A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias

Abstract

Cardiac sensitization is the term used for malignant ventricular arrhythmias associated with exposure to inhaled halocarbons in the presence of catecholamines. We investigated the electrophysiological changes associated with cardiomyocyte exposure to epinephrine and a halocarbon known to be associated with cardiac sensitization (halon 1301, CF 3 Br). Cardiomyocytes (CMs) were isolated from neonatal rats and grown on multielectrode arrays (MEAs). Upon exposure to epinephrine, the CM inter-spike interval (ISI) was decreased 14% at 10 µg/L (P<0.05) and 27% at 100 µg/L (P<0.05) as compared to baseline. Halon alone (50 mg/L) mildly prolonged the field potential (FP) duration (7%). CMs exposed to combinations of epinephrine (100 µg/L) and halon (50 mg/L) for 15 min showed a blunted increase in the ISI (35±12%) and a 38% decrease in conduction velocity (P<0.05) when compared to epinephrine alone. There was no change in field potential properties, but dephosphorylated connexin 43 (Cx43) was increased 60±16% with the combination as compared to epinephrine alone (P<0.05). Treatment with okadaic acid, a phosphatase inhibitor, prevented the Cx43 dephosphorylation and the reduction in conduction velocity upon exposure to halon and epinephrine. Moreover, the electrophysiological changes induced by epinephrine and halon were indistinguishable from those seen with the gap junction inhibitor heptanol. In conclusion, the combination of a halocarbon and epinephrine results in a unique electrophysiological signature including slow conduction that may explain, in part, the basis for cardiac sensitization. The slowing of conduction is most likely related to changes in the phosphorylation state of Cx43.

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“…CRL-1446), or acutely isolated neonatal rat heart cardiomyocytes were used. Rat neonatal ventricular cells were isolated from 3-day-old Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) using a kit and following the manufacturer's instructions (Worthington Biochemical, Lakewood, NJ) (22). Briefly, ventricles were isolated and minced in sterile calcium-and magnesium-free Hank's balanced salt solution (pH 7.4) and incubated with trypsin (50 g/ml) overnight at 4°C.…”

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“…15 Conduction velocity was calculated using the activation time at each point and a threshold-crossing algorithm to form an isochrone map. Three noncolinear points from an area with uniform, parallel isochrones were chosen to calculate conduction velocity in 2 orthogonal directions (eg, vx and vy).…”

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“…Invasive testing, such as electrophysiology studies, is not useful for making the diagnosis, although it may be useful to exclude the presence of a supraventricular tachycardia mechanism [11]. Several possible causes have been proposed, but none of them have been confirmed: autoantibodies to ganglionic acetylcholine receptor [11], anti-beta receptor immunoglobulin G antibodies [12], viral infection or toxin exposure as a trigger [13], an excess of hydrocarbon exposure or halogenated hydrocarbons which could sensitize the myocardium to catecholamines [14,15] but none of these have found enough proof to have any confirmation. To be noted that in one report, 100% of the patients with IST had some psychiatric diagnosis [16].…”