Single ventricle lesions are the leading cause of illness and death from congenital heart disease. The modified Fontan Operation is the corrective surgery for these lesions. The operation is done in stages over a few years and children who complete the operation are known to have greater neurodevelopmental (ND) deficits than the general population. The purpose of this study is to understand how blood flow to the brain (CBF) and brain lesions relate to ND outcome, as well as how CMRO2 relates to anatomic brain lesions. These relationships will be studied through Magnetic Resonance Imaging (MRI) and ND Testing.

Single ventricle (SV) lesions are the leading cause of morbidity and mortality from congenital heart disease (CHD) in the United States. The definitive palliative surgery is the modified Fontan operation where systemic venous return is routed directly to the pulmonary arteries. The surgical reconstruction is performed in stages over a few years which includes the "Stage I" and hemiFontan or bidirectional Glenn operations. These children are known to have greater neurodevelopmental (ND) deficits than the general population and other forms of CHD. For example, a study at Children's Hospital of Philadelphia revealed that at 9 years old, 1/3 were receiving some form of special education; the median intelligence quotient (IQ) was 86 with mental retardation in 18%. One component to ultimate ND outcome is cerebral blood flow (CBF). Preliminary data in SV in the literature across all age ranges and multiple disease states, suggests that CBF is related to ND; a recent review of 25 studies bears this out. Another component to ND outcome is anatomic brain lesions. Preliminary data from a current NIH study of CBF study suggests a link between CBF and brain lesions (decreased CBF is associated with more brain lesions), weaving a complex interaction leading to ultimate ND outcome. There is a pressing need to understand CBF and brain lesions as it relates to childhood ND; this rapid growth stage may be especially important to ultimate cognitive function having not only a humanistic/social impact but a large economic one as well.

Data from a previous NIH grant which ended November 2014 indicates that CBF in SV patients changes throughout the staged surgeries and in the first 2 stages, under stressed conditions such as hypercarbia; in addition, initial look at the data suggests a difference in brain abnormalities as well. These children are especially at risk for altered CBF and brain abnormalities with their changing physiology. At Stage I, a "runoff" physiology is present created by the aorto-pulmonary shunt potentially causing a "steal" from the cerebral circulation. In the 2nd stage (e.g. hemiFontan), cerebral and pulmonary circulations are connected directly and exclusively in series with each other; aortic blood flows to the brain and then directly to the lungs via the superior vena cava. After Fontan completion, downstream cerebral venous pressures are elevated. Finally, SV patients develop aorto-pulmonary collaterals (APC) at all stages and another ongoing research project found a strong inverse correlation between CBF and the degree of APC flow, further putting CBF of SV at risk.

In another study, magnetic resonance imaging (MRI) was utilized to measure blood flow and visualize cerebral anatomy by phase contrast MRI arterial spin labeling and anatomic imaging such as T1 weighted sequences and diffusion tensor imaging. MRI utilizing susceptometry (oximetry) recently developed by an investigator on this renewal, can also quantify the cerebral metabolic rate of oxygen consumption (CMRO2). This combination of MRI capabilities offers a unique opportunity to assess cerebral anatomy, hemodynamics and oxygen metabolism in the same study; by combining this with ND testing, this study is poised to link the two in the hopes of not only understanding cognitive function but to positively intervene in ND outcome. A comprehensive assessment of brain anatomy and function linked to ND outcomes has never been reported in any group of patients nor with utilizing measures at 2 time points.

This is a prospective, single center study of SV patients and seeks to relate cerebral anatomy, hemodynamics and CMRO2 with ND outcome using another patient cohort obtained under a previous study as a basis and utilizing data from 2 time points (original grant and renewal). This approach along with using cerebral carbon dioxide (CO2) reactivity and CMRO2 are major strengths of this study. Elucidating these factors may ultimately lead to modifications in management (e.g. timing of surgery) and identifying children at cognitive risk to implement early intervention and possibly improve ND outcome.

Inclusion Criteria:

SV Patients

• Subjects ages 3 to 15 years old who have completed their Fontan procedure and their parents/guardians.
• Any complex congenital heart lesion that has SV physiology of either right ventricle (RV) or left ventricle (LV) morphology.
• Ability to undergo a 60-90 minute MRI scan under general anesthesia or deep sedation if general anesthesia or sedation is needed.
• Parents signing informed consent. Healthy Controls
• Males and females ages 3 to 15 years old if in the original cohort and if not in the original cohort, age matched with Groups I and II, and their parents/guardians.
• Normal cerebral and cardiac anatomy who are normocephalic and who are asymptomatic.
• For normal controls being prospectively enrolled and not part of the original grant, the ability to extend the clinical MRI an extra 15-20 minutes.
• For normal controls undergoing sedation, the ability to extend anesthesia for approximately 15-30 minutes for research purposes only.
• Parents signing informed consent. Volunteers
• Patients who come to CHOP for a clinically indicated MRI.
• The ability to extend the clinical MRI an extra 15-20 minutes.
• If 18 or over, patient signing informed consent.
• If under 18, parents signing informed consent.

Exclusion Criteria:

SV Patients

• A patient whose primary language is not English. Patients who speak English who have parents or guardians who do not speak English would not be excluded.
• Any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
• Any known significant neurological disease outside of the usual state of SV patients.
• Any major anomalies which would confound neurological outcome.
• A patient with a pacemaker or cardioverter/defibrillator in place.
• A contraindicated ferromagnetic foreign body).
• Pregnancy Healthy Controls
• An individual whose primary language is not English. Patients who speak English who have parents or guardians who do not speak English would not be excluded
• Any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
• Any known significant neurological disease.
• Any contraindication to extending the MRI.
• Pregnancy. Volunteers
• A patient whose primary language is not English. Patients who speak English who have parents or guardians who do not speak English would not be excluded.
• Any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
• Any contraindication to extending the MRI.
• Pregnancy.

Group I (cohort) will be patients enrolled in the original NIH CBF grant. Group II (cross-sectional) will be recruited from SV patients after Fontan operation but were not participants in the original study to enrich the patient population and to maximize Group I enrollment. Group III will be normal controls enrolled in the original CBF grant. Group IV will be patients at The Children's Hospital of Philadelphia (CHOP) for clinical MRIs and found to have structurally normal cardiac and brain anatomy. Parents/guardians of Group I-IV patients will be enrolled, as well. There will be a group of 1-5 volunteers enrolled to test the study MRI protocol. Volunteers will be patients who come to CHOP for clinical MRIs.

Dr. Felix Werhil from the University of Penn will be analyzing the CMRO2 studies from the MRI images. Data will be transferred to him on a flash drive that has been encrypted and password-protected according to CHOP IT standards and hand delivered by the PI or a member of the study team.

Dr. Alexandra Hanlon from University of Penn School of Nursing will be performing the statistics for the study. Investigators will have a REDCap database, which Dr. Hanlon has been approved for and received CHOP identity to access.