https://orcid.org/0000-0003-3281-2081
Serial cardiovascular magnetic resonance evaluation of children and young adults with SCD who underwent hematopoietic cell transplantation showed mean ECV, representing diffuse myocardial fibrosis, decreased 3.4% from baseline to 12 months posttransplantation. This trial was registered at www.clinicaltrials.gov as #NCT04362293.
TO THE EDITOR:
Cardiovascular complications are a leading cause of early mortality in individuals with sickle cell disease (SCD).1 Chronic anemia, intravascular hemolysis, and episodic vascular occlusion cause repeated microvascular ischemic insults, with reperfusion injury often resulting in progressive myocardial damage and maladaptive remodeling in individuals with SCD.2,3 Almost all individuals with SCD develop progressive diffuse myocardial fibrosis,2-5 which can be detected by quantifying the myocardial extracellular volume (ECV) with cardiovascular magnetic resonance (CMR) imaging.6-9 An increased ECV fraction on CMR correlates strongly with histologically quantified myocardial fibrosis.6,7 We have previously shown that disease-modifying therapies (DMTs), such as hydroxyurea or chronic transfusions, may not be protective against the development of diffuse myocardial fibrosis in children with SCD.4 Elevated myocardial ECV was found even in patients with SCD who began DMT at the age of <6 years.4 Myocardial fibrosis may be associated with dysrhythmias and may be responsible for sudden cardiac death10 in individuals with SCD.11 Hematopoietic cell transplantation (HCT) can cure SCD, but the myocardial effects of this therapy are unknown. Specifically, no prior studies have evaluated the impact of HCT on the progression of diffuse myocardial fibrosis. We evaluated the progression of diffuse myocardial fibrosis by comparing serial CMR evaluations performed before and after HCT in individuals with SCD.
We performed prospective CMR evaluation of children and young adults with SCD who underwent HCT from a matched sibling donor or a haploidentical donor after reduced-toxicity conditioning on a clinical trial (#NCT04362293). This study was approved by the institutional review committee, and all participants or their legal guardians provided written informed consent. CMR was performed before HCT and at 1, 12, and 24 months after HCT on a 1.5-T scanner (Avanto Fit; Siemens Medical Solutions, Inc, Erlangen, Germany). The imaging protocol included ventricular long- and short-axis planes for chamber size, ejection fraction, and myocardial mass. CMR-derived ventricular and atrial volumes were calculated. The ECV was calculated using T1 values from a modified Look-Locker inversion recovery sequence.4 All parametric values (T1, T2, and T2∗) were obtained by drawing regions of interest in the interventricular septum at the midmyocardial level on short-axis images.4 All planimetric and region-of-interest analyses were performed with cvi42 (Circle Imaging, Alberta, Canada) by a single technologist (C.G.) and reviewed for accuracy by a cardiac imaging specialist (C.E.M., A.M., or J.N.J.). T2 and T2∗ maps were obtained before contrast administration. All patients had a hematocrit drawn within 24 hours of the CMR. In addition, the echocardiogram performed closest to the CMR for that time frame was also reviewed.
We performed paired t tests to compare the mean ECV before HCT with that at the 1- and 12-month time points. Other measures were explored similarly. We also fit a linear mixed effects model to assess whether mean ECV differed from baseline at 1 and/or 12 months post-HCT using a likelihood ratio test with random intercepts for each patient. All statistical analyses were conducted using R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria).
Fourteen patients with SCD underwent serial CMR evaluations. Patient demographics and treatment characteristics are shown in Table 1. All patients were receiving some DMT before undergoing HCT. All 14 patients had pre-HCT CMR evaluations. Eight patients had a CMR evaluation at the pre-HCT time point and at 1 and 12 months after HCT. Two patients had evaluations at baseline and at the 1-month time point, and 4 patients had evaluations at baseline and at the 12-month time point only. At 1 and 12 months after HCT, both the right ventricular ejection fraction and the left ventricular (LV) ejection fraction were preserved, and there was improvement in the systolic and diastolic biventricular volumes, as well as in the biventricular cardiac indexes and the LV end-diastolic mass (Table 1; supplemental Figure 1 [available on the Blood website]). On the basis of the echocardiogram data and using published algorithms,12 diastolic dysfunction was rare in our cohort. Only 2 echocardiograms met the criteria for diastolic dysfunction (grade 1), and it was primarily because they had decreased systolic function (supplemental Table 1).
Baseline demographic and cardiac magnetic resonance characteristics at various time points
| Variable | Baseline (N = 14) | 1 mo after HCT (N = 10) | 12 mo after HCT (N = 12) |
|---|---|---|---|
| Demographics | |||
| Age at CMR, y | 14.1 (4.34) | 14.7 (4.46) | 15.6 (3.96) |
| Sex | |||
| F | 6 (42.9) | 4 (40.0) | 4 (33.3) |
| M | 8 (57.1) | 6 (60.0) | 8 (66.7) |
| Genotype | |||
| SS | 13 (92.9) | 9 (90.0) | 11 (91.7) |
| SC | 1 (7.1) | 1 (10.0) | 1 (8.3) |
| Weight, kg | 48.5 (17.5) | 48.0 (14.8) | 51.8 (17.8) |
| Height, cm | 154 (20.7) | 156 (21.3) | 158 (20.6) |
| BSA, m2 | 1.43 (0.358) | 1.44 (0.321) | 1.50 (0.354) |
| Heart rate at baseline, per min | 76.2 (13.8) | 76.5 (13.0) | 73.7 (13.9) |
| Hematocrit, % | 26.5 (3.03) | 31.4 (2.89) | 36.4 (3.22) |
| Graft source | |||
| Matched sibling | — | 5 (50.0) | 5 (41.7) |
| Haploidentical | — | 5 (50.0) | 7 (58.3) |
| CMR data | |||
| RVEF, % | 57.3 (6.29) | 57.1 (8.07) | 56.3 (6.32) |
| RVESVI, mL/m2 | 45.4 (13.2) | 39.1 (10.4)∗ | 41.7 (12.9) |
| RVEDVI, mL/m2 | 105 (17.3) | 90.6 (14.8)∗ | 94.0 (20.4)† |
| RVCI, L/min per m2 | 4.56 (1.16) | 3.89 (0.759)∗ | 3.85 (1.05)† |
| LVEF, % | 58.2 (3.40) | 55.9 (4.94) | 57.9 (3.34) |
| LVESVI, mL/m2 | 43.6 (8.36) | 40.6 (6.79) | 37.8 (8.26)† |
| LVEDVI, mL/m2 | 104 (16.3) | 92.8 (15.5)∗ | 89.3 (16.7)† |
| LVCI, L/min per m2 | 4.63 (1.24) | 3.94 (0.846)∗ | 3.78 (0.959)† |
| LVED mass I, g/m2 | 58.8 (12.5) | 57.0 (15.3) | 51.0 (9.80)† |
| LA volume, mL/m2 | 35.0 (6.66) | 31.1 (8.46) | 31.2 (7.26) |
| Native T1, ms | 1000 (55.4) | 999 (33.6) | 1000 (41.9) |
| Native T2, ms | 46.3 (3.01) | 45.0 (5.07) | 44.2 (2.46)† |
| T2∗, ms | 32.8 (5.48) | 34.7 (6.30) | 32.4 (7.40) |
| ECV, % | 30.3 (3.07) | 27.6 (3.72) | 27.1 (2.50)† |
| ECV ≥ 30 | |||
| Yes | 6 (42.9) | 2 (20.0) | 2 (16.7) |
| No | 8 (57.1) | 8 (80.0) | 10 (83.3) |
| Variable | Baseline (N = 14) | 1 mo after HCT (N = 10) | 12 mo after HCT (N = 12) |
|---|---|---|---|
| Demographics | |||
| Age at CMR, y | 14.1 (4.34) | 14.7 (4.46) | 15.6 (3.96) |
| Sex | |||
| F | 6 (42.9) | 4 (40.0) | 4 (33.3) |
| M | 8 (57.1) | 6 (60.0) | 8 (66.7) |
| Genotype | |||
| SS | 13 (92.9) | 9 (90.0) | 11 (91.7) |
| SC | 1 (7.1) | 1 (10.0) | 1 (8.3) |
| Weight, kg | 48.5 (17.5) | 48.0 (14.8) | 51.8 (17.8) |
| Height, cm | 154 (20.7) | 156 (21.3) | 158 (20.6) |
| BSA, m2 | 1.43 (0.358) | 1.44 (0.321) | 1.50 (0.354) |
| Heart rate at baseline, per min | 76.2 (13.8) | 76.5 (13.0) | 73.7 (13.9) |
| Hematocrit, % | 26.5 (3.03) | 31.4 (2.89) | 36.4 (3.22) |
| Graft source | |||
| Matched sibling | — | 5 (50.0) | 5 (41.7) |
| Haploidentical | — | 5 (50.0) | 7 (58.3) |
| CMR data | |||
| RVEF, % | 57.3 (6.29) | 57.1 (8.07) | 56.3 (6.32) |
| RVESVI, mL/m2 | 45.4 (13.2) | 39.1 (10.4)∗ | 41.7 (12.9) |
| RVEDVI, mL/m2 | 105 (17.3) | 90.6 (14.8)∗ | 94.0 (20.4)† |
| RVCI, L/min per m2 | 4.56 (1.16) | 3.89 (0.759)∗ | 3.85 (1.05)† |
| LVEF, % | 58.2 (3.40) | 55.9 (4.94) | 57.9 (3.34) |
| LVESVI, mL/m2 | 43.6 (8.36) | 40.6 (6.79) | 37.8 (8.26)† |
| LVEDVI, mL/m2 | 104 (16.3) | 92.8 (15.5)∗ | 89.3 (16.7)† |
| LVCI, L/min per m2 | 4.63 (1.24) | 3.94 (0.846)∗ | 3.78 (0.959)† |
| LVED mass I, g/m2 | 58.8 (12.5) | 57.0 (15.3) | 51.0 (9.80)† |
| LA volume, mL/m2 | 35.0 (6.66) | 31.1 (8.46) | 31.2 (7.26) |
| Native T1, ms | 1000 (55.4) | 999 (33.6) | 1000 (41.9) |
| Native T2, ms | 46.3 (3.01) | 45.0 (5.07) | 44.2 (2.46)† |
| T2∗, ms | 32.8 (5.48) | 34.7 (6.30) | 32.4 (7.40) |
| ECV, % | 30.3 (3.07) | 27.6 (3.72) | 27.1 (2.50)† |
| ECV ≥ 30 | |||
| Yes | 6 (42.9) | 2 (20.0) | 2 (16.7) |
| No | 8 (57.1) | 8 (80.0) | 10 (83.3) |
Data are given as mean (SD) or number (percentage).
BSA, body surface area; F, female; LA, left atrial; LVCI, left ventricular cardiac index; LVED mass I, left ventricular end-diastolic mass index; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; M, male; RVCI, right ventricular cardiac index; RVEDVI, right ventricular end-diastolic volume index; RVEF, right ventricular ejection fraction; RVESVI, right ventricular end-systolic volume index.
Paired t test P ≤ .05 comparing 1-month post-HCT and baseline.
Paired t test P ≤ .05 comparing 12-month post-HCT and baseline.
In the paired analysis of patients with both baseline and 12-month measurements (n = 12), the mean ECV decreased by 3.4% (95% confidence interval, 1.49%-5.34%; P = .002) from the baseline to 12 months after HCT (Figure 1; supplemental Figure 2). There were fewer patients with ECV values exceeding 30% (which would be generally considered abnormal) at 1 and 12 months after HCT than at baseline (Table 1; supplemental Figure 2). In 6 participants who have completed 24 months of post-HCT follow-up, the ECV values declined further to a mean of 26.0 (SD = 2.10) (an average decline of 4.8% [95% confidence interval, 0.88%-8.78%] from their respective baseline values), and no participant had an ECV value exceeding 30% (supplemental Figure 2). We acknowledge that native T1 times can be variable depending on intersequence and magnetic resonance imaging vendor variability, which may affect the absolute value of the calculated ECV.13 However, ECV is derived from the ratio of T1 signal values, and therefore may be more reproducible between different field strengths, vendors, and acquisition techniques.3,13 We further note that the cardiac imaging specialists who reviewed these scans were not blinded to the study time points and that could have biased the results. However, the postprocessing of the images (planimetric and region-of-interest analyses) was performed by a single technologist who was blinded to the study time points, thus potentially limiting bias. Last, we found that there was no difference in the cardiac chamber sizes or the ECV measurements according to whether patients received a transplant from a matched sibling donor or a haploidentical donor.
Significant decrease in ECV from baseline to 1- and 12-month post-HCT. The gray points connected by gray lines are the individual values of the ECV at the baseline, 1-month, and 12-month time point for each participant. The genotype is denoted by solid lines with circles (HbSS) or dashed lines with triangles (HbSC). The red dots and red line represent the mean of these ECV values, and the red shaded area connects the 95% confidence intervals for the mean at baseline, 1 month after HCT, and 12 months after HCT. The gray rectangular area next to the vertical axis represents the normal range for ECV levels. The P value shown (.005) is from a likelihood ratio test from the linear mixed effects model to assess whether mean ECV differed from baseline at 1 and/or 12 months. The time point–specific paired t test P values are .061 and .002 for the 1- and 12-month comparisons with baseline, respectively.
Significant decrease in ECV from baseline to 1- and 12-month post-HCT. The gray points connected by gray lines are the individual values of the ECV at the baseline, 1-month, and 12-month time point for each participant. The genotype is denoted by solid lines with circles (HbSS) or dashed lines with triangles (HbSC). The red dots and red line represent the mean of these ECV values, and the red shaded area connects the 95% confidence intervals for the mean at baseline, 1 month after HCT, and 12 months after HCT. The gray rectangular area next to the vertical axis represents the normal range for ECV levels. The P value shown (.005) is from a likelihood ratio test from the linear mixed effects model to assess whether mean ECV differed from baseline at 1 and/or 12 months. The time point–specific paired t test P values are .061 and .002 for the 1- and 12-month comparisons with baseline, respectively.
To our knowledge, this is the first study to indicate that diffuse myocardial fibrosis can improve in patients with SCD after HCT. Although other studies have shown a risk of cardiac dysfunction after HCT,14-16 we observed an improvement in cardiac chamber size, with preservation of cardiac function, as early as 1 month after HCT in patients with SCD who were treated with the reduced-toxicity conditioning regimen. We further noted a reduction in ECV, indicating a decrease in diffuse myocardial fibrosis, in these young patients. Despite receiving either hydroxyurea or chronic transfusions before undergoing HCT, most patients had abnormal cardiac indexes at baseline, before HCT. This further corroborates our prior report that, even if DMT is initiated earlier in life for patients with SCD, abnormal cardiac findings persist and myocardial fibrosis and cardiac function often worsen through young adulthood.4
As ECV does not detect fibrous tissue directly but instead measures the total interstitial space in the myocardium, increased ECV can also result from myocardial edema and inflammation, or LV hypertrophy secondary to anemia in individuals with SCD.17,18 Nevertheless, in a transgenic sickle cell anemia mouse model (Berkeley),19 histologically confirmed ischemic cardiomyocyte loss and secondary fibrosis have been shown to be consistent with ECV measured by CMR, suggesting that ECV may be representative of myocardial fibrosis in individuals with SCD.3 As the anemia and myocardial hypertrophy improve after HCT, the LV mass decreases and so does the ECV. Therefore, the rapid early decrease in ECV at 1 month after HCT could be a consequence of the resolution of SCD-induced inflammation and improvement in anemia after HCT. However, we found that not only did LV mass decrease further after HCT, but there was a continued robust decline in the ECV as a fraction of that mass over time at 12 and 24 months after HCT, despite a relatively stable hematocrit. Several animal models have shown a decline in histologically quantified myocardial fibrosis over time as well, after the inciting insult is removed.20-22 Hence, we posit that the improvement in ECV at 12 and 24 months is probably a result of continued cardiac remodeling and the absence of repetitive episodic microvascular ischemic insults after successful HCT. Perhaps there are several physiological mechanisms responsible for the decrease in ECV after HCT, and the predominant mechanism may be different at early and late time points.
To conclude, these data demonstrate the utility of CMR as a noninvasive tool for assessing the effects of therapeutic interventions on SCD-induced cardiac injury.23 CMR is the only imaging modality that can evaluate the myocardial fibrosis, in addition to cardiac structure and function, which may be critical in prognostic evaluation of various therapeutic modalities.24 We found that ECV measured by CMR, which is reflective of myocardial fibrosis, improves after successful HCT in patients with SCD. This may translate into improved cardiac outcomes for these patients. Our study provides the impetus to study the potential myocardial protective effect of HCT in a larger patient cohort.
Acknowledgments
The authors thank Keith A. Laycock for scientific editing of the manuscript. They thank their colleagues, advanced practice providers, nurses, and other health care professionals who participated in patient care. The authors also thank the parents who entrusted the care of their children to them.
This work was partially supported by the American Society of Hematology (by a Scholar Award to A.S.), the American Lebanese Syrian Associated Charities, and a National Institutes of Health/National Heart, Lung, and Blood Institute award (1U01HL163983 to A.S.).
Authorship
Contribution: A.S. is the principal investigator of the transplant study and developed the study design, contributed to data interpretation, wrote the first draft, and revised the manuscript; J.N.J. contributed to the data collection, analysis, and interpretation and to writing the manuscript; A.M. and C.E.M. contributed to the data collection, analysis, and interpretation and to editing the manuscript; S.S. and Y.B. contributed to the data analysis and interpretation and to editing the manuscript; C.G., P.R., J.A.T., J.S.H., P.R., and B.T. contributed to study design and edited the manuscript. All authors have reviewed and approved the manuscript.
Conflict-of-interest disclosure: This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
A.S. has received consultant fees from Spotlight Therapeutics, Medexus Inc, Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine, is a medical monitor for the Conditioning SCID Infants Diagnosed Early (CSIDE) clinical trial for which he receives financial compensation, and has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. A.S. is the St. Jude Children’s Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to A.S.’s institution. A.S. has no direct financial interest in these therapies. S.G. is a coinventor on patent applications in the fields of cell or gene therapy for cancer, a member of the Scientific Advisory Board of Be Biopharma and CARGO, a member of the Data and Safety Monitoring Board of Immatics, and has received honoraria from TESSA Therapeutics within the past year. The remaining authors declare no competing financial interests.
Correspondence: Akshay Sharma, Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl, MS1130, Memphis TN 38103; email: akshay.sharma@stjude.org.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal