Probenecid Improves Cardiac Function in Subjects with a Fontan Circulation and Augments Cardiomyocyte Calcium Homeostasis.

Abstract

Subjects with functionally univentricular circulation who have completed staged single ventricle palliation, with the final stage culminating in the Fontan procedure, are often living into adulthood. However, high morbidity and mortality remain prevalent in these patients, as diastolic and systolic dysfunction of the single systemic ventricle are linked to Fontan circulatory failure. We presently investigated the effects of probenecid in post-Fontan patients. Used for decades for the treatment of gout, probenecid has been shown in recent years to positively influence cardiac function via effects on the Transient Receptor Potential Vanilloid 2 (TRPV2) channel in cardiomyocytes. Indeed, we observed that probenecid improved cardiac function and exercise performance in patients with a functionally univentricular circulation. This was consistent with our findings from a retrospective cohort of patients with single ventricle physiology where TRPV2 expression was increased. Experiments in isolated cardiomyocytes associated these positive actions to augmentation of diastolic calcium homeostasis.

• Authors: Jack Rubinstein, Jessica G Woo, Anastacia M Garcia, Tarek Alsaied, Jia Li, Per Kristian Lunde, Ryan A Moore, Martin Laasmaa, Amanda Sammons, Wayne A Mays, Shelley D Miyamoto, William E Louch, Gruschen R Veldtman
• Journal: Pediatric cardiology (Pediatr Cardiol) Vol. 41 Issue 8 Pg. 1675-1688 (Dec 2020) ISSN: 1432-1971 [Electronic] United States
• PMID: 32770262 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Calcium Channel Agonists
• TRPV Cation Channels
• TRPV2 protein, human
• Probenecid
• Calcium

Topics

• Administration, Oral
• Adolescent
• Adult
• Calcium (metabolism)
• Calcium Channel Agonists (therapeutic use)
• Child
• Exercise Test
• Female
• Fontan Procedure (methods)
• Heart Defects, Congenital (drug therapy, surgery)
• Heart Ventricles (abnormalities, surgery)
• Homeostasis (drug effects)
• Humans
• Male
• Myocytes, Cardiac (drug effects, metabolism)
• Probenecid (therapeutic use)
• Retrospective Studies
• TRPV Cation Channels (metabolism)
• Treatment Outcome
• Young Adult