Aim/Hypothesis: Tachycardia-induced cardiomyopathy (TCM) is a reversible condition of left-ventricular dysfunction, which is caused by persistent tachycardia. The pathophysiological mechanism underlying TCM is not understood and mainly based on artificially paced animal models. In humans, manifestation of TCM is more unpredictable since a similar burden of arrhythmia can have variable effects on systolic function in different individuals. We hypothesized that a genetic predisposition plays a role in the development of TCM.

Methods and Results: To investigate genetic predisposition and mechanisms of early tachycardia-induced electrophysiological remodeling, we generated human induced pluripotent stem cells (iPSCs) from three patients with precisely diagnosed TCM (MRI, coronary angiography, myocardial biopsy and full recovery of initially largely depressed LV function upon rhythm therapy) due to tachyarrhythmia and compared them to three patients who did not develop TCM (control) despite incessant and for many months untreated tachyarrhythmia.

Whole exome sequencing analysis demonstrated mutations in cardiomyopathy-associated genes and/or missense or truncating mutations in the cardiac ion channel KCNQ1 in all TCM patients. To confirm the relevance of these mutations, we generated 2-month-old iPSC-cardiomyocytes (iPSC-CM) and found significant reduced sarcomeric regulation, already under basal conditions in TCM patients with sarcomeric mutations. The effect of persistent tachycardia on cardiomyocytes was evaluated by chronical culture field pacing of theiPSC-CM either by tachycardia (Tachy, 120 bpm) or normal frequency (SR, 60 bpm) for 24 h or 7 days. Whole-cell current clamp showed a significantly prolonged action potential duration (APD₈₀) in all TCM patients with KCNQ1 mutations after 24 h and 7d Tachy stimulation compared to normal frequency and control patients. Resting membrane potential (RMP) or action potential amplitude (APA) were not altered.

The effect of tachycardia on the iPSC-CM Ca^2+-handling was studied via Fura-2 AM epifluorescence measurements. Systolic Ca²⁺ -transient amplitude was already significantly reduced in TCM patients after 24 h of SR stimulation compared to control iPSC-CM patient lines under the same conditions. Therefore, tachycardia stimulation had no additional effect in TCM patients, but decreases Ca²⁺-transients in control patients compared to SR.  Sarcomeric regulation was significantly decreased after 7d of Tachy stimulation compared to SR in all patients. We further elucidated the underlying mechanism by showing that markers of oxidative stress (H₂O₂) are potently increased after 7d of field stimulation (SR and Tachy in all patients and controls) with a significantly higher amount of H₂O₂ after Tachy versus SR in one TCM patient.

Conclusion: This study provides the first hint of a genetic predisposition as potential underlying cause for the development of TCM patients. Investigation of the underlying mechanisms and involved key targets may define new translational understanding of TCM.