Introduction: Maladaptive cardiac remodeling in sickle cell disease (SCD) begins early in childhood, with a high cardiovascular disease burden in adults. Features of anemia-related hyperdynamic and restrictive physiology characterize SCD cardiomyopathy. We have previously reported a high prevalence of diffuse myocardial fibrosis (quantified by myocardial extracellular volume [ECV] with cardiac magnetic resonance imaging [CMR]) in children and young adults with SCD, despite early exposure to disease-modifying therapies (DMT), suggesting that DMTs are not sufficient to halt the progression of SCD-associated cardiac injury. We have also shown improvement in diffuse myocardial fibrosis following hematopoietic cell transplantation (HCT), with a significant decline in ECV at the 12-month evaluation compared to before HCT. In this study, we report the 36-month follow-up CMR data for the cohort of patients who received HCT. Furthermore, we compare the impact of HCT and DMT on the cardiac structural and functional alterations in a selected age-matched cohort of SCD patients.

Methods: Individuals with SCD enrolled on the SCDHCT clinical trial (NCT04362293) who received either a matched sibling or haploidentical donor HCT following a reduced toxicity conditioning regimen and had serial CMR/echocardiographic assessments were included in these analyses. These cardiac assessments were performed in the SCDHCT cohort before HCT (pre-HCT) and then annually following HCT (post-HCT). CMR-derived ventricular and atrial volumes were calculated, and ECV was measured from T1 maps with a modified Look-Locker inversion recovery (MOLLI) sequence in short-axis. We report descriptive statistics for CMR measures at baseline, 12, 24, and 36 months post-HCT. To compare the effect of HCT and DMT on cardiac outcomes in SCD, we compared the echocardiographic measurements performed at 1-year post-HCT in the SCDHCT cohort with a matched cohort of participants enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP, NCT02098863) who had not received HCT and were on DMT. We randomly selected 3 SCCRIP participants within a 6-month window of age for each SCDHCT participant who was at 1-year post-HCT evaluation. A linear regression model was used to explore the association between each echocardiogram variable and receipt of HCT (yes/no), while controlling for age as a covariate.

Results: Our SCDHCT cohort consisted of 20 patients; 95% (19/20) completed the pre-HCT assessment, 80% (16/20) completed the 12-month post-HCT assessment, 70% (14/20) completed the 24-month assessment, and 45% (9/20) completed the 36-month evaluation. Participants were predominantly male (60%), with HbSS genotype (95%), and a median age of 15.3 years at the time of HCT. Using CMR, the biventricular volume, left atrial volume, and cardiac index decreased from pre-HCT over the 36-month follow-up period post-HCT. Furthermore, the median ECV at baseline (31%) declined to 27% at the 12-month time-point post-HCT, 26% at 24 months, and 25% at 36 months post-HCT. While 57.9% (11/19) of participants had an elevated ECV (>30%) at the pre-HCT assessment, only 14.3% (2/14) had an elevated ECV at the 24-month time point, and none (0/9) assessed at the 36-month time point had an elevated ECV. When we performed an age-adjusted comparison of echocardiographic variables of those receiving DMT versus those 12-months post-HCT, we found no difference in the chamber volumes (left atrial and ventricular volume) but found a lower mean in EF (59.4% vs 65.1%, p <0.001) and peak tricuspid regurgitant velocity [TRV] (2.05 m/sec vs 2.31 m/sec, p=0.002) in the HCT groupConclusions: We demonstrate a steady improvement in the cardiac parameters post-HCT, with a decrease in cardiac chamber size and improvement in diffuse myocardial fibrosis noted in participants 36 months post-HCT. When compared to age-matched patients receiving DMT, those post-HCT had similar chamber size but had lower TRV and EF. The lower EF in the post-HCT group was within the normal range (55%-65%) and reflected a normal cardiac index, which remained elevated in the DMT group, as indicated by a high EF, suggestive of high cardiac output failure in the setting of persistent anemia. Given the burden of cardiac complications in SCD, there is a critical need to identify therapeutic options that will slow down SCD-cardiac injury. Our data further corroborate the long-term organ-protective effects of HCT in patients with SCD.

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2025
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