Ryanodine receptor inhibition with acute dantrolene treatment reduces arrhythmia susceptibility in human hearts

Am J Physiol Heart Circ Physiol. 2023 Oct 1;325(4):H720-H728. doi: 10.1152/ajpheart.00103.2023. Epub 2023 Aug 11.

Abstract

Ryanodine receptor 2 (RyR2) hyperactivity is observed in structural heart diseases that are a result of ischemia or heart failure. It causes abnormal calcium handling and calcium leaks that cause metabolic, electrical, and mechanical dysfunction, which can trigger arrhythmias. Here, we tested the antiarrhythmic potential of dantrolene (RyR inhibitor) in human hearts. Human hearts not used in transplantation were obtained, and right ventricular outflow tract (RVOT) wedges and left ventricular (LV) slices were prepared. Pseudo-ECGs were recorded to determine premature ventricular contraction (PVC) incidences. Optical mapping was performed to determine arrhythmogenic substrates. After baseline optical recordings, tissues were treated with 1) isoproterenol (250 nM), 2) caffeine (200 mM), and 3) dantrolene (2 or 10 mM). Optical recordings were obtained after each treatment. Isoproterenol and caffeine treatment increased PVC incidence, whereas dantrolene reduced the PVC burden. Isoproterenol shortened action potential duration (APD) in the RV, RVOT, and LV regions and shortened calcium transient duration (CaTD) in the LV. Caffeine further shortened APD in the RV, did not modulate APD in the RVOT, and prolonged APD in the LV. In addition, in the LV, CaTD prolongation was also observed. More importantly, adding dantrolene did not alter APD in the RV or RVOT regions but produced a trend toward APD prolongation and significant CaTD prolongation in the LV, restoring these parameters to baseline values. In conclusions, dantrolene treatment suppresses triggers and reverses arrhythmogenic substrates in the human heart and could be a novel antiarrhythmic therapy in patients with structural heart disease.NEW & NOTEWORTHY Ryanodine receptor 2 hyperactivity is observed in structural heart diseases caused by ischemia or heart failure. It causes abnormal calcium leaks, which can trigger arrhythmias. To prevent arrhythmias, we applied dantrolene in human hearts ex vivo. Isoproterenol and caffeine treatment increased PVC incidence, whereas dantrolene reduced the PVC burden. Dantrolene treatment suppresses triggers and reverses arrhythmogenic substrates and could be a novel antiarrhythmic therapy in patients with structural heart disease.

Keywords: arrhythmia; heart failure; infarction; optical mapping; ryanodine receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Anti-Arrhythmia Agents / pharmacology
  • Arrhythmias, Cardiac / drug therapy
  • Caffeine / pharmacology
  • Calcium / metabolism
  • Dantrolene / pharmacology
  • Heart Failure*
  • Humans
  • Isoproterenol / pharmacology
  • Ryanodine / pharmacology
  • Ryanodine Receptor Calcium Release Channel* / metabolism

Substances

  • Ryanodine Receptor Calcium Release Channel
  • Dantrolene
  • Isoproterenol
  • Ryanodine
  • Calcium
  • Caffeine
  • Anti-Arrhythmia Agents