TRPV2 Agonists in the Fontan Circulation
Condition: Fontan
Intervention: Probenecid; Placebo
Intervention description: This is a cross-over pilot study where participants will receive both the study medication (probenecid), as well as a placebo to see if the study medication improves magnetic resonance parameters of systolic and diastolic dysfunction that occurs in the Fontan population.; placebo
Intervention MeSH terms: Probenecid
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 8.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No

Summary:

      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.