Background: Tachycardia-induced cardiomyopathy (TCM) is a reversible form of ventricular dysfunction due to chronically elevated heart rates. Despite its clinical relevance, the time course and underlying cellular mechanisms of TCM are unclear. Thus, this study investigated the early mechanisms of TCM.

Methods and results: To study key electrophysiological effects at different early time points in a translational human model, human induced pluripotent stem cell cardiomyocytes were subjected to chronic tachycardic (120bpm) or normofrequent (control, 60bpm) electric field stimulation for 24h or 7d. 

Already after 24h of tachycardic stimulation, we detected a significant decrease in Ca²⁺ transient (CaT) amplitude compared to control (Fura-2 AM, n=49/44 cells/9 diff.). Diastolic Ca²⁺ levels and CaT elimination were not changed after 24h (n=49/44/9). Using caffeine application for evaluation of sarcoplasmic reticulum (SR) Ca²⁺ handling, we detected no difference in SR Ca²⁺ load or SERCA activity (K_sys-K_caff) after 24h of tachycardic stimulation (n=13/5) compared to control (n=15/6). Demonstrating the progress of TCM, 7d of tachycardic pacing resulted in progressive decline of CaT amplitude compared to control, while diastolic Ca²⁺ concentration was unchanged (n=73/66/8). Cellular Ca²⁺ elimination was significantly slowed after 7d of tachycardic pacing (n=73/66/8). These findings could be explained by a significantly reduced SR Ca²⁺ load accompanied by reduced SERCA activity (n=13/7) compared to control (n=13/4). 

Using confocal microscopy (Fluo-4 AM) we detected no difference in Ca²⁺ spark frequency after 24h of tachycardic pacing compared to control (n=82/66/8). 7d of tachycardic pacing resulted in significant increase of Ca²⁺ spark frequency compared to control (n=76/79/7), demonstrating increased diastolic SR Ca²⁺ release. 

Preliminary voltage clamp measurements of L-type Ca²⁺ current (I_Ca) showed no difference in maximum I_Ca density after 24h of pacing (n=8/8/3). After 7d, I_Ca current density was significantly reduced compared to control (n=13/13/3), thereby serving as a potential explanation for the impaired Ca²⁺ cycling. 

Whole-cell current clamp experiments revealed a prolongation of the cellular action potential after 7d of tachycardic pacing compared to control (n=21/6 vs. 19/5), while no difference of action potential duration could be detected after 24h (n=37/31/8). A significantly increased late sodium current (I_NaL) after 7d of tachycardic stimulation (n=26/7 vs. 19/6) serves as an explanation for the prolonged action potential following tachycardic stimulation.

Finally, we investigated tachycardia-mediated effects on pre-existing human heart failure (HF). 8h of tachycardic stimulation (120bpm) of human HF ventricular trabeculae significantly compromised systolic force, while diastolic tension and relaxation time were markedly increased compared to control (60bpm) (n=8/6 trabeculae /7/6 human hearts).

Conclusion: This study demonstrates that persistent tachycardia adversely alters cardiomyocyte excitation-contraction coupling via early electrophysiological cellular remodeling. Our translational investigation in human myocardium may help to understand the pathophysiology of an underrated and prevalent disease.