Mechano-electrical interactions and heterogeneities in wild-type and drug-induced long QT syndrome rabbits.

Abstract

Electromechanical reciprocity - comprising electro-mechanical (EMC) and mechano-electric coupling (MEC) - provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions - such as (drug-induced) acquired long QT syndrome (aLQTS) - might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and 24-lead ECG vest in healthy (control) and IKr -blocker E-4031-induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT-interval, RTn370) was prolonged compared to control (p<0.0001) with increased spatial and temporal RT heterogeneity (p<0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico-basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (p<0.0001). Additionally, regional RT-dispersion increased in aLQTS. Motion-correction allowed to determine APD-prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload-changes prevented a clear analysis of MEC ex vivo. Mechano-induced RT-prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT-related arrhythmogenesis, warranting further mechanistic investigations. Electromechanical reciprocity - comprising excitation-contraction coupling (EMC) and mechano-electric feedback loops (MEC) - is essential for physiological cardiac function. Alterations in electrical and/or mechanical heterogeneity are known to have potentially pro-arrhythmic effects. In this study, we aimed to investigate how electrical changes impact on the mechanical function (EMC) and vice versa (MEC) - both under physiological conditions (control) and in acquired long QT syndrome (aLQTS). We show that changing the electrical function (in aLQTS) results in significantly altered mechanical heterogeneity via EMC and - vice versa - that increasing the preload acutely prolongs repolarization duration and increases electrical heterogeneity, particularly in aLQTS as compared to control. Our results substantiate the hypothesis that LQTS is an 'electro-mechanical' - rather than a 'purely electrical' - disease and suggest that acute MEC effects may play an additional role in LQT-related arrhythmogenesis. Abstract figure legend Electromechanical reciprocity in healthy (control) and acquired long QT syndrome (aLQTS) rabbit hearts. A.-B. Electrical alteration in aLQTS. A. Exemplary ECG traces demonstrating IKr -blocker E-4031-induced RT prolongation in aLQTS. B. Visualization of heart rate corrected RTn370 (each color-coded scale includes 20ms) on rabbits' torso in aLQTS compared to control (n = 6 each). C. Electro-mechanical coupling (EMC). Exemplary myocardial longitudinal velocity curve in base (cm/s) during cardiac cycle in control (blue) and aLQTS (red). Indicated are peak amplitudes (AMPsys, AMPdia) and time-to-diastolic peak (TTPdia). D. Mechano-electrical coupling (MEC). Box plots of preload induced changes in repolarization. Comparison between the timepoints baseline (15 sec before increase in preload) and time of the maximal RTn370 increase peak-preload (around 20 sec after NaCl bolus injection). Heart rate corrected RTn370 demonstrates more pronounced RT-changes in aLQTS compared to control (n = 13 each). This article is protected by copyright. All rights reserved.