Longitudinal Assessment of Myocardial Fibrosis in Sickle Cell Disease

Introduction

Diffuse myocardial fibrosis is a common feature of the cardiomyopathy of sickle cell disease (SCD) strongly associated with diastolic dysfunction. Cardiovascular magnetic resonance imaging (CMR) can estimate diffuse myocardial fibrosis noninvasively by quantifying extracellular volume fraction (ECV). However, the variability of ECV measurements over time and the natural progression of myocardial fibrosis in people with SCD have not been studied.

Methods

We evaluated children and adults with SCD in a prospective, longitudinal study to characterize the cardiomyopathy of SCD (NCT02410811). Participants underwent yearly CMR over a 3-year period. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium. Diastolic function was assessed and classified by echocardiography.

Results

Twenty-three patients with HbSS at steady state with a mean age of 22 ± 10 y.o (mean ± S.D.), underwent yearly CMR imaging. Nineteen patients had two or more evaluable ECV measurements and were included in this longitudinal analysis. ECV measurements did not show high variability over a 1-2-year period. Mean ECV measurements were 32.7% in year 1, 32.2% in year 2, and 31.8% in year 3. The coefficient of variation of ECV measurements at each time point was 15.6%, 13%, and 18.7% in years 1, 2, and 3, respectively. The mean change in ECV was -1.1 ± 13 % per year. Three patients had an average decrease in ECV of >15% per year, and one had an average increase of >15% per year. None had an average change of >25%. ECV increase correlated with age. Older patients (>20 y.o) had a significant increase in ECV with a mean change of +6.3 ±12% per year compared to -7.8 ±10% per year in younger patients (<20 y.o) (P=0.01). Patients with normal diastolic function at the study entry showed a trend of increasing ECV over time with a mean ECV change of +4.3% compared to -4.3% in patients with abnormal diastolic function. While there was an inverse correlation between hemoglobin concentration and ECV measurements at baseline and throughout the study, there was no association between the change in hemoglobin concentration during the study and ECV change over time. Additionally, two adult patients who initially had a normal ECV value (24% and 25%) had an abnormal ECV at the last measurement point (30% and 28%). The association between increasing ECV and age remained significant after correcting for change in hemoglobin and the presence of diastolic dysfunction (P=0.04).

Discussion

ECV measurements can estimate the degree of myocardial fibrosis with low variability over a short follow-up, making ECV a reliable imaging marker for clinical trials testing antifibrotic and disease-modifying therapies in SCD. ECV tends to increase in adults over time, which may suggest worsening of myocardial fibrosis. However, other causes of myocardial injury, such as inflammation, can also increase ECV, and this may explain at least some changes in ECV over time, especially in young patients. The extent to which acute cardiac inflammation, detected by ECV, also leads to measurable fibrosis remains unknown. Elevated ECV may serve as an early indicator of cardiac involvement, potentially preceding the onset of diastolic dysfunction, as suggested by the observed trend of ECV progression in patients with preserved diastolic function. Ongoing studies of ECV as a biomarker of fibrotic and inflammatory cardiac disease in patients with SCD are needed.