolonged by E4031 in 5 out of 6 basal and mid segments (p<0.05) except for the basal-inferior and mid-inferior segment.

These alterations led to a decreased apicobasal heterogeneity of Vz diastolic peak velocities upon E4031 (basal-apical Vz_dia [cm/s], Baseline: -4.4±1.3 vs. E4031: -3.3±0.9; p<0.01; n=19) and to an increased apicobasal heterogeneity of Vz diastolic TTP duration (basal-apical Vz_dia_TTP [ms], Baseline: 2.2±11.8 vs. E4031: 21.7±24.1; p<0.02; n=8)

Conclusion and Outlook: E4031-induced changes in regional electrical function resulted in marked regional alterations in mechanical features via EMC. To investigate the role of MEC, we are currently assessing the effects of changed cardiac mechanics (altered preload and contractility) on electrical features using 32-channel vest ECG in vivo and combined optical mapping and strain ECHO ex vivo. This will help us to better understand EMC and MEC in the 'electrical' disease LQTS.