Carbon Monoxide Effects on Electrophysiological Mechanisms of Ventricular Arrhythmogenesis

Moza Al-Owais, Arun Holden, Chris Peers, Derek Steele, Alan Benson
University of Leeds


Abstract

Background.: Carbon monoxide (CO) has both pro- (air exposure) and anti-arrhythmic (on reperfusion induced VF post MI) effects in humans. In rat and guinea pig ventricular myocytes increased CO decreases L-type Ca: 44.5 ± 8.3; Na 53.4 ± 7.7; IK1 34.4±4.3; IKr 43.5 ±2.3 and increase Na-late currents 105 ± 31.1% under patch clamp. CO prolongs cell action potential durations, decreases AP amplitudes and leads to early after depolarisations. Methods.: Cell models and tissue models were solved with a space step of 0.2mm, an adaptive time step of 0.01ms - 0.25ms. Model conductance parameters were Gaussian distributed with a 5% standard deviation, and for CO with a changed mean and standard deviation from the values above, with N=10000. Results: The effects of CO on rat and guinea pig ventricular action potentials are reproduced by scaling the currents in the Gattoni et al., 2016 (rat) and Luo and Rudy, 1994 (guinea cell models). For the O’Hara et al, 2011 (human) models the endo-, epicardial APD90 is prolonged from 267.5±8.7, 234.7±7.3 to 387.6±17.9, 335.7±12.3ms for the CO effects on all ion channels, on IKr only to 362.5±13.9, 320.5±11.2 , or IKr in combination with peak and late Na currents to 407.0± 334.0±11.1 ms at BCL of 1000ms. CO abolishes alternans in endo-, and induces alternans in epicardial cell models . In the homogenous human ventricular tissue models these CO effects decrease epi-, endocardial conduction velocities from 0.4 to 0.32m/s, and increase vulnerable windows +9%,+8% . In the ventricular wall model (a third each of endo-,midmyo- and epicardial ) CO increased transmural propagation times from 44 to 55 ms and maximal difference in propagating APD from 68 to 73 ms.
Conclusion. :The computed effects of CO on human ventricular tissue are pro-arrhythmogenic.