Severity of pulmonary hypertension during vaso‐occlusive pain crisis and exercise in patients with sickle cell disease

Machado, Roberto F.; Mack, Alexandra; Martyr, Sabrina; Barnett, Christopher F.; MacArthur, Peter H.; Sachdev, Vandana; Ernst, Inez; Hunter, Lori A.; Coles, Wynona; Nichols, James; Kato, Gregory J.; Gladwin, Mark T.

doi:10.1111/j.1365-2141.2006.06417.x

Cited by 110 publications

(93 citation statements)

References 44 publications

(46 reference statements)

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“…6,11 The present study was prospective, included children as young as 3 years of age with mild to severe sickle phenotypes, and avoided effects of exercise or acute vaso-occlusive crisis, known to be confounding factors for the determination of steady state jet velocity in patients. 27 In particular, patients who were hospitalized in the preceding 3 weeks could not be enrolled and this …”

Section: Discussionmentioning

confidence: 99%

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

Minniti¹,

Sable²,

Campbell³

et al. 2009

Haematologica

165

144

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BackgroundElevation of echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The definition, prevalence and clinical correlates of elevated jet velocity have not been established in pediatric patients. The present study tested the hypotheses that elevated jet velocity affects 10% of pediatric patients, is associated with both hemolysis and hypoxia, and has clinical correlates with acute chest syndrome, stroke, transfusion requirement and abnormal 6-minute walk test results. Design and MethodsA prospective multicenter study of 310 patients aged 3-20 years old with sickle cell disease under basal conditions and 54 matched controls was conducted. A hemolytic index was generated by principal component analysis of the levels of lactate dehydrogenase, aspartate aminotransferase and bilirubin and reticulocyte count. ResultsElevated jet velocity (defined as ≥2.60 m/sec based on the mean±2 SD in controls) occurred in 32 patients (11.0%) including one child of 3 years old. After adjustment for hemoglobin concentration, systolic blood pressure and left ventricular diastolic function, a 2 SD increase in the hemolytic index was associated with a 4.5-fold increase in the odds of elevated jet velocity (p=0.009) and oxygen saturation ≤98% with a 3.2-fold increase (p=0.028). Two or more episodes of acute chest syndrome had occurred in 28% of children with elevated jet velocity compared to in 13% of other children (p=0.012), more than ten units of blood had been transfused in 39% versus 18% (p=0.017) and stroke had occurred in 19% versus 11% (p=0.2). The distance walked in 6-minute walk tests did not differ significantly, but oxygen saturation declined during the tests in 68% of children with elevated jet velocity compared to in 32% of other children (p=0.0002). ConclusionsAccording to a pediatric-specific definition the prevalence of elevated jet velocity in this population of young patients with sickle cell disease was 11%. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation. Further investigations should address whether elevated jet velocity may indicate future complications and whether early intervention is beneficial.Key words: sickle cell disease, pulmonary hypertension, hemolysis, oxygen saturation, tricuspid regurgitant jet velocity, children.Citation: Minniti CP, Sable C, Campbell A, Rana S, Ensing G, Dham N, Onyekwere O, Nouraie M, Kato GJ, Gladwin MT, Castro OL, and Gordeuk VR. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 2009; 94:340-347. doi:10.3324/haematol.13812 ©2009 Ferrata Storti Foundation.

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Section: Discussionmentioning

confidence: 99%

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

Minniti¹,

Sable²,

Campbell³

et al. 2009

Haematologica

165

144

View full text Add to dashboard Cite

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“…Various markers of hemolysis, such as plasma LDH concentration, reticulocyte count, plasma arginase activity and hemoglobin, have been correlated with pulmonary hypertension in those patients [40]. A recent study in SCD patients showed that pulmonary artery pressure and pulmonary vascular resistance were increased during vaso-occlusive crises in parallel to hemolysis and hemoglobin level drop [41]. This correlation may represent the functional component of a strong hemolytic effect on the top of chronic lung vascular injury, an injury that may vary according to patients' age.…”

Section: Discussionmentioning

confidence: 99%

Cardiac involvement in sickle β-thalassemia

et al. 2008

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Cardiovascular involvement is a leading cause of mortality and morbidity in patients with inherited hemoglobinopathies, but it has not been adequately assessed in sickle β-thalassemia. We evaluated 115 sickle β-thalassemia patients, aged 34±14 years, along with 50 healthy controls, by resting echocardiography. Patients with systolic left ventricular (LV) dysfunction or severe pulmonary hypertension (PHT) also underwent left and right cardiac catheterization and cardiac magnetic resonance imaging (CMR). Left and right chamber dimensions, LV mass, and cardiac index were significantly higher in patients compared to controls (p<0.001 in most cases). Three patients (2.9%) had reduced LV ejection fraction (<55%); mean LV ejection fraction was significantly lower in patients (p< 0.001). Left and right ventricular systolic tissue Doppler indices and LV diastolic tissue Doppler indices were also impaired in patients. All three patients with systolic LV dysfunction had normal coronary arteries and mild myocardial iron load (CMR T2* values, 18-25 ms). Systolic pulmonary artery pressure was significantly higher in patients compared to controls (p=0.002); PHT was present in 28 patients (27%), while severe PHT in three (2.9%). In three patients with severe PHT, only one had impaired LV ejection fraction and increased pulmonary wedge pressure. Overall, three patients (2.9%) had a history of heart failure, two with systolic LV dysfunction, and one with severe PHT. Cardiac involvement in sickle β-thalassemia concerns biventricular dilatation and dysfunction along with PHT, leading to congestive heart failure.

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“…We propose that in our SCA mice, LAE is a downstream consequence of microscopic myocardial fibrosis, leading to ventricular diastolic dysfunction and in turn, impaired LA emptying and LA hypertension. Restrictive LV filling and LA hypertension may lead to elevated pulmonary venous pressure, a feature associated with increased TRV in patients with SCA (18,65,66).…”

Section: Berk-ss Mice Develop Corrected Qt Prolongation and Widening mentioning

confidence: 99%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Severity of pulmonary hypertension during vaso‐occlusive pain crisis and exercise in patients with sickle cell disease

Cited by 110 publications

References 44 publications

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

Cardiac involvement in sickle β-thalassemia

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

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