New aspects of vulnerability in heterogeneous models of ventricular wall and its modulation by loss of cardiac sodium channel function.

This numerical study quantified the vulnerable period (VP) in heterogeneous models of the cardiac ventricular wall and its modulation by loss of cardiac sodium channel function (NaLOF). According to several articles, NaLOF prolongs the VP and therefore increases the risk of re-entrant arrhythmias, but the studies used uniform models, neglecting spatial variation of action potential duration (APD). Here, physiological transmural heterogeneity was introduced into one-dimensional cables of the Luo-Rudy model cells. Based on the results with paired S1-S2 stimulation, a generalised formula for the VP was proposed that takes into account APD dispersion, and new phenomena pertaining to the VP are described that are not present in homogeneous excitable media. Under normal conditions, the vulnerable period in the heterogeneous cable with M cells was in the range of 0-21 ms, depending on S2 localisation, but only 2.4 ms throughout the uniform fibre. Unidirectional propagation induced during the VP could be antegrade or retrograde, depending on the localisation of the test stimulus and cable parameters, but, in a uniform model, it was always in the retrograde direction. Reduced sodium channel conductance from control 16 mS microF(-1) to 4 mS microF(-1) decreased the maximum VP to 11 ms in the heterogeneous cable, but increased the VP to 3 ms in the homogeneous model. It was concluded that realistic models of cardiac vulnerability should take into account spatial variations of cellular refractoriness. Several new qualitative and quantitative aspects of the VP were revealed, and the modulation of the VP by NaLOF differed significantly in heterogeneous and homogeneous models.