Longitudinal changes and predictors of cardiac extracellular volume fraction in sickle cell anemia

Diffuse myocardial fibrosis is a key feature of the cardiomyopathy of sickle cell anemia (SCA) that is linked to diastolic dysfunction. Cardiac MRI (CMR)-derived extracellular volume fraction (ECV) is a quantitative biomarker of myocardial fibrosis that is elevated in SCA. The stability of ECV in SCA and its clinical associations over time are unknown. To measure longitudinal changes in ECV, without specific intervention, and identify correlates of ECV change in patients with SCA, we conducted a prospective, 2-year study involving annual CMR, echocardiography, and laboratory assessments in 24 patients with SCA (mean age 21.4±10 years). ECV was calculated using T1 mapping pre- and post-gadolinium, and extracellular matrix and cellular volumes were calculated to account for relative changes. Diastolic function was classified by echocardiography. Longitudinal associations were assessed using linear mixed-effects models. ECV was abnormally increased at baseline and remained stable over time (mean change -1.1±2.7% per year). Intra-subject ECV variability was low (mean 2.4%), with no differences by age or sex. ECV correlated with diastolic dysfunction at all timepoints (P=0.01). Changes in ECV were more closely associated with changes in extracellular matrix volume (P=0.01) than with myocardial cell volume. In a longitudinal multivariable analysis, ECV was independently associated with diastolic dysfunction, hemoglobin, NT-proBNP, left atrial volume, and peak pulmonary artery velocity. In summary, ECV is a stable and reliable metric of myocardial extracellular matrix expansion in SCA. Its strong associations with diastolic dysfunction and biomarkers of cardiac stress support its use as an imaging biomarker for antifibrotic therapies in SCA. This trial was registered at www.ClinicalTrials.gov as #NCT02410811.