Mechanismen der Tachykardie-induzierten Kardiomyopathie im humanen Myokard und Kardiomyozyten

Mechanisms of tachycardia-induced cardiomyopathy in human myocardium and cardiomyocytes

by Maria Knierim
Doctoral thesis
Date of Examination:2025-05-28
Date of issue:2025-04-14
Advisor:Prof. Dr. Samuel T. Sossalla
Referee:Prof. Dr. Samuel T. Sossalla
Referee:Prof. Dr. Niels Voigt
Referee:Prof. Dr. Ralf Dressel
Persistent Address: http://dx.doi.org/10.53846/goediss-11198

 

 

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Abstract

English

Tachycardia-induced cardiomyopathy (TCM) describes a reversible form of left-ventricular dysfunction based on a persisting tachycardia. Its clinical impact is relevant but often underestimated, hence its mechanisms remain mostly unknown. The aim of this work was the electrophysiological investigation and characterization of the early stages of TCM in human ventricular tissue. Human induced pluripotent stem-cell cardiomyocytes (hiPSC-CM) were subjected to 24 hours or 7 days of electrical pacing at 60 bpm (control) or 120 bpm (tachycardia) in vitro followed by detailed investigation of cellular calcium cycling via epifluorescence microscopy (Fura-2 AM), as well as l-type calcium current and action potentials via the use of the patch-clamp method. 24h of tachycardic pacing induced a reduction of calcium release from the sarcoplasmic reticulum (SR) compared to control, which was progressively increased after 7d of tachycardia. Concomitantly, after 7d of tachycardia, the l-type calcium current was significantly decreased and SR function began to decline, which was represented by a reduction of calcium reuptake velocity leading to reduced SR calcium content and thus reduced systolic release. Furthermore, after 7d of tachycardic pacing, the action potential was significantly prolonged compared to control pacing. Additionally, human ventricular trabecular from patients with terminal heart failure were isolated and in vitro pacing at 60 bpm or 120 bpm was initiated for up to 8h. Afterwards, myocardial contractile function was evaluated. Tachycardic pacing led to a rapid decompensation of the contractile function with drastic systolic and diastolic dysfunction compared to control stimulation. The early stages of tachycardia-induced ventricular dysfunction seem to be dominated by alterations of cellular calcium cycling and electrophysiological disturbance. Additionally, the relevance of tachycardia-induced dysfunction in pre-existing heart failure and the vulnerability of failing myocardium was demonstrated. From a translational perspective, this work emphasizes the importance of early rhythm control in tachycardia-induced ventricular dysfunction and offers new insights for further investigation.
Keywords: Tachycardia-induced cardiomyopathy; Calcium; Electrophysiology; Heart failure