Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing...

Area of Science:

• Cardiology
• Biomedical Engineering
• Stem Cell Biology

Background:

• Long-term ventricular pacing can harm heart function, especially when cumulative percent ventricular pacing (Cum%VP) exceeds 40%.
• The cellular mechanisms linking pacing to myocardial disorders are not fully understood.
• Existing research is limited by the difficulty of obtaining human cardiac tissue and the lack of long-term in vitro pacing models.

Purpose of the Study:

• To investigate the cellular disturbances and molecular pathways underlying pacing-induced myocardial dysfunction.
• To establish and utilize a novel in vitro model for studying long-term cardiac pacing effects.

Main Methods:

• Human induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were subjected to electrical stimulation for 2 weeks.
• Quantitative structural and electrophysiological analyses were performed to assess pacing-induced changes.

Main Results:

• Paced VCMs showed reduced contractile protein expression, increased apoptosis, and electrophysiological remodeling in a Cum%VP-dependent manner.
• Long-term pacing activated both endoplasmic reticulum (ER) stress and calpain.
• Calpain inhibition mitigated adverse structural remodeling and improved I_{Ca, L} in paced VCMs.

Conclusions:

• Two weeks of in vitro pacing induced structural and electrophysiological dysfunction in VCMs.
• Increased ER stress and calpain activation appear to be central mechanisms in pacing-induced heart disease.
• Targeting calpain may represent a novel therapeutic strategy for managing patients with long-term ventricular pacing.