Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups - revisiting this controversial concept after 16 years of additional evidence.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty-eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional-hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end-organ failure. On Cox proportional-hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S' results in a 91% increase, and 1 cm/s decrease in E' results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.

Rosette Trajectories Enable Ungated, Motion-Robust, Simultaneous Cardiac and Liver T2 * Iron Assessment.

BACKGROUND: Quantitative T2 * MRI is the standard of care for the assessment of iron overload. However, patient motion corrupts T2 * estimates. PURPOSE: To develop and evaluate a motion-robust, simultaneous cardiac and liver T2 * imaging approach using non-Cartesian, rosette sampling and a model-based reconstruction as compared to clinical-standard Cartesian MRI. STUDY TYPE: Prospective. PHANTOM/POPULATION: Six ferumoxytol-containing phantoms (26-288 µg/mL). Eight healthy subjects and 18 patients referred for clinically indicated iron overload assessment. FIELD STRENGTH/SEQUENCE: 1.5T, 2D Cartesian and rosette gradient echo (GRE) ASSESSMENT: GRE T2 * values were validated in ferumoxytol phantoms. In healthy subjects, test-retest and spatial coefficient of variation (CoV) analysis was performed during three breathing conditions. Cartesian and rosette T2 * were compared using correlation and Bland-Altman analysis. Images were rated by three experienced radiologists on a 5-point scale. STATISTICAL TESTS: Linear regression, analysis of variance (ANOVA), and paired Student's t-testing were used to compare reproducibility and variability metrics in Cartesian and rosette scans. The Wilcoxon rank test was used to assess reader score comparisons and reader reliability was measured using intraclass correlation analysis. RESULTS: Rosette R2* (1/T2 *) was linearly correlated with ferumoxytol concentration (r2 = 1.00) and not significantly different than Cartesian values (P = 0.16). During breath-holding, ungated rosette liver and heart T2 * had lower spatial CoV (liver: 18.4 ± 9.3% Cartesian, 8.8% ± 3.4% rosette, P = 0.02, heart: 37.7% ± 14.3% Cartesian, 13.4% ± 1.7% rosette, P = 0.001) and higher-quality scores (liver: 3.3 [3.0-3.6] Cartesian, 4.7 [4.1-4.9] rosette, P = 0.005, heart: 3.0 [2.3-3] Cartesian, 4.5 [3.8-5.0] rosette, P = 0.005) compared to Cartesian values. During free-breathing and failed breath-holding, Cartesian images had very poor to average image quality with significant artifacts, whereas rosette remained very good, with minimal artifacts (P = 0.001). DATA CONCLUSION: Rosette k-sampling with a model-based reconstruction offers a clinically useful motion-robust T2 * mapping approach for iron quantification. J. MAGN. RESON. IMAGING 2020;52:1688-1698.

Anemia predicts lower white matter volume and cognitive performance in sickle and non-sickle cell anemia syndrome.

Severe chronic anemia is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction in the elderly. Severe anemia also predisposes to white matter strokes in young children, independent of the anemia subtype. We previously demonstrated symmetrically decreased white matter (WM) volumes in patients with sickle cell disease (SCD). In the current study, we investigated whether patients with non-sickle anemia also have lower WM volumes and cognitive dysfunction. Magnetic Resonance Imaging was performed on 52 clinically asymptomatic SCD patients (age = 21.4 ± 7.7; F = 27, M = 25; hemoglobin = 9.6 ± 1.6 g/dL), 26 non-sickle anemic patients (age = 23.9 ± 7.9; F = 14, M = 12; hemoglobin = 10.8 ± 2.5 g/dL) and 40 control subjects (age = 27.7 ± 11.3; F = 28, M = 12; hemoglobin = 13.4 ± 1.3 g/dL). Voxel-wise changes in WM brain volumes were compared to hemoglobin levels to identify brain regions that are vulnerable to anemia. White matter volume was diffusely lower in deep, watershed areas proportionally to anemia severity. After controlling for age, sex, and hemoglobin level, brain volumes were independent of disease. WM volume loss was associated with lower Full Scale Intelligence Quotient (FSIQ; P = .0048; r2 = .18) and an abnormal burden of silent cerebral infarctions (P = .029) in males, but not in females. Hemoglobin count and cognitive measures were similar between subjects with and without white-matter hyperintensities. The spatial distribution of volume loss suggests chronic hypoxic cerebrovascular injury, despite compensatory hyperemia. Neurocognitive consequences of WM volume changes and silent cerebral infarction were strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.

White matter has impaired resting oxygen delivery in sickle cell patients.

Although modern medical management has lowered overt stroke occurrence in patients with sickle cell disease (SCD), progressive white matter (WM) damage remains common. It is known that cerebral blood flow (CBF) increases to compensate for anemia, but sufficiency of cerebral oxygen delivery, especially in the WM, has not been systematically investigated. Cerebral perfusion was measured by arterial spin labeling in 32 SCD patients (age range: 10-42 years old, 14 males, 7 with HbSC, 25 HbSS) and 25 age and race-matched healthy controls (age range: 15-45 years old, 10 males, 12 with HbAS, 13 HbAA); 8/24 SCD patients were receiving regular blood transfusions and 14/24 non-transfused SCD patients were taking hydroxyurea. Imaging data from control subjects were used to calculate maps for CBF and oxygen delivery in SCD patients and their T-score maps. Whole brain CBF was increased in SCD patients with a mean T-score of 0.5 and correlated with lactate dehydrogenase (r2 = 0.58, P < 0.0001). When corrected for oxygen content and arterial saturation, whole brain and gray matter (GM) oxygen delivery were normal in SCD, but WM oxygen delivery was 35% lower than in controls. Age and hematocrit were the strongest predictors for WM CBF and oxygen delivery in patients with SCD. There was spatial co-localization between regions of low oxygen delivery and WM hyperintensities on T2 FLAIR imaging. To conclude, oxygen delivery is preserved in the GM of SCD patients, but is decreased throughout the WM, particularly in areas prone to WM silent strokes.

Diminished cerebral oxygen extraction and metabolic rate in sickle cell disease using T2 relaxation under spin tagging MRI.

PURPOSE: T2 MRI oximetry can noninvasively determine oxygen saturation (Y) but requires empirical MR calibration models to convert the measured blood transverse relaxation (T2b ) into Y. The accuracy of existing T2b models in the presence of blood disorders such as sickle cell disease (SCD) remains unknown. METHODS: A Carr Purcell Meiboom Gill T2 preparation sequence was used to make 83 whole blood measurements from 11 subjects with SCD to derive an ex vivo sickle hemoglobin (HbS) T2b model. Forearm venous blood gas, sagittal sinus T2 (T2 Relaxation Under Spin Tagging) and total brain blood flow (phase contrast MRI) were measured in 37 healthy controls and 33 SCD subjects (age 24.6 ± 10.2 years). Cerebral oxygen saturation, extraction fraction, and metabolic rate estimates were calculated using three separate T2b models. Cerebral and forearm oxygen extraction fraction were compared. RESULTS: Ex vivo, SCD blood had greater saturation dependent relaxivity than control blood, with a weak dependence on HbS and no dependence on hematocrit. In vivo, the HbS T2b model predicted Yv values with lowest coefficient of variation (compared with existing T2b models) and the strongest correlation with peripheral venous oximetry (r2 = .29). The HbS T2b model predicted systematically higher Yv measurements in SCD patients (73 ± 5 and 61 ± 6; P < 0.0001) which was mirrored by peripheral venous measurements (75 ± 20 and 45 ± 20; P < 0.0001). CONCLUSION: Cerebral and peripheral oxygen extraction are decreased in SCD patients, suggesting either blood flow is increased beyond metabolic demands or the presence of physiological arterial-venous shunting. Magn Reson Med 80:294-303, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Hemoglobin and mean platelet volume predicts diffuse T1-MRI white matter volume decrease in sickle cell disease patients.

Sickle cell disease (SCD) is a life-threatening genetic condition. Patients suffer from chronic systemic and cerebral vascular disease that leads to early and cumulative neurological damage. Few studies have quantified the effects of this disease on brain morphometry and even fewer efforts have been devoted to older patients despite the progressive nature of the disease. This study quantifies global and regional brain volumes in adolescent and young adult patients with SCD and racially matched controls with the aim of distinguishing between age related changes associated with normal brain maturation and damage from sickle cell disease. T1 weighted images were acquired on 33 clinically asymptomatic SCD patients (age = 21.3 ± 7.8; F = 18, M = 15) and 32 racially matched control subjects (age = 24.4 ± 7.5; F = 22, M = 10). Exclusion criteria included pregnancy, previous overt stroke, acute chest, or pain crisis hospitalization within one month. All brain volume comparisons were corrected for age and sex. Globally, grey matter volume was not different but white matter volume was 8.1% lower (p = 0.0056) in the right hemisphere and 6.8% (p = 0.0068) in the left hemisphere in SCD patients compared with controls. Multivariate analysis retained hemoglobin (ß = 0.33; p = 0.0036), sex (ß = 0.35; p = 0.0017) and mean platelet volume (ß = 0.27; p = 0.016) as significant factors in the final prediction model for white matter volume for a combined r2 of 0.37 (p < 0.0001). Lower white matter volume was confined to phylogenetically younger brain regions in the anterior and middle cerebral artery distributions. Our findings suggest that there are diffuse white matter abnormalities in SCD patients, especially in the frontal, parietal and temporal lobes, that are associated with low hemoglobin levels and mean platelet volume. The pattern of brain loss suggests chronic microvascular insufficiency and tissue hypoxia as the causal mechanism. However, longitudinal studies of global and regional brain morphometry can help us give further insights on the pathophysiology of SCD in the brain.

Determinants of resting cerebral blood flow in sickle cell disease.

Stroke is common in children with sickle cell disease and results from an imbalance in oxygen supply and demand. Cerebral blood flow (CBF) is increased in patients with sickle cell disease to compensate for their anemia, but adequacy of their oxygen delivery has not been systematically demonstrated. This study examined the physiological determinants of CBF in 37 patients with sickle cell disease, 38 ethnicity matched control subjects and 16 patients with anemia of non-sickle origin. Cerebral blood flow was measured using phase contrast MRI of the carotid and vertebral arteries. CBF increased inversely to oxygen content (r(2) = 0.69, P < 0.0001). Brain oxygen delivery, the product of CBF and oxygen content, was normal in all groups. Brain composition, specifically the relative amounts of grey and white matter, was the next strongest CBF predictor, presumably by influencing cerebral metabolic rate. Grey matter/white matter ratio and CBF declined monotonically until the age of 25 in all subjects, consistent with known maturational changes in brain composition. Further CBF reductions were observed with age in subjects older than 35 years of age, likely reflecting microvascular aging. On multivariate regression, CBF was independent of disease state, hemoglobin S, hemoglobin F, reticulocyte count and cell free hemoglobin, suggesting that it is regulated similarly in patients and control subjects. In conclusion, sickle cell disease patients had sufficient oxygen delivery at rest, but accomplish this only by marked increases in their resting CBF, potentially limiting their ability to further augment flow in response to stress. Am. J. Hematol. 91:912-917, 2016. © 2016 Wiley Periodicals, Inc.

Predictors of cerebral blood flow in patients with and without anemia.

Sickle cell disease (SCD) is the most common cause of stroke in childhood and results primarily from a mismatch of cerebral oxygen supply and demand rather than arterial obstruction. However, resting cerebral blood flow (CBF) has not been examined in the general African American population, in whom obesity, hypertension, cerebrovascular disease, and diminished cerebrovascular reserve capacity are common. To better understand the underlying physiological substrate upon which SCD is superimposed, we measured CBF in 32 young (age 28 ± 10 yr), asymptomatic African American subjects with and without sickle cell trait (n= 14). To characterize the effects of chronic anemia, in isolation of sickle hemoglobin we also studied a cohort of 13 subjects with thalassemia major (n= 10), dyserythropoetic anemia (n= 1), or spherocytosis (n= 2). Blood was analyzed for complete blood count, hemoglobin electrophoresis, cell free hemoglobin, and lactate dehydrogenase. Multivariate regression analysis showed that oxygen content was the strongest predictor of CBF (r(2)= 0.33,P< 0.001). CBF declined rapidly in the second and third decades of life, but this drop was explained by reductions in cerebral gray matter. However, age effects persisted after correction for brain composition, possibly representing microvascular impairment. CBF was independent of viscosity, hemoglobin S%, and body mass index. Hyperoxia resulted in reduced CBF by 12.6% (P= 0.0002), and CBF changes were proportional to baseline oxygen content (r(2)= 0.16,P= 0.02). These data suggest that these hemoglobin subtypes do not alter the normal CBF regulation of the balance of oxygen supply and demand.