Arrhythmogenic right ventricular cardiomyopathy: considerations from in silico experiments

Abstract

Objective: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with remodeling of gap junctions and also, although less well-defined, down-regulation of the fast sodium current. The gap junction remodeling and down-regulation of sodium current have been proposed as contributors to arrhythmogenesis in ARVC by slowing conduction. The objective of the present study was to assess the amount of conduction slowing due to the observed gap junction remodeling and down-regulation of sodium current.

Methods: The effects of (changes in) gap junctional conductance, cell dimensions, and sodium current on both longitudinal and transversal conduction velocity were tested by simulating action potential propagation in linear strands of human ventricular cells that were either arranged end-to-end or side-by-side.

Results: A 50% reduction in gap junction content, as commonly observed in ARVC, gives rise to an 11% decrease in longitudinal conduction velocity and a 29% decrease in transverse conduction velocity. A down-regulation of the sodium current through a 50% decrease in peak current density as well as a -15 mV shift in steady-state inactivation, as observed in an experimental model of ARVC, decreases conduction velocity in either direction by 32%. In combination, the gap junction remodeling and down-regulation of sodium current result in a 40% decrease in longitudinal conduction velocity and a 52% decrease in transverse conduction velocity.

Conclusion: The gap junction remodeling and down-regulation of sodium current do result in conduction slowing, but heterogeneity of gap junction remodeling, in combination with down-regulation of sodium current, rather than gap junction remodeling per se may be a critical factor in arrhythmogenesis in ARVC.

Keywords: arrhythmogenic right ventricular cardiomyopathy; cardiac arrhythmias; cardiac electrophysiology; cardiac myocytes; computer simulations; connexin43; gap junctions; sodium channels.

Figure 1

Diagram of linear strand model. The strand is composed of 90 human ventricular cells, coupled by an ohmic gap junctional conductance g_j. Myoplasmic resistivity is set to 150 Ω cm. Action potential propagation is initiated by applying an external stimulus to the leftmost cell of the strand. (A) Cells arranged longitudinally. (B) Cells arranged transversally.

Figure 2

Relation between conduction velocity and gap junctional conductance for the strands of Figure 1.

Figure 3

Relation between gap junctional resistivity and gap junctional conductance for longitudinal (circles) or transverse arrangement of cells (squares). (A) Gap junctional resistivity in Ω·cm. Dashed horizontal line indicates the myoplasmic resistivity of 150 Ω cm. Note logarithmic ordinate scale. (B) Gap junctional resistivity expressed as percent of total resistivity.

Figure 4

Effect of changes in cell dimensions on conduction velocity. (A,B) Effect of 50% increase in cell length on (A) longitudinal and (B) transverse conduction velocity. (C,D) Effect of 50% increase in cell width on (C) longitudinal and (D) transverse conduction velocity.

Figure 5

Dependence on myoplasmic resistivity (ρ_myo) of relationship between (A) longitudinal or (B) transverse conduction velocity and gap junctional conductance.

Figure 6

Effect of halving or doubling sodium current (I_Na) conductance on (A) longitudinal and (B) transverse conduction velocity.

Figure 7

Percent change in longitudinal (top) and transverse conduction velocity (bottom) upon −50% or +50% change in gap junctional conductance (g_j), cell length, cell width, myoplasmic resistivity (ρ_myo), or sodium current conductance (g_Na). (A) g_j = 2 μS. (B) g_j = 4 μS. (C) g_j = 8 μS. (D) g_j = 12 μS.

Figure 8

Effect of a 50% decrease in gap junctional conductance (labeled “g_j ↓”), a 50% decrease in sodium current conductance (“g_Na ↓”) or a −15 mV shift in the I_Na steady-state inactivation curve (“shift”), as implicated in ARVC, on (A) longitudinal and (B) transverse conduction velocity. Also shown are the combined effects of a 50% decrease in g_Na and a −15 mV shift (“g_Na ↓ and shift”) and the combined effects of a 50% decrease in g_j, a 50% decrease in g_Na and a −15 mV shift (“ARVC”).