Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): German Research Foundation Background Electrical and mechanical heterogeneities and their interactions (electro-mechanical and mechano-electrical coupling; EMC / MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation. Purpose With this study, we aim to investigate EMC and MEC under physiological and pathological conditions to better understand their roles in arrhythmia development. Methods Multi-channel ECG and TPM-MRI were used to measure regional differences in EMC in healthy ("control") and IKr-blocker E-4031 induced acute LQTS ("E-4031") 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). Results In acute LQTS hearts (E-4031 10µg/kg bolus + 1µg/(kg*min) iv), cardiac repolarization was markedly prolonged compared to healthy controls, (p < 0.0001; n = 13), with increased QT-dispersion (Max-Min), a marker for regional heterogeneity of repolarization (p < 0.01; n = 13). Changing electrical function by E-4031 resulted in changes of mechanical features (EMC): in acute LQTS hearts, diastolic longitudinal velocity (Vz) was reduced in all basal (p = 0.003; n = 19) and 4/6 mid segments (p = 0.006; n = 19). Longitudinal diastolic TTP was prolonged significantly in 5/6 basal and 4/6 mid segments by E-4031. These alterations led to an increased apicobasal heterogeneity of longitudinal contraction duration (basal-apical Vz_dia_TTP [ms] 2.9 ± 10.6 vs. 21.1 ± 21.3; p = 0.01; n = 9). Increased preload acutely prolonged QTc in both "control" and "E-4031" hearts (‘control’ 156.6 ± 11.6 to 198.3 ± 20.3; p < 0.0001 vs. ‘E-4031’ 193.9 ± 19.6 to 256.0 ± 37.5; p < 0.0001; n = 13) (MEC). This effect was more pronounced in "E-4031" acute LQTS hearts than in healthy hearts (Figure 1; delta QTc [ms] ‘control’ 41.6 ± 14.9 vs. ‘E4031’ 62.1 ± 32.1; p < 0.006, n = 13). QT-dispersion (Max-Min) was increased significantly upon mechanical change only in "E-4031" (‘E-4031’ 25.8 ± 5.5 to 32.7 ± 12.3; p < 0.03, n = 13). Conclusion E-4031-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, as well as its effects on regional heterogeneity of repolarization, were more pronounced in E-4031-induced acute LQTS hearts, indicating that cardiac repolarization in LQTS may be more susceptible to acute MEC effects than in healthy hearts. Acute MEC effects may thus play an additional role in LQT-related arrhythmogenesis. Abstract Figure.
Background Electro-mechanical (EMC) and mechano-electrical coupling (MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation. In “electrical” cardiac diseases, long-QT and short-QT syndrome, regional mechanical function is altered via EMC. Purpose In this study, we aimed to investigate how acute changes in mechanics may impact on electrical function (MEC) in these diseases. Methods To determine how acute changes in preload impact on QT duration, adult rabbits of both sexes were given a 6ml/kg BW bolus of 0.9% NaCl IV and 12-lead-ECGs were assessed first in wildtype (WT) and acquired drug-induced (E4031 to block IKr) LQT2 (“aLQT2”) rabbits, and in a second step in transgenic short-QT type 1 (“SQT1”, KCNH2-N588K) and WT littermate control rabbits (“WT-LMC”). Results At baseline, aLQT2 rabbits demonstrated a markedly prolonged heart-rate corrected QTc duration compared to WT (p<0.0001; n=13), with increased QT-dispersion (QTMax-Min [ms], WT 21.4±5.7 vs. aLQT2 25.8±5.8; p=0.003; n=13) and increased short-term variability of QT (STVQT [ms], WT 3.5±1.0 vs. aLQT2 5.3±1.7; p=0.02; n=13), markers for regional and temporal heterogeneity of repolarization, respectively. SQT1 rabbits (n=8) demonstrated a shorter QTc duration compared to WT-LMC (n=10; p=0.04), with no differences in QT-dispersion and STVQT between the two groups. Increased preload acutely prolonged QT and heart-rate corrected QTc in all groups (despite a slight increase in heart-rate by an average of 25 beats/min): in WT [ms] 171.6±11.6 to 213.3±20.3 (p<0.0001) vs. aLQT2 208.9±19.6 to 271.0±37.5 (p<0.0001; n=13 each), and in WT-LMC 171.3±4.8 to 199.2±5.4 (p<0.0001; n=10) vs. SQT1 156.0±4.7 to 177.3±3.5 (p=0.0004; n=8). Importantly, the extent of mechano-induced electrical changes differed among genotypes, with less pronounced QTc prolongation in SQT1 compared to WT-LMC (delta QTc [ms], SQT1 21.2±3.4 (n=8) vs. WT-LMC 27.9±2.8 (n=10; p=0.15)), and a more pronounced QTc prolongation in aLQT2 compared to WT (delta QTc [ms], WT 41.6±14.9 vs. aLQT2 62.1±32.1; p=0.006; n=13 each). Moreover, QT-dispersion was increased significantly upon global mechanical change only in aLQTS (QTMax-Min [ms], 25.8±5.5 to 32.7±12.3; p=0.03; n=13). Conclusion Acute changes in mechanical function result in electrical changes via MEC in SQT1, WT and aLQT2 rabbits. The extent of these changes, however, depends on the underlying QTc duration, with the least pronounced QTc prolongation in SQT1 rabbits, with the shortest QTc, and the most pronounced QTc prolongation in aLQT2 rabbits, with the longest QTc. The most pronounced MEC effects on global QT duration as well as on regional QT dispersion in aLQT2 indicate that acute MEC effects may play an additional role in LQTS-related arrhythmogenesis. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Research Foundation (DFG) andSwiss National Science Foundation (SNF)
Computational modeling of electrophysiological properties of the rabbit heart is a commonly used way to enhance and/or complement findings from classic lab work on single cell or tissue levels. Yet, thus far, there was no possibility to extend the scope to include the resulting body surface potentials as a way of validation or to investigate the effect of certain pathologies. Based on CT imaging, we developed the first openly available computational geometrical model not only of the whole heart but also the complete torso of the rabbit. Additionally, we fabricated a 32-lead ECG-vest to record body surface potential signals of the aforementioned rabbit. Based on the developed geometrical model and the measured signals, we then optimized the activation sequence of the ventricles, recreating the functionality of the Purkinje network, and we investigated different apico-basal and transmural gradients in action potential duration. Optimization of the activation sequence resulted in an average root mean square error between measured and simulated signal of 0.074 mV/ms for all leads. The best-fit T-Wave, compared to measured data (0.038 mV/ms), resulted from incorporating an action potential duration gradient from base to apex with a respective shortening of 20 ms and a transmural gradient with a shortening of 15 ms from endocardium to epicardium. By making our model and measured data openly available, we hope to give other researchers the opportunity to verify their research, as well as to create the possibility to investigate the impact of electrophysiological alterations on body surface signals for translational research.
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