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

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 Ca²⁺ handling in recipient cardiomyocytes.

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 Ca²⁺ transients, sarcoplasmic reticulum (SR) Ca²⁺ content, and the expression of Ca²⁺-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 Ca²⁺ decay and reduced SERCA2a protein expression in recipient NMCMs.

Our study demonstrates that sEVs derived from tachy-paced cardiomyocytes suppress SERCA2a expression, thereby leading to impaired SR Ca²⁺ reuptake and prolonged Ca²⁺ transients. These findings suggest that sEV-mediated signaling may contribute to Ca²⁺ dysregulation during sustained tachycardia.