Abstract 255 Genetic predisposition as a crucial mechanism in the development of tachycardia-induced cardiomyopathy

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02302-4
Genetic predisposition as a crucial mechanism in the development of tachycardia-induced cardiomyopathy
N. Dybkova¹, M. Anders¹, C. Brand¹, N. Hartmann¹, S. Rebs², P. Tirilomis¹, J. Beier¹, A. Zibat³, D. Vollmann⁴, G. Hasenfuß¹, B. Wollnik³, S. T. Sossalla⁵, K. Streckfuß-Bömeke²
¹Herzzentrum, Klinik für Kardiologie und Pneumologie, Universitätsmedizin Göttingen, Göttingen; ²Institut für Pharmakologie und Toxikologie, Universitätsklinikum Würzburg, Würzburg; ³Institute for Human Genetics,University Medical Center Göttingen, Göttingen; ⁴Kardiologie, Herz- und Gefäßzentrum am Krankenhaus Neu-Bethlehem, Göttingen; ⁵Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg;
Aim/Hypothesis: Tachycardia-induced cardiomyopathy (TCM) can trigger a potentially reversible condition of left-ventricular systolic dysfunction. The molecular mechanism underlying TCM is unclear. It remains completely unexplained why some patients develop TCM with a similar burden of atrial fibrillation and others do not. Thus, we hypothesized that a genetic predisposition contributes to the development of TCM. Methods and Results: To evaluate mechanisms of early tachycardia-induced electrophysiological remodeling and genetic predisposition, we generated human induced pluripotent stem cells (iPSCs) from a patient with precisely diagnosed TCM (MRI, coronary angiography, myocardial biopsy and full recovery of initially largely depressed LV function upon rhythm therapy) due to tachyarrhythmia. This patient was compared with a control patient who did not develop TCM despite persistent tachyarrhythmia for many months. Using whole exome sequencing analysis we detected a mutation in a cardiomyopathy-associated gene and a truncating mutation in the cardiac ion channel KCNQ1 in the TCM patient. To confirm the relevance of these mutations, we generated genetically modified rescue KCNQ1 iPSC-lines (TCM-res-KCNQ1) and differentiated all iPSCs to 2-month-old iPSC-cardiomyocytes (iPSC-CM). In TCM patient we revealed a significant reduction of sarcomeric regularity already under basal condition. The effect of persistent tachycardia on iPSC-CM was evaluated by chronical culture field pacing of the cells by either tachycardia (Tachy, 120 bpm) or normal frequency/sinus rhythm (SR, 60 bpm) for 24 hours or 7 days. Using whole-cell current clamp we observed a significant prolongation of action potential duration (APD₈₀) in the TCM patient after 24 hours or 7 days Tachy stimulation compared to SR and basal level. The effect of tachycardia on Ca²⁺transients was assessed via Fura-2 AM epifluorescence measurements. Interestingly, after either SR or Tachy field stimulation Ca²⁺ transients amplitude was already significantly reduced in TCM patient’s iPSC-CMs compared to control patient under the same conditions. Therefore, tachycardia stimulation had no additional effect in TCM patient, but decreases Ca²⁺ transients in control patients compared to SR. Interestingly, we could demonstrate that the decreased Ca²⁺transient amplitude after SR stimulation was completely rescued in TCM-res-KCNQ1-CMs. Conclusion: The question of why some patients develops TCM due to atrial fibrillation and some do not may at least partially be answered by genetic predispositions of TCM patients. This study provides first evidence that combinations of cardiomyopathy- as well as ion channel- associated mutations functionally alter cellular electrophysiology and seem to play an important role for the development of TCM. Therefore, examination of the precise mutation via CRISPR Cas9 genome editing may define new translational understanding of TCM.
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