Mechano-electrical feedback in transgenic rabbit models of long QT syndrome Type 2 and short QT syndrome Type 1

AIMS: Electromechanical coupling and mechano-electrical feedback (MEF) are crucial for cardiac function, but their pro-arrhythmic roles in short and long QT syndromes (SQT1 and LQT2) are not fully understood. We aimed to evaluate MEF-induced electrical changes, their arrhythmic impact, and the involvement of stretch-activated channels (SACs) in transgenic rabbit models of SQT1 and LQT2. METHODS AND RESULTS: Patch-clamp and fluorescence imaging were used to analyse action potential duration (APD), Ca²⁺ transients, and contractility in ventricular cardiomyocytes (VCMs) from LQT2, SQT1 and wild-type (WT) rabbits. LQT2 cells showed prolonged APD and Ca²⁺ transients, increased early afterdepolarizations, Ca²⁺ oscillations, and impaired mechanics compared to WT and SQT1. The cellular electromechanical window (Ca²⁺-transient duration minus APD) was more negative in LQT2 and more positive in SQT1 than in WT. QTc prolonged with preload/afterload increase and decreased with preload reduction across all genotypes, but MEF-induced QTc changes and dispersion were most pronounced in LQT2. Ex vivo Langendorff experiments showed that increased right ventricular (RV) pressure prolonged APD and QTc in WT hearts. This was attenuated by the SAC blocker GSMTx4, suggesting a role for SACs in MEF. In silico models of human VCMs including SACs confirmed higher vulnerability to stretch/MEF-induced arrhythmias, including re-entry, in SQT1 and LQT2. CONCLUSION: Mechano-electrical feedback-induced electrical changes, partly mediated by SACs, occur in WT, SQT1, and LQT2, but MEF effects are strongest in LQT2. Mechano-electrical feedback induces pro-arrhythmic effects in silico more prominently in LQT2 and SQT1 than in WT, highlighting the potential pro-arrhythmic role of MEF in a vulnerable electrophysiological substrate.