Novel Cardiac Magnetic Resonance Imaging to Define a Unique Restrictive Cardiomyopathy in Sickle Cell Disease

Sickle cell disease (SCD) causes progressive cardiopulmonary morbidity, beginning in
childhood, which can ultimately be fatal. As a group, cardiopulmonary complications, such as
acute chest syndrome and sudden death, are now the most common causes of death in SCD,
especially in adolescents and adults.

Patients with SCD have features of both an anemia-related, high cardiac output state and a
restrictive cardiomyopathy (RCM). The investigators propose that this unique RCM is an
overlooked and understudied complication of SCD. RCM could explain the modest increases in
pulmonary artery pressure in patients with SCD, as measured by cardiac catheterization or
estimated by tricuspid regurgitant jet velocity (TRJV), which has often been attributed to a
primary pulmonary arterial hypertension (PAH). RCM could also be the cause of unexplained
sudden cardiac death in SCD, which is a feature of other forms of RCM.

The investigators overarching hypothesis is that increased reactive oxygen species
(ROS)-mediated angiotensin-1 receptor (AT1R)-TGFβ1 signaling is pro-fibrotic and, in
combination with vaso-occlusive ischemia-reperfusion injury, results in an age-dependent,
progressive RCM that can be detected by non-invasive cardiac imaging.

This pilot, longitudinal, observational study uses a novel, comprehensive, multimodal cardiac
imaging strategy, combining cutting-edge cardiac magnetic resonance imaging (CMR) and
echocardiographic tissue Doppler imaging (TDI), to demonstrate the unique RCM of SCD,
characterizing its frequency and the temporal evolution over a 2-year period. The
investigators will also correlate the RCM phenotype with biomarkers of ROS and renin
angiotensin system (RAS)-TGFβ1 signaling.

This research could change the investigators understanding of how SCD affects the heart and
lungs. The investigators propose studies that will change the current concept of primary
pulmonary vasculopathy to a cardiomyopathy-centered model with secondary pulmonary vascular
changes leading to sudden death. This translational pilot study will deliver a novel, clear,
quantifiable CMR phenotype with established diagnostic performance that will be used in phase
II/III clinical trials to test anti-fibrotic therapy to prevent or reverse SCD-related RCM.

Inclusion Criteria:

- Sickle cell anemia (HbSS) or sickle-β°-thalassemia (HbSβ°) confirmed by hemoglobin
separation and identification techniques

- Ability to cooperate with and undergo CMR without sedation or anesthesia.

- Ability to cooperate with and undergo echocardiogram

- Written informed consent in accordance with the institutional policies and federal
guidelines must be provided by the participant (if ≥18 years of age) or parent or
legally authorized guardian (if the participant is <18 years of age) Minor
participants ≥11 years of age will be requested to provide assent

The following additional inclusion criterion applies to Age Stratum A:

Age 6 to 13.99 years

The following additional inclusion criteria apply to Age Stratum B:

- Age 14 to 20.99 years

- Detectible and quantifiable TRJV with reported value

The following additional inclusion criteria apply to Age Stratum C:

- Age ≥21 years

- Detectible and quantifiable TRJV with reported value

The following additional inclusion criteria apply to Stratum D:

- Age ≥6 years.

- Current use of disease-modifying therapy [hydroxyurea, chronic transfusions, or both
(given concurrently, sequentially, or both)] that was initiated at <3 years of age,
and for which there has been no interruption of therapy for >6 consecutive months
since the initiation of disease-modifying therapy.

Exclusion Criteria:

- Any contraindication to MRI or physical or behavioral factor that could degrade the
quality of MRI data or interfere with a participant's tolerance of the MRI, such as
permanent or semi-permanent metallic implants, including pacemakers and
defibrillators, or severe claustrophobia

- Known ventricular septal defect (VSD) documented in medical record

- Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2 (estimated by serum
creatinine or cystatin-C)

- Pregnancy (documented by serum or urine pregnancy test)

The following additional inclusion criterion applies to strata A, B and C only:

- Current chronic transfusion therapy (defined as regular, approximately monthly,
transfusions of packed red blood cells given for at least 6 consecutive months for the
treatment of prevention of SCD-related complications with the plan to continue this therapy
at the time of potential enrollment).