Experimental and computational approach to understand regional heterogeneity and electro-mechanical interactions in the rabbit heart

• Applicants: Professor Dr. Peter Kohl, since 2/2021; Professorin Dr. Katja Elisabeth Odening
• Subject Area: Cardiology, Angiology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394630089

Pronounced electrical and mechanical heterogeneities exist in the healthy heart, enabling physiological cardiac function. This electro-mechanical (E-M) heterogeneity exits on all levels, from cellular to whole heart, and it is driven by regional apico-basal, transmural, and interventricular heterogeneities in ion channel and Ca2+ handling proteins. Alterations of physiological E-M heterogeneity have been identified in various "electrical" and "mechanical" cardiac diseases and can be causatively linked to arrhythmogenesis. The mechanisms driving the pathological heterogeneity and their role in arrhythmia formation are unclear.Electrical and mechanical processes interact in a bi-directional way via electro-mechanical (EMC) and mechano-electrical coupling (MEC), so that acute or chronic alterations of either will lead to consecutive changes of the other. This can be observed in long QT syndrome (LQTS), which is considered a typical "electrical" disease, but demonstrates also mechanical heterogeneity correlating with - and presumably altering - the individual arrhythmic risk.Information on the relative importance of the two directions of interaction, EMC and MEC, is sparse in healthy and diseased hearts. We hypothesize that 1) In the healthy heart, electrical heterogeneities are main sources of mechanical heterogeneities that enable physiological pump function.2) In the "acutely diseased" (drug-induced LQTS) heart, this ordered E-M heterogeneity becomes disturbed, and mechanical changes become important drivers for electrical heterogeneities that may be pro-arrhythmic.As E-M remodelling occurs in the "chronically" diseased heart, it is difficult to dissect drivers of bi-directional E-M-E interactions. In this project, we will therefore 1) characterize E-M heterogeneities and interactions in healthy and "acute" drug-induced LQTS hearts (without remodelling) and 2) investigate consequences of acute changes of electrics and/or mechanics on E-M-E cross-talk by using targeted interventions (change in preload, contractility). We will utilize multi-channel ECG, tissue-phase mapping MRI in vivo, and simultaneous Ca2+/voltage optical mapping combined with transmural ultrasound ex vivo (Objective 1). Multi-dimensional and -modal experimental data will be integrated into computational whole heart models to understand underlying bi-directional interactions (Objective 2). In silico alterations of electrical or mechanical parameters will be performed to elucidate drivers of E-M-E cross-talk that will then be validated experimentally in Langendorff-perfused hearts using pharmacological modulation of the identified "drivers" (Objective 3).A thorough understanding of EMC and MEC in healthy and "acute LQTS" hearts will allow us to predict the role of E-M-E cross-talk as causative link between E-M heterogeneity and arrhythmogenesis in more complex, chronic diseases with remodelled substrate - which will form a follow-on target for our research.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr.-Ing. Gunnar Seemann, until 1/2021