Probenecid Improves Cardiac Function in Subjects with a Fontan Circulation and Augments Cardiomyocyte Calcium Homeostasis
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...
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| Published in | Pediatric cardiology Vol. 41; no. 8; pp. 1675 - 1688 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Springer US
01.12.2020
Springer |
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| Online Access | Get full text |
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| 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. |
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| AbstractList | 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. 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.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. |
| Audience | Academic |
| Author | Woo, Jessica G. Garcia, Anastacia M. Miyamoto, Shelley D. Moore, Ryan A. Veldtman, Gruschen R. Lunde, Per Kristian Alsaied, Tarek Li, Jia Sammons, Amanda Rubinstein, Jack Laasmaa, Martin Mays, Wayne A. Louch, William E. |
| AuthorAffiliation | 1 Department of Internal Medicine, Division of Cardiovascular Health & Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio USA 6 Adult Congenital Heart Disease Service, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia 5 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K. G. Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway 3 Department of Pediatrics, Division of Cardiology, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, CO 4 The Heart Institute, Cincinnati Children’s Hospital Medical Center. Department of Pediatrics, University of Cincinnati College of Medicine 2 Department of Pediatrics, University of Cincinnati College of Medicine; Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center |
| AuthorAffiliation_xml | – name: 1 Department of Internal Medicine, Division of Cardiovascular Health & Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio USA – name: 5 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K. G. Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway – name: 4 The Heart Institute, Cincinnati Children’s Hospital Medical Center. Department of Pediatrics, University of Cincinnati College of Medicine – name: 6 Adult Congenital Heart Disease Service, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia – name: 2 Department of Pediatrics, University of Cincinnati College of Medicine; Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center – name: 3 Department of Pediatrics, Division of Cardiology, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, CO |
| Author_xml | – sequence: 1 givenname: Jack orcidid: 0000-0002-8811-1551 surname: Rubinstein fullname: Rubinstein, Jack email: rubinsjk@ucmail.uc.edu organization: Department of Internal Medicine, Division of Cardiovascular Health & Disease, University of Cincinnati College of Medicine – sequence: 2 givenname: Jessica G. surname: Woo fullname: Woo, Jessica G. organization: Department of Pediatrics, University of Cincinnati College of Medicine, Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center – sequence: 3 givenname: Anastacia M. surname: Garcia fullname: Garcia, Anastacia M. organization: Department of Pediatrics, Division of Cardiology, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus – sequence: 4 givenname: Tarek surname: Alsaied fullname: Alsaied, Tarek organization: Department of Pediatrics, University of Cincinnati College of Medicine, The Heart Institute, Cincinnati Children’s Hospital Medical Center – sequence: 5 givenname: Jia surname: Li fullname: Li, Jia organization: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, K. G. Jebsen Cardiac Research Center, University of Oslo – sequence: 6 givenname: Per Kristian surname: Lunde fullname: Lunde, Per Kristian organization: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, K. G. Jebsen Cardiac Research Center, University of Oslo – sequence: 7 givenname: Ryan A. surname: Moore fullname: Moore, Ryan A. organization: Department of Pediatrics, University of Cincinnati College of Medicine, The Heart Institute, Cincinnati Children’s Hospital Medical Center – sequence: 8 givenname: Martin surname: Laasmaa fullname: Laasmaa, Martin organization: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, K. G. Jebsen Cardiac Research Center, University of Oslo – sequence: 9 givenname: Amanda surname: Sammons fullname: Sammons, Amanda organization: The Heart Institute, Cincinnati Children’s Hospital Medical Center – sequence: 10 givenname: Wayne A. surname: Mays fullname: Mays, Wayne A. organization: The Heart Institute, Cincinnati Children’s Hospital Medical Center – sequence: 11 givenname: Shelley D. surname: Miyamoto fullname: Miyamoto, Shelley D. organization: Department of Pediatrics, Division of Cardiology, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus – sequence: 12 givenname: William E. surname: Louch fullname: Louch, William E. organization: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, K. G. Jebsen Cardiac Research Center, University of Oslo – sequence: 13 givenname: Gruschen R. surname: Veldtman fullname: Veldtman, Gruschen R. organization: Adult Congenital Heart Disease Service, King Faisal Specialist Hospital and Research Centre |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32770262$$D View this record in MEDLINE/PubMed |
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| Keywords | TRPV2 Congenital heart disease Fontan procedure Univentricular circulation Probenecid |
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| SubjectTerms | Administration, Oral Adolescent Adult Calcium - metabolism Calcium Channel Agonists - therapeutic use Cardiac Surgery Cardiology Child Exercise Test Female Fontan Procedure - methods Health aspects Heart Heart Defects, Congenital - drug therapy Heart Defects, Congenital - surgery Heart Ventricles - abnormalities Heart Ventricles - surgery Homeostasis Homeostasis - drug effects Humans Male Medical colleges Medical research Medicine Medicine & Public Health Medicine, Experimental Mortality Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Original Article Physiological aspects Probenecid Probenecid - therapeutic use Retrospective Studies Treatment Outcome TRPV Cation Channels - metabolism Vascular Surgery Young Adult |
| Title | Probenecid Improves Cardiac Function in Subjects with a Fontan Circulation and Augments Cardiomyocyte Calcium Homeostasis |
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