Tachy-paced cardiomyocyte-derived small extracellular vesicles impair SERCA2a-dependent Ca2+ handling in recipient cardiomyocytes

Background Sustained tachyarrhythmia is a major cause of cardiac dysfunction and can lead to tachycardia-induced cardiomyopathy (TIC). However, the role of small extracellular vesicle (sEV)-mediated intercellular communication in the pathogenesis of TIC remains poorly understood. We aimed to investigate whether sEVs derived from tachy-paced cardiomyocytes affect intracellular Ca 2+ handling in recipient cardiomyocytes. Methods and results Cultured murine atrial cardiomyocytes (HL-1 cells) were subjected to high-frequency electrical stimulation (tachy-pacing, 10 Hz), and sEVs were isolated from the culture supernatant. sEVs derived from the tachy-paced cells and non-paced control cells were subsequently applied to neonatal mouse cardiomyocytes (NMCMs). Intracellular Ca 2+ transients, sarcoplasmic reticulum (SR) Ca 2+ content, and the expression of Ca 2+ -handling proteins were evaluated. High-frequency electrical stimulation significantly increased sEV secretion from HL-1 cells. sEVs derived from tachy-paced HL-1 cells markedly slowed Ca 2+ decay and reduced SERCA2a protein expression in recipient NMCMs. Conclusions Our study demonstrates that sEVs derived from tachy-paced cardiomyocytes suppress SERCA2a expression, thereby leading to impaired SR Ca 2+ reuptake and prolonged Ca 2+ transients. These findings suggest that sEV-mediated signaling may contribute to Ca 2+ dysregulation during sustained tachycardia.