Methylmercury Poisoning Induces Cardiac Electrical Remodeling and Increases Arrhythmia Susceptibility and Mortality

Abstract

This study aims to investigate the cardiac electrical remodeling associated with intoxication by methylmercury (MeHg). We evaluated the chronic effects of MeHg on in vivo electrocardiograms and on ex vivo action potentials and depolarizing (I_Ca-L) and repolarizing (I_to) currents. The acute effect of MeHg was evaluated on HEK293 cells expressing human ERG, Kv4.3 and KCNQ1/KCNE1 channels. Chronic MeHg treatment increased QTc and T_peak-T_end interval duration, prolonged action potential duration and decreased amplitude of I_to and I_Ca-L. In addition, heterologously expressed I_hKv4.3, I_hERG or I_hKCNQ1/KCNE1 decreased after acute exposure to MeHg at subnanomolar range. The introduction of the in vitro effects of MeHg in a computer model of human ventricular action potentials triggered early afterdepolarizations and arrhythmia. In conclusion, cardiac electrical remodeling induced by MeHg poisoning is related to the reduction of I_to and I_Ca-L. The acute effect of MeHg on hKv4.3; hERG and hKCNQ1/KCNE1 currents and their transposition to in silico models show an association between MeHg intoxication and acquired Long QT Syndrome in humans. MeHg can exert its high toxicity either after chronic or acute exposure to concentrations as low as picomolar.

Keywords: arrhythmia; cardiac; electrical remodeling; ion current; mercury.

Figure 1

Chronic MeHg treatment prolongs cardiac repolarization in vivo. (A) Electrocardiograms of a conscious animal before and 4 weeks after treatment with MeHg 3 mg/kg·day (dashed lines show the QT interval). RR interval (B), QT interval, (C) heart rate corrected QT interval, QTc, (D) and repolarization dispersion, T_peak–T_end (E) were prolonged after MeHg treatment. n = 13 control and 15 MeHg-treated animals. * p < 0.05; ** p < 0.01.

Figure 2

MeHg prolongs ventricular action potential duration. (A) ventricular action potentials were recorded in epicardial strips from control and MeHg-treated animals; (B) action potential duration at 90% of repolarization (APD₉₀) and (C) action potential (AP) triangulation at different basic cycle length (BCL), in control (open symbols) or after 4 weeks of treatment with MeHg (filled symbols). * p < 0.05. n = 7 control and 14 MeHg-treated hearts per group.

Figure 3

MeHg treatment reduces the transient outward K⁺ and the L-type Ca²⁺ currents in ventricular myocytes. (A) I_Ca-L currents were recorded at voltages from −50 to +60 mV in ventricular myocytes isolated from animals after 4 weeks in control conditions or treated with MeHg. Current–voltage relationship obtained in myocytes from animals treated with vehicle (open symbols, n = 7) or with MeHg (filled symbols, n = 6). (B) I_to traces recorded at potentials between −50 and +60 mV in ventricular myocytes isolated from animals after 4 weeks in control conditions or treated with MeHg. Current–voltage relationship obtained in myocytes from animals treated with vehicle (open symbols, n = 18) or with MeHg (filled symbols, n = 14). ** p < 0.01.

Figure 4

MeHg reduces repolarization capability in human cells in vitro. Representative traces and average current density-voltage relationships obtained in HEK293 cells expressing (A) Kv4.3 channels, (B) hERG channels, or (C) Kv7.1/KCNE1 channels. MeHg acute exposure reduces all currents in a concentration dependent manner. n = 8–15 cells. * p < 0.05; ** p < 0.01.

Figure 5

Modeling the effects of acute MeHg-induced changes in ion currents on human ventricular action potential. Computational models were generated to simulate action potential of 100 control individuals in resting conditions and under β-adrenergic stimulation. For clarity, only the first 15 traces are shown. When the ionic conductances were changed to simulate the effects of 0.01 nM MeHg AP duration increases in resting conditions, but after β-adrenergic stimulation, 33% of action potentials generated early afterdepolarizations and arrhythmia. When the ionic conductances were changed to simulate the effects of 0.1 nM MeHg 98% models showed early afterdepolarizations (EADs) and arrhythmia in resting conditions and 100% after β-adrenergic stimulation.