Objective To identify a unifying cardiac pathophysiology that explains the cardiac pathology in SCD. Background Cardiopulmonary complications, the leading cause of adult mortality in sickle cell disease (SCD), are associated with heart chamber dilation, diastolic dysfunction, elevated tricuspid regurgitant jet velocity (TRV) and pulmonary hypertension (PH). However, no unifying cardiac pathophysiology has been identified to explain these findings. Methods In a two-part study, we first examined SCD patients who underwent screening echocardiography during steady state at our institution. We then conducted a meta-analysis of cardiac studies in SCD. Results In the 134 SCD patients studied (median age 11 years), a significant enlargement of the left atrial volume was present (z-score 3.1, P=0.002), shortening fraction (SF) was normal (37.6 ± 4.7%), and lateral and septal ratios of mitral velocity to early diastolic velocity of the mitral annulus (E/e′) were severely abnormal in 8% and 14% of patients, respectively, indicating impaired diastolic function. Both TRV and lateral E/e′ correlated with enlarged left atrial volume in SCD (P=0.003 and P=0.006, respectively). Meta-analysis of 68 studies confirmed significant left atrial diameter enlargement in SCD patients compared to controls, evidence of diastolic dysfunction and enlarged left ventricular end-diastolic dimension with normal SF. The majority of patients with catheter-confirmed PH had mild pulmonary venous hypertension consistent with restrictive cardiac physiology. Conclusions Patients with SCD have a unique cardiomyopathy with restrictive physiology that is superimposed on hyperdynamic physiology, and is characterized by diastolic dysfunction, left atrial dilation and normal systolic function. This results in mild, secondary, pulmonary venous hypertension and elevated TRV. Sudden death is common in other forms of restrictive cardiomyopathy. Our finding of this unique restrictive cardiomyopathy may explain the increased mortality and sudden death seen in patients with SCD with mildly elevated TRV.

Sickle cell anemia (SCA)-related cardiomyopathy is characterized by diastolic dysfunction and hyperdynamic features. Diastolic dysfunction portends early mortality in SCA. Diastolic dysfunction is associated with microscopic myocardial fibrosis in SCA mice, but the cause of diastolic dysfunction in humans with SCA is unknown. We used cardiac magnetic resonance measurements of extracellular volume fraction (ECV) to discover and quantify diffuse myocardial fibrosis in 25 individuals with SCA (mean age, 23 ± 13 years) and determine the association between diffuse myocardial fibrosis and diastolic dysfunction. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and diastolic function was assessed by echocardiography. ECV was markedly increased in all participants compared with controls (0.44 ± 0.08 vs 0.26 ± 0.02, < .0001), indicating the presence of diffuse myocardial fibrosis. Seventeen patients (71%) had diastolic abnormalities, and 7 patients (29%) met the definition of diastolic dysfunction. Participants with diastolic dysfunction had higher ECV (0.49 ± 0.07 vs 0.37 ± 0.04, = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction ( = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m, = .04) compared with those with ECV<0.4. ECV correlated with hemoglobin ( = -0.46, = .03) and NT-proBNP ( = 0.62, = .001). In conclusion, diffuse myocardial fibrosis, determined by ECV, is a common and previously underappreciated feature of SCA that is associated with diastolic dysfunction, anemia, and high NT-proBNP. Diffuse myocardial fibrosis is a novel mechanism that appears to underlie diastolic dysfunction in SCA.

Hydroxyurea is FDA‐approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight‐based dosing with step‐wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinical benefits, but often takes 6 to 12 months to achieve. The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single‐center study designed to prospectively validate a novel personalized PK‐guided hydroxyurea dosing strategy with a primary endpoint of time to MTD. Enrolled participants received a single oral 20 mg/kg dose of hydroxyurea, followed by a sparse PK sampling approach with three samples collected over three hours. Analysis of individual PK data into a population PK model generated a starting dose that targets the MTD. The TREAT cohort (n = 50) was young, starting hydroxyurea at a median age of 11 months (IQR 9‐26 months), and PK‐guided starting doses were high (27.7 ± 4.9 mg/kg/d). Time to MTD was 4.8 months (IQR 3.3‐9.3), significantly shorter than comparison studies (p < 0.0001), thus meeting the primary endpoint. More remarkably, the laboratory response for participants starting with a PK‐guided dose was quite robust, achieving higher hemoglobin (10.1 ± 1.3 g/dL) and HbF (33.3 ± 9.1%) levels than traditional dosing. Though higher than traditional dosing, PK‐guided doses were safe without excess hematologic toxicities. Our data suggest early initiation of hydroxyurea, using a personalized dosing strategy for children with SCA, provides laboratory and clinical response beyond what has been seen historically, with traditional weight‐based dosing.

Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.sickle cell anemia | cardiomyopathy | restrictive physiology | arrhythmias | sudden death S ickle cell anemia (SCA) results from a point mutation in the β-globin gene and affects millions world-wide. It is characterized by production of the mutant hemoglobin S (HbS), which polymerizes upon deoxygenation and distorts the shape of RBCs, increasing their propensity to hemolysis and microvascular occlusion. Recurrent cycles of HbS polymerization result in a host of acute and chronic complications, including vaso-occlusive pain crisis, chronic hemolytic anemia, and organ damage. SCA-associated mortality rates have improved because of early diagnosis with universal newborn screening, immunization, and penicillin prophylaxis, which has changed the natural history of SCA (1, 2) and the impact of SCA on organ pathologies is now becoming evident.Despite improved early survival, nearly one-third of young adults with SCA die suddenly (3-9). The sickle myocardium has been presumed to be relatively resistant to the effects of sickling (10), and studies/autopsies show little evidence of atherosclerosis or coronary disease (11)(12)(13)(14). Mildly increased systolic pulmonary arterial pressure (PAP) estimated by tricuspid regurgitant jet vel...