June 8, 2023

Targeting calcium handling in A-fib

The drug ent-verticilide reduced A-fib incidence and duration in an animal model, suggesting it may be a viable therapeutic option.

Atrial fibrillation (A-fib) — the most common cardiac arrhythmia (irregular heartbeat) — is associated with increased risk of stroke, heart failure, dementia and death. Antiarrhythmic drug therapy to prevent A-fib has remained elusive. 

The strongest genetic risk factors for A-fib in humans are variants in a chromosomal region including the gene Pitx2. Mice with Pitx2 deficiency have increased A-fib susceptibility, making them a good model for studying A-fib biology and potential therapeutics. 

Björn Knollmann, MD, PhD, and colleagues found that the ryanodine receptor (RyR2) inhibitor ent-verticilide reduced spontaneous calcium release in isolated atrial cells from Pitx2-deficient mice and reduced A-fib incidence and duration in vivo. 

The findings reported in the Journal of Molecular and Cellular Cardiology support the hypothesis that RyR2 hyperactivity, which causes abnormal intracellular calcium handling, increases susceptibility to A-fib. Therapeutic targeting of hyperactive RyR2 using ent-verticilide may be a viable option to treat A-fib caused by Pitx2 deficiency, the authors note.

Co-authors of the study included Kyungsoo Kim, PhD, and Daniel Blackwell, PhD, in the Vanderbilt Center for Arrhythmia Research and Therapeutics, Madelaine Thorpe, and Jeffrey Johnston, PhD, in the Department of Chemistry at Vanderbilt, and Samantha Yuen, and Razvan Cornea, PhD, at the University of Minnesota. The research was supported in part by the National Institutes of Health (grants HL144980, HL151223, HL139065, HL1385390), PhRMA Foundation, American Heart Association, and Leducq Foundation.