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Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype.

Drug-induced delayed cardiac repolarization is a recognized risk factor for proarrhythmia and is associated with block of IKr(the potassium current encoded by the human ether-a- go-go-relatedgene hERG). To evaluate the utility of 2 in vitroassays widely used to assess delayed repolarization, we compared the effects of haloperidol and 9 structurally diverse drugs in a hERG and repolarization (canine Purkinje fiber action potential duration APD) assay over wide concentrations. Despite potent hERG current block (IC500.174 M), haloperidol elicited a bell-shaped concentration–response relationship for APD prolongation, with lesser prolongation (and reduced plateau height) observed with concentrations eliciting maximal hERG block, consistent with multi-channel block at higher concentrations. Consistent with this hypothesis, APD prolongation with the specific IKrblocker dofetilide was a) reduced by concomitant administration of nifedipine (calcium current block) and b) reversed by lidocaine (late sodium current block). Additional studies demonstrated prominent (>50) hERG inhibition with most (9/10) drugs despite wide APD changes (158 prolongation − 16 shortening), consistent with multi-channel block. The poor correlation between hERG and repolarization assays suggests that the hERG assay oversimplifies drug effects on the complex repolarization process for drugs demonstrating multi-channel block and that neither assay alone adequately predicts proarrhythmic risk.

Torsade de pointes is a rare but potentially fatal ventricular arrhythmia associated with drug-induced delayed repolarization and prolongation of the QT interval. To determine if the arrhythmogenic potential of noncardiac drugs can be assessed in vitro, we evaluated the effects of 12 drugs on the action potential duration (APD) of cardiac Purkinje fibers and compared results with clinical observations. APD changes in canine and porcine fibers were evaluated under physiologic conditions (37°C, K04 m M) using standard microelectrode techniques. Six of seven drugs associated with QT prolongation or torsade de pointes in man (cisapride, erythromycin, grepafloxacin, moxifloxacin, sertindole, and sotalol) affected concentration-dependent prolongation of the APD in canine fibers during slow stimulation (2-s basic cycle length), attaining greater than 15 prolongation at high concentrations (≥10-fold clinically encountered plasma levels). Each of five drugs not linked clinically to QT prolongation and torsade de pointes (azithromycin, enalaprilat, fluoxetine, indomethacin, and pinacidil) failed to attain 15 prolongation, with fluoxetine, indomethacin, and pinacidil abbreviating the APD. Drugs eliciting the greatest prolongation also demonstrated prominent reverse rate-dependent effects. The antihistamine terfenadine (linked to dose-dependent QT prolongation and torsade de pointes clinically) only minimally prolonged the APD in canine and porcine fibers (and exerted no effect on midmyocardial fibers from left ventricular free wall) at supratherapeutic concentrations. On the basis of concentration-dependent APD prolongation and reverse rate-dependent effects, this Purkinje fiber model detects six of seven drugs linked clinically to acquired long QT syndrome and torsade de pointes, and clears each of five drugs not associated with repolarization abnormalities (overall 92 accuracy), validating the utility of this Purkinje fiber model in the preclinical evaluation of QT prolongation and proarrhythmic risk by noncardiac drugs.

Introduction:Initial reports of hypertrophic growth in cultured cardiac myocytes exposed to the cardiotonic steroid (CTS) ouabain have led to the discovery of non-ion pumping functions served by the ?-isoforms of the CTS receptor Na/K-ATPase (NKA). There is compelling evidence that NKA ?1, encoded by ATP1A1, modulates cardiac remodeling and resilience through its receptor function. However, establishing the isoform-specific role of NKA ?1 in the proposed resilience pathway has been complicated by the promiscuous nature of key modulators such as Na+or reactive oxygen species (ROS), and the lack of NKA isoform selectivity of most exogenous and endogenous CTS.Hypothesis:This study challenged the role of NKA ?1 in cardiac resilience by exposing 16 week-old male mice with genetic alterations of ATP1A1 to a pressor dose of angiotensin II (Ang-II, 1.5 mg.kg-1. d-1for 14 days).Methods & Results:Five to eight mice/genotype/treatment group were used. In mice with a mutation of Atp1a1 to increase NKA ?1 affinity for CTS (NKA ?1 receptor gain-of-function model), the expected increase in NKA ?1 affinity for ouabain and activation of the endogenous CTS/Src/ROS were detected biochemically, with no change in cardiac structure or function. Compared to wild-type littermates, Ang-II induced adverse remodeling was significantly reduced in the Atp1a1 gain-of-function mutant as measured by heart weight/tibia length ratios (110?2 vs 136?9 % increase, P<0.05), myocyte cross-sectional areas (479?17 vs 525?7?m2, P<0.05), and fibrosis evaluated by trichrome staining (3.3?0.3 vs 5.6?0.4 % area, P<0.05). In contrast, cardiac resilience was drastically reduced in a cardiac-specific loss-of-function model obtained by Myh6-Cre-mediated ablation of Atp1a1. Fifty % mortality was observed in the loss-of-function mutant after only 8 days of treatment, while all wild-type littermates survived up to 14 days. Mechanistically, morphometric and histological analyses revealed that myocyte hypertrophic growth did not occur in response to Ang II in the absence of Atp1a1, while the fibrotic response was exacerbated.Conclusion:The contrasting outcomes observed in these two models provide a genetic evidence for the fundamental role of NKA ?1 receptor function in cardiac resilience.