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.