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

Figures

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  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, Tpeak–Tend (E) were prolonged after MeHg treatment. n = 13 control and 15 MeHg-treated animals. * p < 0.05; ** p < 0.01.

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  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.

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  Figure 3. MeHg treatment reduces the transient outward K+ and the L-type Ca2+ currents in ventricular myocytes. (A) ICa-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) Ito 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.

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  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.

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  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.