Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.

Summary

Selective LTCC inhibition, via drugs (e.g., nifedipine) or genetic RRAD overexpression, triggers cardiomyocyte cell-cycle re-entry by modulating calcineurin. Combining RRAD with CDK4/CCND further enhances proliferation and improves function while reducing scar size post-MI in vivo.

Key Findings

• In hESC-derived cardiac organoids, only LTCC inhibition triggered cardiomyocyte cell-cycle activity among calcium-cycle targets.
• RRAD overexpression induced cardiomyocyte cell-cycle activity in vitro, in human cardiac slices, and in vivo.
• LTCC inhibition (RRAD or nifedipine) promoted proliferation via calcineurin modulation.
• Co-expression of RRAD/CDK4/CCND increased cardiomyocyte proliferation, improved cardiac function, and reduced scar size after MI in vivo.

Clinical Implications

Suggests repurposing or timing strategies for LTCC inhibitors and gene-based approaches (RRAD/CDK4/CCND) to enhance myocardial repair post-infarction, pending safety and arrhythmia risk evaluation.

Limitations

• Preclinical evidence; long-term safety, arrhythmogenicity, and off-target effects are unknown
• Translational dosing/timing of LTCC blockade for regeneration remains to be defined

Future Directions

Define safe therapeutic windows for LTCC modulation, assess arrhythmia risk, and conduct large-animal and early-phase clinical studies targeting RRAD/calcineurin pathways.