Background: 
Tachycardia-induced cardiomyopathy (TCM) is a reversible form of heart failure. However, the effects of persistent tachycardia leading to TCM in human myocardium are scarcely understood limiting appropriate management of patients with this condition. This study investigated the electrophysiological mechanisms leading to TCM in human models. 

Methods and results:
Tachycardic in vitro electrical stimulation (120 bpm vs. 60 bpm as control) of human ventricular trabeculae was performed. In human twitching ventricular trabeculae from patients with pre-existing heart failure, tachycardia for 8h compromised systolic force, while diastolic tension and relaxation time were increased (n=8/6 trabeculae /7/6 patients).

To study possible electrophysiological mechanisms mediating those effects human iPSC-cardiomyocytes (hiPSC-CM) were used for in vitro simulation of chronic tachycardia for up to 7 days (120 bpm vs. 60 bpm). Already after 24h of tachycardic stimulation of iPSC-CM, we detected a significant decrease in Ca²⁺-transient amplitude compared to control. Diastolic Ca²⁺ levels and cytosolic Ca²⁺ elimination were not affected after 24h tachycardia (Fura-2 AM, n=49/44 cells /9 differentiations). 7d of tachycardia resulted in a progressive decline of Ca²⁺-transient amplitude together with an impaired Ca²⁺ elimination (n=73/66/8) thereby demonstrating the progression of TCM. As an underlying mechanism we found a reduced sarcoplasmic reticulum (SR) Ca²⁺ load (caffeine application). We could detect a reduced SERCA activity (K_sys-K_caff (n=13/4 vs. 13/7) as well as an increase of Ca²⁺ spark frequency (confocal line scanning, Fluo-4 AM, n=76/79/7) after 7d of tachycardia. Both constitute typical mechanisms of maladaptive remodeling in heart failure and likely contribute to the observed reduction of SR Ca²⁺ load after persistent tachycardia. In voltage clamp studies, I_CaL density was reduced after 7d of tachycardia (n=11/12/3), which further contributes to the impairment of systolic Ca²⁺ handling . Whole-cell current clamp experiments revealed a prolongation of the action potential after 7d of tachycardia compared to control (n=21/6 vs. 19/5), which was associated with an enhancement of late sodium current (I_NaL) after 7d of tachycardia.

Conclusion: 
This study demonstrates for the first time in human myocardium that persistent tachycardia induces early adverse electrophysiological remodeling that may underlie the progression of TCM. These findings may help to understand the pathophysiology of an underrated but prevalent disease.