Abstract
Background: The J-wave syndromes (JWS), comprised of Brugada (BrS) and early repolarization syndromes (ERS), increase the risk of life-threatening ventricular arrhythmias in patients resulting in sudden cardiac death. There are limited therapeutic strategies to treat these life-threatening conditions. Present management is via an implantable cardioverter defibrillator and/or medication, including quinidine. However, these treatments may have serious side-effects. Thus, novel therapies are needed to treat JWS. In this study, we investigate the effects of ARumenamide-787 (AR-787) in suppressing the electrocardiographic and arrhythmic manifestations of JWS and hypothermia. Methods: We studied the effects of AR-787 on sodium current (I Na ) and the delayed-rectifier potassium current (I Kr ) in HEK-293 cells stably expressing the α- and β1-subunits of the cardiac (Na V 1.5) sodium channel or the hERG channel. In addition, we studied its effect on the transient outward potassium current (I to ) and calcium current (I Ca ) from dissociated canine ventricular myocytes, along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The I to agonist, NS5806, I Ca blocker, verapamil, and sodium current (I Na ) blocker, ajmaline, to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves/ST segment elevation, phase 2 reentry, and polymorphic VT/VF) in right and left canine ventricular wedge preparations. Results: AR-787 exerted pleiotropic effects on the cardiac ion channels. The predominant effect was an inhibition of I to and enhancement of I Na , with subtle effects to inhibit the I Kr and augment I Ca . AR-787 diminished the electrocardiographic J wave and prevented and/or suppressed all arrhythmic activity in canine RV and LV experimental models of BrS, ERS and hypothermia. We observed no arrhythmogenic effects of AR-787 on I Kr . Conclusions: Our findings point to AR-787 as a promising candidate for the pharmacologic treatment of JWS and hypothermia. AR-787 suppresses the electrocardiographic and arrhythmic manifestations of JWS and hypothermia without significant prolongation of the QT interval, as with the classic BrS drug, quinidine.
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