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Background Chagas disease (CD) is a neglected disease that induces heart failure and arrhythmias in approximately 30% of patients during the chronic phase of the disease. Despite major efforts to understand the cellular pathophysiology of CD there are still relevant open questions to be addressed. In the present investigation we aimed to evaluate the contribution of the Na+/Ca2+ exchanger (NCX) in the electrical remodeling of isolated cardiomyocytes from an experimental murine model of chronic CD. Methodology/Principal findings Male C57BL/6 mice were infected with Colombian strain of Trypanosoma cruzi. Experiments were conducted in isolated left ventricular cardiomyocytes from mice 180–200 days post-infection and with age-matched controls. Whole-cell patch-clamp technique was used to measure cellular excitability and Real-time PCR for parasite detection. In current-clamp experiments, we found that action potential (AP) repolarization was prolonged in cardiomyocytes from chagasic mice paced at 0.2 and 1 Hz. After-depolarizations, both subthreshold and with spontaneous APs events, were more evident in the chronic phase of experimental CD. In voltage-clamp experiments, pause-induced spontaneous activity with the presence of diastolic transient inward current was enhanced in chagasic cardiomyocytes. AP waveform disturbances and diastolic transient inward current were largely attenuated in chagasic cardiomyocytes exposed to Ni2+ or SEA0400. Conclusions/Significance The present study is the first to describe NCX as a cellular arrhythmogenic substrate in chagasic cardiomyocytes. Our data suggest that NCX could be relevant to further understanding of arrhythmogenesis in the chronic phase of experimental CD and blocking NCX may be a new therapeutic strategy to treat arrhythmias in this condition.

Nav1.5-derived Na + current (I Na ) exerts a pivotal role in the depolarization phase of cardiomyocytes' action potential, and therefore, changes in I Na can contribute to fatal arrhythmias. Nav1.5 displays naturally occurring ethnic-related polymorphisms, which might alter the functioning and pharmacology of the channel. Some studies have shown how single nucleotide polymorphism can change the response to antiarrhythmic drugs. Investigations on the role of Nav1.5 in arrhythmogenesis, associated with its functional polymorphisms, are currently growing, as well as the possible variability in the antiarrhythmic pharmacotherapy among ethnic-groups. The influence of the ethnic-related polymorphisms (S524Y, S1103Y, R1193Q, V1951L) on the responsiveness, selectivity, and pharmacological efficacy of the clinically used antiarrhythmic, amiodarone (AMIO), is not completely known. Our objectives were to analyze biophysical and pharmacological aspects of four ethnic-related polymorphisms before and after exposure to AMIO. Polymorphisms caused reduced AMIO potency compared to wild-type (WT) that can vary up to 4x between them.AMIO shifted the voltage dependency for current inactivation, without significant effect in voltage-dependent activation to a similar extend in WT and polymorphisms.The recovery from inactivation was altered between the polymorphisms when compared to WT. Finally, the use-dependency of AMIO differed between studied groups, especially at a more depolarized cell membrane. Thus, our work may guide future studies focusing on the efficiency of AMIO in treating different arrhythmias and to establish more individualized guidelines for its use depending on the Nav1.5polymorphism, after validating our findings using in vivo studies.

β-Cyfluthrin, a class II Pyrethroid, is an insecticide used worldwide in agriculture, horticulture (field and protected crops), viticulture, and domestic applications. β-Cyfluthrin may impair the function of biological systems; however, little information is available about its potential cardiotoxic effect. Here, we explored the acute toxicity of β-Cyfluthrin in isolated heart preparations and its cellular basis, using isolated cardiomyocytes. Moreover, β-Cyfluthrin effects on the sodium current, especially late sodium current (INa-L), were investigated using HEK-293 cells transiently expressing human NaV1.5 channels. We report that β-Cyfluthrin raised INa-L in a dose-dependent manner. β-Cyfluthrin prolonged the repolarization of the action potential and triggered oscillations on its duration. Cardiomyocytes contraction and calcium dynamics were disrupted by the pesticide with a marked incidence of non-electronic stimulated contractions. The antiarrhythmic drug Ranolazine was able to reverse most of the phenotypes observed in isolated cells. Lastly, ventricular premature beats and long QT intervals were found during β-Cyfluthrin exposure, and Ranolazine was able to attenuate them. Overall, we demonstrated that β-Cyfluthrin can cause significant cardiac alterations and Ranolazine ameliorated the phenotype. Understanding the insecticides’ impacts upon electromechanical properties of the heart is important for the development of therapeutic approaches to treat cases of pesticides intoxication.

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