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Background: The three-ringed polycyclic aromatic hydrocarbon (PAH) phenanthrene (Phe) has been implicated in the cardiotoxicity of petroleum-based pollution in aquatic systems, where it disrupts the contractile and electrical function of the fish heart. Phe is also found adsorbed to particulate matter and in the gas phase of air pollution, but to date, no studies have investigated the impact of Phe on mammalian cardiac function. Objectives: Our objectives were to determine the arrhythmogenic potential of acute Phe exposure on mammalian cardiac function and define the underlying mechanisms to provide insight into the toxicity risk to humans. Methods: Ex vivo Langendorff-perfused mouse hearts were used to test the arrhythmogenic potential of Phe on myocardial function, and voltageand current-clamp recordings were used to define underlying cellular mechanisms in isolated cardiomyocytes. Results: Mouse hearts exposed to ~8 [micro]M Phe for 15-min exhibited a significantly slower heart rate (p = 0.0006, N =10 hearts), a prolonged PR interval (p = 0.036, N = 8 hearts), and a slower conduction velocity (p = 0.0143, N = 7 hearts). Whole-cell recordings from isolated cardiomyocytes revealed action potential (AP) duration prolongation (at 80% repolarization; p = 0.0408, n = 9 cells) and inhibition of key murine repolarizing currents-transient outward potassium current ([I.sub.to]) and ultrarapid potassium current ([I.sub.Kur])--following Phe exposure. A significant reduction in AP upstroke velocity (p = 0.0445, n = 9 cells) and inhibition of the fast sodium current ([I.sub.Na]; p = 0.001, n = 8 cells) and calcium current ([I.sub.Ca]; p = 0.0001) were also observed, explaining the slowed conduction velocity in intact hearts. Finally, acute exposure to ~8 [micro]M Phe significantly increased susceptibility to arrhythmias (p = 0.0455, N = 9 hearts). Discussion: To the best of our knowledge, this is the first evidence of direct inhibitory effects of Phe on mammalian cardiac electrical activity at both the whole-heart and cell levels. This electrical dysfunction manifested as an increase in arrhythmia susceptibility due to impairment of both conduction and repolarization. Similar effects in humans could have serious health consequences, warranting greater regulatory attention and toxicological investigation into this ubiquitous PAH pollutant generated from fossil-fuel combustion. https://doi.org/10.1289/EHP12775, Introduction Air pollution is one of the leading risk factors for global disease burden, (1-7) and accounts for an estimated 6.7 million premature deaths each year worldwide. (8) With 99% [...]

Cavutilide (niferidil, refralon) is a new class III antiarrhythmic drug which effectively terminates persistent atrial fibrillation (AF; 84.6% of patients, mean AF duration 3 months) and demonstrates low risk of torsade de pointes (1.7%). ERG channels of rapid delayed rectifier current(IKr) are the primary target of cavutilide, but the particular reasons of higher effectiveness and lower proarrhythmic risk in comparison with other class III IKr blockers are unclear. The inhibition of hERG channels expressed in CHO-K1 cells by cavutilide was studied using whole-cell patch-clamp. The present study demonstrates high sensitivity of IhERG expressed in CHO-K1 cells to cavutilide (IC50 = 12.8 nM). Similarly to methanesulfonanilide class III agents, but unlike amiodarone and related drugs, cavutilide does not bind to hERG channels in their resting state. However, in contrast to dofetilide, cavutilide binds not only to opened, but also to inactivated channels. Moreover, at positive constantly set membrane potential (+ 60 mV) inhibition of IhERG by 100 nM cavutilide develops faster than at 0 mV and, especially, − 30 mV (τ of inhibition was 78.8, 103, and 153 ms, respectively). Thereby, cavutilide produces IhERG inhibition only when the cell is depolarized. During the same period of time, cavutilide produces greater block of IhERG when the cell is depolarized with 2 Hz frequency, if compared to 0.2 Hz. We suggest that, during the limited time after injection, cavutilide produces stronger inhibition of IKr in fibrillating atrium than in non-fibrillating ventricle. This leads to beneficial combination of antiarrhythmic effectiveness and low proarrhythmicity of cavutilide. [ABSTRACT FROM AUTHOR]