What happens when cardiac Na channels lose their function? 1 – Numerical studies of the vulnerable period in tissue expressing mutant channels

OBJECTIVE: The vulnerable period (VP) defines an interval during which premature impulses can trigger reentrant arrhythmias leading to ventricular fibrillation and sudden death. The mechanistic basis of the success or failure of impulse propagation during the VP remains unclear. Recent clinical reports of gene mutations, drugs and cardiac disease link a variety of often lethal conditions with loss of cardiac Na channel function (NaLOF) and reentrant proarrhythmia. We hypothesized that during the VP, the Na conductance at the stimulus site is graded and that NaLOF would favor reentry specifically by flattening this gradient, which would destabilize antegrade front formation. METHODS: Using numerical studies of propagation in a one-dimensional cable of ventricular cells, we identified the boundaries of the VP using paired (s1-s2) stimulation. We explored VP alterations associated with different NaLOF scenarios including reduced channel density, accelerated rate of inactivation, and prolonged recovery from inactivation. RESULTS: Following the passage of a wave over the s2 site, a gradient in the restoration of Na channel conductance was demonstrated to exist during the VP. The VP boundaries coincided with different thresholds for stable retrograde and antegrade impulse propagation. Reducing channel density, accelerating inactivation and slowing the recovery from inactivation flattened the restoration gradient and extended the VP. VP extension was directly proportional to the time constant of Na channel recovery. CONCLUSIONS: Mutations that accelerate inactivation, slow recovery from inactivation, or reduce Na channel density flatten the restoration gradient within the VP which prolongs the VP and increases the probability that a premature impulse will initiate reentry. These studies define a new mechanism that links alterations in Na channel function with conditions that enable premature excitation to generate proarrhythmia and sudden death.