Stochastic spontaneous calcium release events trigger premature ventricular complexes by overcoming electrotonic load

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Arrhythmogenesis

Background:

• Premature ventricular complexes (PVCs) can arise from spontaneous calcium release (SCR) events within cardiac cells.
• The precise mechanisms linking subcellular SCR events to PVC initiation, particularly overcoming electrotonic source-sink mismatch, require further elucidation.

Purpose of the Study:

• To investigate the conditions under which delayed afterdepolarizations, driven by stochastic subcellular SCR events, can trigger PVCs.
• To determine the critical thresholds and conditions for PVC initiation originating from SCR events.

Main Methods:

• Development and implementation of a stochastic subcellular-scale mathematical model of SCR within a realistic rabbit ventricular and Purkinje system model.
• Systematic elevation of diastolic sarcoplasmic reticulum calcium (CaSR) to quantify PVC probability, timing, and location.

Main Results:

• PVCs were initiated in the Purkinje system (PS) at CaSR ≥ 1500 µmol/L. Incapacitating SCR in the PS led to ventricular PVCs at higher CaSR (≥1550 µmol/L) with longer delays.
• A critical CaSR range was identified where PVC probability transitions from 0 to 100%, with this transition being more abrupt in organ-scale models compared to tissue or single-cell models.
• Approximately 68% of PS-initiated PVCs occurred near Purkinje-ventricular junctions.

Conclusions:

• SCR events successfully trigger PVCs by overcoming source-sink mismatch once a critical CaSR threshold is surpassed.
• Elevated CaSR increases the probability and reduces the timing variability of SCR events, causing significant diastolic depolarization and PVCs.
• Locations with lower electrotonic load, such as the Purkinje system, serve as preferential sites for PVC initiation.