Project Details
Projekt
Analysis of functional and molecular mechanism of the arrhythmia-induced cardiomyopathy (AIC): Effects of atrial fibrillation on the left ventricle
Subject Area
Cardiology, Angiology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 471241922
Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) often coexist in daily clinical practice. The causal relationship between AF and LVSD is usually difficult to assess, since any form of LVSD can in principle lead to AF, but AF per se can also lead to LVSD. Despite its high clinical relevance, no functional, structural or molecular investigations of AF on human, non-failing ventricular myocardium have so far been carried out. Animal models are limited due to tachycardiac pacemaker stimulation of the right ventricle, which by itself can cause LVSD. Our preliminary work on isolated cardiomyocytes (CM) and multicellular preparations from human hearts with AF suggests an electrical and contractile phenotype. Moreover, an in vitro simulated normofrequent arrhythmia induced electrical remodeling in human induced pluripotent stem cell CM (iPSC-CM).Due to its high clinical relevance, the translational goal of this project is the comprehensive investigation of the functional and molecular effects of AF on human ventricular myocardium and ventricular CMs.Detailed investigations will be carried out in healthy human LV myocardium as well as in hypertrophic LV myocardium from patients with aortic valve stenosis in order to investigate the characteristics of AF compared to sinus rhythm at the ventricular level. Furthermore, in vitro simulation of AF will be performed by established electrical stimulation for 24 hours of isolated cultured LV CM of the patients described above. Longer electrical stimulation periods will be carried out in human iPSC-CM as well as in iPS-derived endothelial cells (EC) using the same stimulation protocols.From the prepared heart samples, the contractile and electrical phenotype (including Ca2+ and Na+ homeostasis) in CM and multicellular preparations will be broadly assessed using fluorescence and patch-clamp techniques as well as contraction experiments. In addition, the histological/structural differences and altered signaling pathways for AF vs. sinus rhythm will be investigated in detail. Furthermore, the cardiac cell populations in the human myocardium of AF patients compared to sinus rhythm patients will be defined and transcriptomically characterized by "single nucleus" RNA sequencing.Finally, isolated human CM (24h) as well as iPSC-CM and -EC in 2D or 3D (24h and 7d) will be treated in culture with arrhythmic stimulation (normofrequent arrhythmia (60 bpm), or tachyarrhythmia (100 bpm) compared to sinus rhythm (60 bpm, regular)) and will be extensively characterized in a time-dependent manner using the same functional methods described above. The affected signaling pathways (protein and RNA levels (NGS bulk sequencing)) will be identified.In summary, the aim of this application is to investigate the influence of AF on the LV using various human-based approaches. This is intended to characterize the underlying pathomechanisms in order to better understand and treat the interaction of AF and LVSD.
DFG Programme
Research Grants
