Aim/Hypothesis: Tachycardia-induced cardiomyopathy (TCM) is a reversible form of ventricular systolic dysfunction solely due to an increase in ventricular rates. The hallmark of this entity is its reversibility once the tachycardia is properly controlled. The pathophysiological mechanism underlying TCM remain unclear. In humans, manifestation of TCM can have variable effects on systolic function in different individuals. It remains completely unexplained why some patients develop TCM from atrial fibrillation and some do not. Thus, we hypothesized that a genetic predisposition contributes to the development of TCM.

Methods and Results: To study 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 therapyrestoration) due to tachyarrhythmia. These patients were compared to two patients (control) who did not develop TCM despite incessant untreated tachyarrhythmia for many months.

Whole exome sequencing analysis showed mutations in cardiomyopathy-associated genes and/or missense or truncating mutations in the cardiac ion channel KCNQ1 in two of three TCM patients. To confirm the relevance of these mutations, we generated 2-month-old iPSC-cardiomyocytes (iPSC-CM). In TCM patients with sarcomeric mutations, we observed a significant reduction of sarcomeric regulation already under basal conditions. We investigated the effect of persistent tachycardia on cardiomyocytes by chronical culture field pacing of the iPSC-CM either by tachycardia (Tachy, 120 bpm) or by normal frequency/sinus rhythm (SR, 60 bpm) for 24 h or 7 days. Sarcomeric regulation was significantly decreased after 7 days of Tachy stimulation compared to SR in all patients.  Using whole-cell current clamp we showed a potent prolongation of action potential duration (APD₈₀) in all TCM patients with KCNQ1 mutations after 24 h Tachy stimulation compared to SR. The effect of tachycardia on Ca²⁺-transients was studied in iPSC-CM via Fura-2 AM epifluorescence measurements. Interestingly, Ca²⁺ -transient amplitude was already significantly reduced in all TCM patients after 24 h of normal frequency 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. Furthermore, we 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:

The question of why some patients develop TCM due to atrial fibrillation and some do not may be at least partially be answered by genetic predispositions of TCM patients. The current study provides the first indirect evidence that combinations of ion channel- as well as cardiomyopathy-associated mutations functionally alter cellular electrophysiology and seem to play an important role for the development of TCM. Thus, investigation of the specific mutations via CRISPR Cas9 genome editing may define new translational understanding of TCM.