Mechanistic Insights and Characterization of Sickle Cell Disease–Associated Cardiomyopathy

Desai, Ankit A.; Patel, Amit R.; Ahmad, Homaa; Groth, John V.; Thiruvoipati, Thejasvi; Turner, Kristen M.; Yodwut, Chattanong; Czobor, Peter; Artz, Nicole; Machado, Roberto F.; Garcia, Joe G.N.; Lang, Roberto M.

doi:10.1161/circimaging.113.001420

Cited by 55 publications

(86 citation statements)

References 21 publications

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“…Thus, LVED enlargement and LVH were more noticeable in meta-analysis results, compared to our data from a younger cohort of SCD patients than most studies in the meta-analysis. A recent publication described 4-chamber dilation, normal systolic function and diastolic dysfunction in adults with SCD(31) that contrasts with our data in a much younger cohort with milder anemia. With increasing age, LV dilation and LVH are expected to worsen, resulting in progressive 4-chamber dilatation.…”

Section: Discussioncontrasting

confidence: 99%

Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease

Niss¹,

Quinn²,

Lane³

et al. 2016

JACC: Cardiovascular Imaging

115

137

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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.

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Section: Discussioncontrasting

confidence: 99%

Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease

Niss¹,

Quinn²,

Lane³

et al. 2016

JACC: Cardiovascular Imaging

115

137

View full text Add to dashboard Cite

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“…It has been recently reported that some degree of focal LV fibrosis measured using late gadolinium enhancement can be seen in young adults with SCA by CMR (42,48), and LV fibrosis was also reported in autopsies of young adults with SCA who died suddenly (77). Moreover, recent reports suggest dysregulated profibrotic pathways are up-regulated in SCA in general, as polymorphisms in TGF-β signaling pathway genes have been found in this patient population (78).…”

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

confidence: 56%

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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“…This was associated with improved left ventricular outflow tract dimensions, suggesting a possible contribution of FD in delaying the progression of SCD cardiovascular disease. [54][55][56] We demonstrated a synergistic effect of ω-3 PUFA on both ET-1-mediated endothelial dysfunction and VCAM-1-mediated endothelial activation on aortas following H/R ( Figure 6A). Notably, FD also significantly reduced VCAM-1 expression in livers of SS mice exposed to H/R stress compared to the expression in SS-SD mice ( Figure 5).…”

Section: Discussionmentioning

confidence: 89%

Dietary -3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease

et al. 2015

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The anemia of sickle cell disease is associated with a severe inflammatory vasculopathy and endothelial dysfunction, which leads to painful and life-threatening clinical complications. Growing evidence supports the anti-inflammatory properties of ω-3 fatty acids in clinical models of endothelial dysfunction. Promising but limited studies show potential therapeutic effects of ω-3 fatty acid supplementation in sickle cell disease. Here, we treated humanized healthy and sickle cell mice for 6 weeks with ω-3 fatty acid diet (fish-oil diet). We found that a ω-3 fatty acid diet: (i) normalizes red cell membrane ω-6/ ω-3 ratio; (ii) reduces neutrophil count; (iii) decreases endothelial activation by targeting endothelin-1 and (iv) improves left ventricular outflow tract dimensions. In a hypoxia-reoxygenation model of acute vaso-occlusive crisis, a ω-3 fatty acid diet reduced systemic and local inflammation and protected against sickle cell-related end-organ injury. Using isolated aortas from sickle cell mice exposed to hypoxia-reoxygenation, we demonstrated a direct impact of a ω-3 fatty acid diet on vascular activation, inflammation, and anti-oxidant systems. Our data provide the rationale for ω-3 dietary supplementation as a therapeutic intervention to reduce vascular dysfunction in sickle cell disease. ABSTRACTmice. 16,17 The animal protocol was approved by the Animal Care and Use Committee of the University of Verona (CIRSAL). Twomonth old animals were fed for 6 weeks with either the standard AIN-93M purified rodent diet (soy-diet with n6/n3 ratio of 8:1 -Dyets Inc., Bethlehem, PA, USA), containing 140 g/kg casein, 1.8 g/kg L-cystine, 100 g/kg sucrose, 465.9 g/kg cornstarch, 155 g/kg dextrose, 40 g/kg soybean oil, 0.8 mg/kg t-butylhydroquinone, 50 g/kg cellulose, 35 g/kg mineral mix, 10 g/kg vitamin mix, and 2.5 g/kg choline bitartrate 18 or the ω-3 FD, an AIN-93M-based purified rodent diet in which all of the calories provided by fat (10%) are replaced by 7.9% from HCO and 2.1% from ω-3 oil (Dyets Inc., Bethlehem, PA, USA). At the end of the 6 weeks of FD supplementation, animals were anesthetized with isofluorane, and whole blood was collected from each mouse via retro-orbital venipuncture by heparinized microcapillaries. Mice were euthanized and organs removed immediately. The organs were divided into two and either frozen immediately in liquid nitrogen or fixed in 10% formalin and embedded in paraffin for histology. Whenever indicated, 6-week old mice were exposed to hypoxia (8% oxygen for 10 h) followed by 3 h of reoxygenation (21% oxygen) (H/R stress) to mimic an acute VOC, as previously described.

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Mechanistic Insights and Characterization of Sickle Cell Disease–Associated Cardiomyopathy

Cited by 55 publications

References 21 publications

Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease

Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Dietary -3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease

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