Mechanisms underlying the antiarrhythmic effect of ARumenamide-787 in experimental models of the J wave syndromes and hypothermia

PLoS One. 2023 May 9;18(5):e0281977. doi: 10.1371/journal.pone.0281977. eCollection 2023.


Background: Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia.

Methods: We studied the effects of AR-787 on INa and IKr in HEK-293 cells stably expressing the α- and β1-subunits of the cardiac (NaV1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on Ito, INa and ICa in dissociated canine ventricular myocytes along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The Ito agonist, NS5806 (5-10 μM), ICa blocker, verapamil (2.5 μM), and INa blocker, ajmaline (2.5 μM), were used to mimic the genetic defects associated with JWS and to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves/ST segment elevation, phase 2 reentry and polymorphic VT/VF) in canine ventricular wedge preparations.

Results: AR-787 (1, 10 and 50 μM) exerted pleiotropic effects on cardiac ion channels. The predominant effect was inhibition of the transient outward current (Ito) and enhancement of the sodium channel current (INa), with lesser effects to inhibit IKr and augment calcium channel current (ICa). 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.

Conclusions: Our findings point to AR-787 as promising candidate for the pharmacologic treatment of JWS and hypothermia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Anti-Arrhythmia Agents / therapeutic use
  • Arrhythmias, Cardiac / drug therapy
  • Dogs
  • HEK293 Cells
  • Humans
  • Hypothermia*
  • Myocytes, Cardiac
  • Syndrome


  • Anti-Arrhythmia Agents

Grants and funding

Supported by National Institutes of Health grants HL47678, HL138103, HL152201 to CA, W.W. Smith Trust to CA and the Wistar and Martha Morris Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.