Abstract
Chronic exposure to low levels of Carbon Monoxide is associated with an increased risk of cardiac arrhythmia. Microelectrode recordings from rat and guinea pig single isolated ventricular myocytes exposed to CO releasing molecule CORM-2 and excited at 0.2/s show repolarisation changes that develop over hundreds of seconds: action potential prolongation by delayed repolarisation, EADs, multiple EADs and oscillations around the plateau, leading to irreversible repolarisation failure. The measured direct effects of CO on currents in these cells, and ion channels expressed in mammalian systems showed an increase in prolonged late Na+, and a decrease in the maximal T- and L-type Ca++. peak and late Na+, ultra-rapid delayed, delayed rectifier, and the inward rectifier K+ currents. Incorporation of these CO induced changes in maximal currents in ventricular cell models; (Gattoni et al., J. Physiol., 2016, 594, 4193–4224) (rat) and (Luo and Rudy, Circ. Res., 1994, 74, 1071–1096) (guinea-pig) and human endo-, mid-myo- and epi-cardial (O’Hara et al., PLoS Comput. Biol., 2011, 7, e1002061) models, by changes in maximal ionic conductance reproduces these repolarisation abnormalities. Simulations of cell populations with Gaussian distributions of maximal conductance parameters predict a CO induced increase in APD and its variability. Incorporation of these predicted CO induced conductance changes in human ventricular cell electrophysiology into ventricular tissue and wall models give changes in indices for the probability of the initiation of re-entrant arrhythmia.
Highlights
Carbon monoxide (CO) is a clear, odourless gas, exposure to which presents significant health risks (Sjostrand, 1970)
Following CO perfusion via CORM-2, the action potential duration (APD) lengthen progressively, doubling over 50 s, (Figure 1A). dV/dtmax decreases linearly with time, from 110 to 50 V/s, the peak-topeak amplitude decreases by 7 mV and the latency increases by 2.3 ms over 90 s (Figure 1A,B)
The stationarity of the APDs for over 200 s, before CORM-2 was applied, suggests that the slow increase in APDs seen after switching was a response to the CO perfusion and not the result of the prolonged period of pacing (Figures 1B,C)
Summary
Carbon monoxide (CO) is a clear, odourless gas, exposure to which presents significant health risks (Sjostrand, 1970). Environmental CO, generated for example, by the incomplete combustion of hydrocarbons found in engine exhaust fumes or by malfunctioning gas appliances, has significant toxicity, with acute CO poisoning accounting for greater than half of all fatal poisonings each year (Varon et al, 1999; Reumuth et al, 2019; Kinoshita et al, 2020). As CO demonstrates a far greater affinity for haemoglobin than oxygen, acute exposure can lead to hypoxia (Von Burg, 1999) and an associated increased risk of sudden death (Gandini et al, 2001; Satran et al, 2005). Chronic exposure to CO, at a lower level may cause acute toxicity and can generate neurological and cardiovascular damage (Von Burg, 1999; Gandini et al, 2001; Omaye, 2002; Prockop and Chichkova, 2007).
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