Early therapeutic interventions and preventative medicine have increased the life expectancy of patients with sickle cell disease (SCD). As survival improved, cardiopulmonary complications became the main cause of premature deaths in adult patients with SCD.
SCD patients are known to have less cardiac iron deposition compared to other transfusion-dependent diseases, however, the cardioprotection in SCD is incomplete (1). Recently Fujikura K, et al.(2) showed significant correlation between myocardial dysfunction assessed by speckle-tracking echocardiography and myocardial iron concentration (MIC) calculated from non-ECG-gated abdominal magnetic resonance imaging (MRI). The purpose of this study was to validate this observation in a larger, independent patient cohort, using cardiac MRI (CMR).
SCD patients undergoing regular transfusion and seen at Children’s Hospital Los Angeles routinely undergo CMR studies as as part of clinical practice. The institution follows the largest documented cohort of patients with SCD and myocardial iron overload (MIO) (3). Between October 2002 and November 2019, there were 129 CMR studies from 63 SCD patients (age 18 years [15, 22], male 22 (34.9%)) that evaluated MIC and had adequate image quality for strain analysis. MIO was defined as R2* ≥50 Hz (T2* 20 ms), and borderline MIO was defined as 41.8 Hz (95 percentile of normal) <R2* <50 Hz (T2* ~24 ms). Feature-tracking analysis was performed using CVi42 (Circle Cardiovascular Imaging, Calgary, Alberta, Canada) to assess global circumferential strain (GCS) (4). This study was approved by the institutional review board of Children’s Hospital Los Angeles. Categorical variables were presented as counts (percentages). Because distributions of continuous variables were parametric, they were presented as median [inter quartile range], and compared between the two groups using the Wilcoxon Rank Test. Maximal and minimal MIC measures are uniformly temporally ordered with the minimal MIC preceding the maximal MIC.
Ten patients developed abnormal or borderline MIO on serial measurements (Figure A). The patients with MIO or borderline were significantly older (23.2 years [22.6, 25.7] vs. 17.2 years [14.9, 19.9]; p=0.0001), had significantly lower hemoglobin S (8.5 % [3.0, 9.1] vs. 34.2 % [23.0, 50.0]; p=0.0006), and had significantly higher ferritin (8983 ng/ml [6660, 9520] vs. 4023 ng/ml [2129, 6505]; p=0.001) compared to patients with normal MIC. Total hemoglobin was similar between the two groups (9.1 g/dl [8.9, 9.3] vs. 9.5 g/dl [8.3, 10.0], p=0.96). Routine clinical CMR parameters were similar between the two groups including left ventricular end-diastolic volume index (p=0.64), end-systolic volume index (p=0.27), and ejection fraction (LVEF) (p=0.69).
Figure.
Serial assessments R2* and left ventricular function in patients who developed abnormal or borderlineMIO. (A) LVEF decreased in 7 of 10 patients (B, p=0.23), radial diastolic strain rate worsened in 9 of 10 patients (C, p=0.024), and circumferential diastolic strain rate worsened in 8 of 10 patients (D, p=0.65).
For the 10 patients who developed abnormal or borderline MIO, cardiac function parameters were compared between CMR studies with maximum and minimum MIC. LVEF was not significantly different (Figure B). However, radial diastolic strain rate was significantly reduced at maximum MIC (p=0.014) (Figure C), and circumferential diastolic strain rate tended to be reduced at maximum MIC (p=0.065) (Figure D). Six out of 10 patients had decreased LVEF, and 8 patients had decreased absolute radial diastolic strain rate at maximum MIC. Similar results were found when analysis was restricted to the 8 patients with R2*≥50 Hz. For 53 patients with normal MIC, there was a significant correlation between radial strain rate and MIC (p=0.048) whereas there was no correlation between age and MIC (p=0.81).
Our results support the hypothesis that MIO causes subclinical myocardial dysfunction in SCD. There is general consensus that cardiac dysfunction in SCD is caused by chronic vascular damage that is multifactorial (5), including multiple endogenous cascades of chemical and mechanical reactions that promote chronical microvascular obstruction, ischemic cell death, and myocardial fibrosis. Additionally, in a state of saturated transferrin (e.g. ≥85%) due to overwhelming iron influx from transfusions, non-transferrin bound iron species enter the heart and vasculature, reinforcing existing pathological cascades and directly impairing cardiac function(6). This study has some limitations. The CMR studies with poor image quality for strain analysis (resulting from motion) were excluded. Among the 10 patients who developed abnormal or borderline MIO, 5 did not have adequate cine quality for strain at maximum and/or minimum MIC. This may have caused underestimation of our results.
This study indicates that strain analysis may be helpful as a gate keeper to identify individuals who would benefit from CMR by guiding potential chelating therapy. A prospective study with CMR and echocardiography will need to investigate the association of MIO, impaired strain values, and adverse cardiac outcome in patients with SCD.
Grants, contracts, and other forms of financial support
This work was supported by the National Heart Lung and Blood Institute (1HL075592, 1RC HL099412), the National Institute for Diabetes, Digestive, and Kidney Diseases (1R01DK097115-01A1) as well as the National Center for Research through the Clinical Translational Science Institute at Children’s Hospital Los Angeles (5UL1 TR000130-05). The work was also funded in part by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health (NIH), United States Department of Health and Human Services (DHHS).
The authors attest they are in compliance with human studies committees and animal welfare regulations of Children’s Hospital Los Angeles, and Food and Drug Administration guidelines, including patient consent where appropriate.
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