Fibrosis and the Fontan

The purpose of this study is to non-invasively characterize the fibrotic consequences of single ventricle physiology, its possible solution and effect on lymphatics. This project investigates the response to acute imposition of Fontan hemodynamics by examining the interrelationship between liver and cardiac fibrosis/dysfunction and lymphatic congestion along with a pilot trial of the antifibrotic agent, spironolactone, to prevent these consequences and to determine if MRI can discern these differences. The combination of serum biomarkers and MRI form a powerful non-invasive tool in putting together this complicated web of dysfunction.

Fontan patients, unfortunately, suffer multiple complications such as liver fibrosis, cardiac fibrosis and lymphatic congestion. While investigations describing the clinical state are taking place in older children and young adults, the onset of these complications remains unclear. The knowledge gap this proposal seeks to fill is understanding how early liver and cardiac fibrosis develops as well as lymphatic abnormalities by assessing these before as well as early after imposition of the Fontan circulation.

Single ventricle case subjects will be between aged 1 and less than or equal to 6 years of age of either gender, whether single left or right ventricle, who are scheduled to undergo a Fontan operation at the Children's Hospital of Philadelphia (CHOP) and control subjects will be aged between 1 and less than or equal to 6 years of age with normal ventricular function and normal livers who present to CHOP for a clinically indicated MRI.

Review of medical records, demographic/social history, physical examination (performed for clinical purposes), administer study drug (spironolactone), blood tests (serum biomarkers), MRI/CMR (including a non-FDA approved MRI sequence), liver assessment, administration of contrast and general anesthesia for case subjects (in some instances, an extension of clinically indicated anesthesia for control and some case subjects approximately 15-20 minutes) as applicable.

The difference between enrollment and 1 year after Fontan surgery for a) liver fibrosis measured by Magnetic Resonance Elastography (MRE) and T1 mapping, b) cardiac fibrosis measured by T1 mapping using global extracellular volume (ECV) and c) percentage of myocardial mass which demonstrates delayed enhancement (DE). This is for both non-drug and spironolactone administered groups

Eligibility Criteria:
Inclusion Criteria:

* Single Ventricle (SV) Patients

Cohort 1 (Observational Group - no study medication):

* Subjects between 1 and ≤ 6 years of age of either gender.
* Either single left or single right ventricle.
* Subjects who are scheduled to undergo a Fontan operation at CHOP.
* Parents signing informed consent.

Cohort 1A (formerly part of study drug group who wish continued participation in the observational group):

* Subjects who were enrolled in this study in Cohort 2 and are either non-compliant with the medication, no longer want to take the medication, or have an AE that requires them to stop the medication, and patient's family would like to continue participation
* Patients were on study medication for 6 weeks or less.
* The principal investigator deems it appropriate for the patient to switch to the observational arm.
* Patients signing the observational informed consent form.

Cohort 1B (observational group - in other studies with intervention):

* Subjects between 1 and ≤6 years of age of either gender.
* Either single left or single right ventricle.
* Subjects who are planned to undergo a Fontan operation at CHOP.
* Patients in other interventional studies approved by principal investigator.
* Patients signing the observational informed consent form.

Cohort 2 (study drug Group - spironolactone):

* Subjects between 1 and ≤ 6 years of age of either gender.
* Either single left or single right ventricle.
* Subjects who are scheduled to undergo a Fontan operation at CHOP.
* Parents signing informed consent.

Controls

* Subjects between 1 and ≤ 6 years of age of either gender
* Subjects with normal ventricular function and normal livers who present to CMR for clinical indications and require anesthesia.
* Receiving contrast for clinical purposes. No control patient will receive contrast for research purposes.
* Parents signing informed consent.

Exclusion Criteria:

-

Cohort 1 (Observational Group - no study medication):

* Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
* Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
* Patient currently taking spironolactone or eplerenone
* Subjects in any study that would preclude participation in the study by altering results

Cohort 1A (formerly part of study drug group who wish continued participation in the observational group):

* Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
* Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
* Subjects in any study that would preclude participation in the current study.

Cohort 1B (observational group - in other studies with intervention):

* Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
* Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
* Patient currently taking spironolactone or eplerenone
* Subjects in any study that would preclude participation in the current study or studies not approved by principal investigator.

Cohort 2 (Study Drug Group - Spironolactone):

* Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
* Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
* Patient currently taking spironolactone or eplerenone
* Subjects with hyperkalemia or Addison disease;
* Subjects on enalapril or other angiotensin receptor blockers
* Subjects with a history of hypersensitivity to spironolactone suspension or any component of the formulation
* Subjects with a clinically documented diagnosis of severe renal insufficiency (implying estimated glomerular filtration rate (eGFR) \<30 mL/minute/1.73 m2).
* Subjects in any study that would preclude participation in the study by altering results

Controls

* Any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
* Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
* Patient currently taking spironolactone, eplerenone or an angiotensin converting the enzyme inhibitor/angiotensin receptor blocker.