TRPV2 Agonists in the Fontan Circulation

There are currently very few proven pharmacologic options available for these patients. The recent discovery of transient receptor potential vanilloid (TRPV) channels, particularly TRPV2 channels, in the cardiovascular system is promising as a potential pathway for pharmacologic intervention for Fontan patients. Probenecid, a drug best known as a treatment for gout or as a penicillin adjunct, acts as a TRPV2 agonist and has recently become the subject of study as a model therapy for the treatment of cardiomyopathy due to its positive inotropic and lusitropic effects. The purpose of this pilot study is to determine if probenecid will improve magnetic resonance (MRI) parameters of systolic and/or diastolic dysfunction as well as associated symptoms in patients with a Fontan circulation. The investigators will quantitatively assess functional improvement with pre- and post-treatment cardiopulmonary exercise testing.


Eligibility Criteria:
Inclusion Criteria:

1. ≥ 12 years old
2. Single ventricle congenital heart disease status post Fontan procedure.
3. Impaired ventricular function as assessed by preexisting echocardiographic studies and any available MRI studies.

   1. LV inclusion criteria: Ejection fraction by cMRI or echo assessment of \<50% or moderate to severe dysfunction.
   2. RV inclusion criteria: Ejection fraction by cMRI of \<45% or moderate to severe dysfunction. Or, given the ASE recommendation to avoid use of 2-D imaging quantification for assessment of right ventricular systolic function, a peak global longitudinal strain value as assessed by a single reviewer with a value greater than -17% will also be included. Peak global longitudinal strain analysis will be performed for all eligible single right ventricles noted by subjective echo reports to have abnormal systolic function if no qualifying cardiac MRI assessment of ejection fraction is available.

Exclusion Criteria:

1. Clinically unstable or ongoing illness.
2. Evidence of untreated Fontan pathway obstruction.
3. Presence of uncontrolled arrhythmias.
4. Evidence of moderate or greater atrioventricular valve regurgitation.
5. Pregnancy.
6. History of sulfonamide allergy
7. Known G6PD deficiency
8. Patients on certain drugs that have potentially dangerous interactions with probenecid: doripenem, zalcitabine, deferiperone, citalopram, methotrexate, ciprofloxacin, amoxicillin, cefprozil, cefpodoxime, cefotaxime, meropenem, ertapenem, valganciclovir, ganciclovir, ziovudine ketorolac, cefdinir, cephalexin, dapsone, indomethacin, and piperacillin.Each subject's medication list will be reviewed prior to study participation.
9. Impaired renal function as defined by a GFR \< 60mL/min/1.73 m2 within the last year.
10. Patients at a higher risk for arrhythmia including those with a prior history of arrhythmia including atrial and ventricular dysrhythmia or those on established anti-arrhythmic therapy.
11. Admission to the hospital due to a clinically significant arrhythmia within the previous month.
12. Greater than moderate atrioventricular regurgitation as denoted on most recent echo report.
13. Patients with atrio-pulmonary Fontan
14. Currently enrolled in an interventional drug trial or completed an interventional drug trial within the past 30 days.
15. Not appropriate for MRI screening due to having an implanted device.