Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease (SCD), Cardiac Magnetic Resonance Imaging (CMR), Cardiomyopathy, Pulmonary Hypertension
Brief summary
The purpose of this study is to use cardiac magnetic resonance imaging (CMR) and echocardiographic tissue Doppler imaging to demonstrate a unique restrictive cardiomyopathy of sickle cell disease. The investigators will characterize its frequency and how it might change (e.g., presence/absence and severity) over a 2-year period.
Detailed description
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.
Interventions
CMR is obtained on all participants in all arms/groups
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
6 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of the Diffuse Myocardial Fibrosis Phenotype | Assessed annually over a 2-year period (3 assessments over 2 years) | The occurrence of an abnormally increased extracellular volume (ECV) measurement \[i.e., the presence of the diffuse myocardial fibrosis phenotype\] as assessed by cardiac magnetic resonance imaging (CMR) using T1 mapping before and after administration of gadolinium. Expressed as number of participants with the diffuse myocardial fibrosis phenotype in each stratum. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Stability of the Diffuse Myocardial Fibrosis Phenotype Over Time | Assessed annually over a 2-year period (3 assessments over 2 years) | The occurrence of a change \[from the baseline assessment\] in the classification \[presence or absence\] of the diffuse myocardial fibrosis phenotype, which is defined as an abnormally increased extracellular volume (ECV) measurement as assessed by cardiac magnetic resonance imaging (CMR) using T1 mapping before and after administration of gadolinium. Expressed as number of participants who had a change in classification of the diffuse myocardial fibrosis phenotype \[e.g., presence to absence, or absence to presence\] during the 2-year study in each stratum. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stratum A (6-13.99 Years) * Age 6 to 13.99 years.
* Sickle cell anemia or sickle-β0-thalassemia. | 5 |
| Stratum B (14-20.99 Years) * Age 14 to 20.99 years.
* Sickle cell anemia or sickle-β0-thalassemia.
* Detectible and quantifiable tricuspid regurgitant jet velocity (TRJV). | 10 |
| Stratum C (≥21 Years) * Age ≥21 years.
* Sickle cell anemia or sickle-β0-thalassemia.
* Detectible and quantifiable tricuspid regurgitant jet velocity (TRJV). | 11 |
| Stratum D (Early Treatment) * Age ≥6 years.
* Sickle cell anemia or sickle-β0-thalassemia.
* 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. | 7 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Stratum A (6-13.99 Years) | Stratum B (14-20.99 Years) | Stratum C (≥21 Years) | Stratum D (Early Treatment) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 6 Participants | 0 Participants | 5 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 4 Participants | 11 Participants | 2 Participants | 17 Participants |
| Age, Continuous | 12.0 years STANDARD_DEVIATION 9.2 | 18.0 years STANDARD_DEVIATION 9.1 | 35.8 years STANDARD_DEVIATION 13.1 | 13.4 years STANDARD_DEVIATION 6.9 | 22.1 years STANDARD_DEVIATION 12.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 10 Participants | 11 Participants | 7 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 10 Participants | 11 Participants | 7 Participants | 33 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 5 participants | 10 participants | 11 participants | 7 participants | 33 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants | 3 Participants | 13 Participants |
| Sickle cell disease genotype Homozygous sickle cell anemia (HbSS) | 4 Participants | 10 Participants | 11 Participants | 7 Participants | 32 Participants |
| Sickle cell disease genotype Sickle-β0-thalassemia (HbSβ0) | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 10 | 0 / 10 | 0 / 7 |
| other Total, other adverse events | 0 / 5 | 3 / 10 | 1 / 10 | 0 / 7 |
| serious Total, serious adverse events | 0 / 5 | 0 / 10 | 0 / 10 | 0 / 7 |
Outcome results
Primary
Frequency of the Diffuse Myocardial Fibrosis Phenotype
The occurrence of an abnormally increased extracellular volume (ECV) measurement \[i.e., the presence of the diffuse myocardial fibrosis phenotype\] as assessed by cardiac magnetic resonance imaging (CMR) using T1 mapping before and after administration of gadolinium. Expressed as number of participants with the diffuse myocardial fibrosis phenotype in each stratum.
Time frame: Assessed annually over a 2-year period (3 assessments over 2 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stratum A (6-13.99 Years) | Frequency of the Diffuse Myocardial Fibrosis Phenotype | 5 Participants |
| Stratum B (14-20.99 Years) | Frequency of the Diffuse Myocardial Fibrosis Phenotype | 10 Participants |
| Stratum C (≥21 Years) | Frequency of the Diffuse Myocardial Fibrosis Phenotype | 10 Participants |
| Stratum D (Early Treatment) | Frequency of the Diffuse Myocardial Fibrosis Phenotype | 1 Participants |
Other Pre-specified
Stability of the Diffuse Myocardial Fibrosis Phenotype Over Time
The occurrence of a change \[from the baseline assessment\] in the classification \[presence or absence\] of the diffuse myocardial fibrosis phenotype, which is defined as an abnormally increased extracellular volume (ECV) measurement as assessed by cardiac magnetic resonance imaging (CMR) using T1 mapping before and after administration of gadolinium. Expressed as number of participants who had a change in classification of the diffuse myocardial fibrosis phenotype \[e.g., presence to absence, or absence to presence\] during the 2-year study in each stratum.
Time frame: Assessed annually over a 2-year period (3 assessments over 2 years)
Population: Stratum D participants had a single CMR assessment only; no longitudinal data were collected.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stratum A (6-13.99 Years) | Stability of the Diffuse Myocardial Fibrosis Phenotype Over Time | 0 Participants |
| Stratum B (14-20.99 Years) | Stability of the Diffuse Myocardial Fibrosis Phenotype Over Time | 0 Participants |
| Stratum C (≥21 Years) | Stability of the Diffuse Myocardial Fibrosis Phenotype Over Time | 0 Participants |