Background: Tachycardia-induced cardiomyopathy (TCM) is a reversible impairment of left ventricular function caused by persistent tachycardia. However, the initial cellular mechanisms mediating the detrimental effects of persistent tachycardia are unknown and the characterization of TCM is mainly based on artificially RV-paced and severe heart failure animal models. This study aimed to investigate early cellular remodeling in TCM using human cardiomyocytes and multicellular tissue.

Methods and results: To elucidate early cellular mechanisms mediating the development of TCM, we chronically paced (120bpm vs 60bpm control) human induced pluripotent stem cells (iPSC-CM) for up to 7d in culture. As a major substrate of contractile dysfunction, we investigated the influence of chronic tachycardia on cellular Ca²⁺ cycling. After 24h of persistent tachycardia we detected a significant decrease in Ca²⁺ transient (CaT) amplitude and reduced diastolic Ca²⁺ levels (Fura-2 AM), while Ca²⁺ elimination time (RT80) was unchanged (n=44 cells control /42 cells tachycardia /8 diff.). Caffeine application was performed to evaluate sarcoplasmic reticulum (SR) Ca²⁺ load. 24h of tachycardic stimulation did not affect the SR Ca²⁺ load (n=12/13 /8). Further illustrating the transition to TCM, CaT amplitude was progressively decreased after 7d of chronic tachycardia. In contrast to 24h of tachycardia, 7d persistent stimulation resulted in slowed relaxation (RT80, n=75/65 /7). These findings could be explained by a significant reduction of SERCA activity (K_sys-K_caff) and SR Ca²⁺ load (n=14/12 /7). Diastolic Ca²⁺ concentration remained reduced (n=75/65 /7), possibly caused by a shift to transsarcolemmal Ca²⁺ elimination.

Na⁺ measurements (SBFI-AM) revealed no significant effects after 24h of tachycardia and a significant increase of intracellular Na⁺ concentration (n=69/69 /5) after 7d of tachycardia.

Patch clamp experiments showed a prolongation of the action potential duration as early as 24h after onset of tachycardia (n=26/21 /4), which persisted throughout 7d of pacing (n=8/12 /3). Resting membrane potential and action potential amplitude were not changed.

Preliminary measurements of an enhanced late Na⁺ current may explain the observed prolongation of action potential duration and increased cellular Na⁺.

The observed electrical changes already after 24h of tachycardia suggest that early remodeling mechanisms could be involved in the development of TCM.

To also test for early effects of tachycardia in human ventricular myocardium we investigated tachycardia-mediated effects on pre-existing human heart failure. 8h of tachycardic stimulation (120bpm) of human failing ventricular trabeculae impaired systolic twitch force. Diastolic tension and relaxation time were explicitly increased compared to control (60bpm) (n=7/6 trabeculae /6 human hearts).

An extensive functional and molecular characterization of involved ion channels and pathways underlying our observations are already under investigation.

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