Right Ventricular and Pulmonary Function in Sickle Cell Disease Patients with Pulmonary Hypertension

2006 ◽  
Vol 27 (4) ◽  
pp. 440-446 ◽  
Author(s):  
Ferit Akgül ◽  
Fatih Yalçin ◽  
Cenk Babayiğit ◽  
Ergün Seyfeli ◽  
Tunzale Seydaliyeva ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Right Ventricular ◽  
Sickle Cell ◽  
Cell Disease

TSP1-CD47 Signaling Modulates the Severity of Pulmonary Hypertension in a Mouse Model of Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 898-898
Author(s):  
Enrico M Novelli ◽  
Mingyi Yao ◽  
Xiaojun Huang ◽  
Jeffrey Baust ◽  
Hunter Champion ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Sickle Cell ◽  
Systolic Pressure ◽  
Cell Disease ◽  
C57bl Mice ◽  
No Signaling

Abstract Abstract 898 In sickle cell disease (SCD), mutant hemoglobin S polymerizes when deoxygenated, driving red blood cell (RBC)-dependent vaso-occlusion and hemolysis. These processes lead to platelet and hemostatic activation, pulmonary hypertension (PH) and vascular disease. Transgenic-knockout sickle (BERK) mice that express exclusively human α- and βS-globins mimic SCD in humans by displaying reduced nitric oxide (NO) bioavailability, impaired NO-mediated vascular reactivity and PH. Recently, the platelet α-granule protein thrombospondin-1 (TSP1) was found to be elevated in the plasma of patients with SCD and to potently inhibit physiologic NO signaling, via binding to the cell surface receptor CD47. We hypothesized that blocking the TSP1-CD47 interaction may restore NO signaling and prevent PH in BERK mice. To test this hypothesis we conducted a transplantation experiment to explore the repopulating potential of BERK bone marrow (BM) in lethally myeloablated CD47KO recipients and the impact of the CD47 null milieu on the PH phenotype. We harvested the BM from 5–6 months old BERK mice and transplanted it into irradiated (10 Gy) 8–9 weeks old CD47KO mice (n=9). All recipients survived transplantation and were terminally evaluated 4 months post transplantation. Mice underwent blood sampling for determination of engraftment by hemoglobin electrophoresis, evaluation of endothelial dependent arterial vasodilation by myography, full pulmonary hemodynamic assessment and measurement of right ventricular hypertrophy (RVH) using the Fulton Index (ratio of ventricular weights (right ventricle/left ventricle including septum). The chimeras had 98.3% (SD 0.6%) hemoglobin S, thereby demonstrating full donor chimerism. Segments of thoracic aortas from the chimeras were mounted on a myograph system and exposed to acetylcholine, a physiologic vasodilator that stimulates endothelial nitric oxide synthase (eNOS) activation. Concentration-response curves showed that the arterial segments from chimeras that lacked tissue CD47 had improved endothelial-dependent vasodilation, as evaluated by % relaxation in response to acetylcholine, as compared to arterial segments from BERK mice (P < 0.05). Hemodynamic data showed that the tissue CD47KO chimeras had lower right ventricular end systolic pressure (RV ESP) as compared to BERK mice (22 vs. 31 mm Hg, p<0.05). Conversely, their RV ESP did not significantly differ from historical control C57BL/6 mice (22 vs. 20 mm Hg, NS, panel A). Measurement of RVH (Fulton Index) similarly revealed that the chimeras were protected from RVH (p<0.05, panel B). Thus, despite the presence of sickle RBC, the absence of the TSP1-CD47 signaling axis improved endothelial-eNOS-NO signaling and reduced pulmonary pressures and RVH responses. These data demonstrate that BM from BERK mice successfully engrafts CD47KO mice, and that in the absence of the TSP1-CD47 axis endothelial and vascular function improves and PH is ameliorated. We now plan to validate these results in controlled experiments where BM from BERK mice is transplanted in CD47KO and C57BL mice as controls. We expect that unlike C57BL mice transplanted with BERK BM, CD47KO mice will be protected from the vascular complications of SCD, including PH.Figurelegend: CD47KO mice transplanted with BERK BM (chimeras) show improved hemodynamics (Panel A) and less right ventricular (RV) hypertrophy as measured by the Fulton Index as compared to BERK mice (Panel B). * = statistically significant, NS = non significant, RV ESP = right ventricle end systolic pressure.Figure. legend: CD47KO mice transplanted with BERK BM (chimeras) show improved hemodynamics (Panel A) and less right ventricular (RV) hypertrophy as measured by the Fulton Index as compared to BERK mice (Panel B). * = statistically significant, NS = non significant, RV ESP = right ventricle end systolic pressure. Disclosures: Isenberg: Vasculox, Inc.: Equity Ownership.

Pulmonary Hypertension in Children and Adolescents with Sickle Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3787-3787 ◽  
Author(s):  
Aziza Sedrak ◽  
Sreedhar P. Rao ◽  
Scott T. Miller ◽  
Vahid Hekmet ◽  
Madu Rao
Keyword(s):  
Obstructive Sleep Apnea ◽  
Pulmonary Hypertension ◽  
Sleep Apnea ◽  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Sickle Cell ◽  
Pulmonary Function Tests ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Obstructive Sleep

Abstract Pulmonary hypertension occurs in 20–40% of adults with sickle cell disease and has a poor prognosis; age of onset and prevalence in childhood are not well established. In adults, recurrent acute chest syndrome is associated with chronic sickle cell lung disease and perhaps pulmonary hypertension. Hematologically normal children with obstructive sleep apnea are at risk for pulmonary hypertension. We sought to determine the prevalence of pulmonary hypertension in children and adolescents with sickle cell disease, explore potential association with abnormal pulmonary function or sleep apnea, and identify other clinical or laboratory factors associated with this potentially life-threatening complication. Forty-eight patients (age 5–21 years, median 12 years) consented to participate. Thirty-eight (79%) had Hb SS; five each had Hb SC and S-beta thalassemia (three beta plus and two beta zero) (10.4%). Eleven (22.9%) were on chronic transfusion (seven for stroke, three for abnormal TCD velocity screening, and one for recurrent pain crises); nineteen (39.5%) were on hydroxyurea (ten for recurrent acute chest syndrome and nine for recurrent pain). A detailed history and physical examination were done on all enrolled subjects (history was comprehensive, but specifically included cardiopulmonary symptoms; neurological problems; number of pain crises and acute chest syndrome; blood transfusions; use of hydroxyurea; and a screening for obstructive sleep apnea). If apnea history was suggestive, polysomnography was done. In addition, all study subjects had Doppler echocardiography and pulmonary function tests (PFT). Pulmonary hypertension was defined as an age and body mass index-adjusted tricuspid regurgitant jet velocity (TRV) of greater than 2.5 mm/sec. Among the study group, 31 (64.5%) had pulmonary function tests; 17 (54.8%) had restrictive abnormalities on PFT, three (9.6%) had obstructive changes and 11 (35.4%) had normal PFT. Three patients (6.2%) had a history suggestive of apnea, then polysomnography; one was normal and two had OSA. Four of the 48 patients (8.3%) had PHT (TRV values 2.52, 2.55, 2.61, and 2.91). All had Hb SS. Two were age 17 and 18 years and two were 10 and 11. All were asymptomatic. One had restrictive PFT and none had OSA. There was no correlation between the presence of PHT and pulmonary function abnormalities or sleep apnea. Of the various other clinical and laboratory parameters examined, only an elevated serum indirect bilirubin was associated with PHT; there was a trend toward association with elevated reticulocyte count and low fetal Hb levels. In summary, the prevalence of PHT our pediatric sickle cell population is 8.3%. As reported in adults, there may be an association between PHT and more severe hemolysis. We could find no association with abnormal pulmonary function or obstructive sleep apnea. Characteristics of study patients PHT No PHT P Value Fetal Hb(%) (Mean) 3.7 7.9 .154 Age (Mean) 13.5 years 12 years .564 Reticulocytes (%) 13.8 8.25 .087 Indirect bilirubin (mg/dl) (Mean) 5.4 2.2 .027

Pulmonary Hypertension in Sickle Cell Disease: Correlation With Echocardiographic Assessment and Serum Brain Natriuretic Peptide Concentration

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4680-4680
Author(s):  
Salam Alkindi ◽  
Zeba Jabeen ◽  
Anil Pathare ◽  
Mohammed Al-Huneini ◽  
Murtadha Al Khabori ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sickle Cell ◽  
Pulmonary Function Tests ◽  
Direct Bilirubin ◽  
Cell Disease ◽  
Function Tests

Background & Purpose Pulmonary hypertension (PH) in sickle cell disease (SCD) is an important risk factor for complications including sudden death. In this study, we aimed to determine the prevalence of PH and correlate the echocardiographic parameters and general laboratory data with markers of hemolysis and serum NT pro-brain natriuretic peptide [BNP] concentrations in Omani SCD patients. Methods A cohort of 163 SCD patients [Mean age 25.4±8.4 years], in steady state was prospectively screened for PH with Doppler echocardiography (defined as a tricuspid regurgitation jet flow velocity of ≥ 2.5 m/sec and/or mean pulmonary artery pressure [mPAP] ≥25 mmHg). After a written informed consent, all patients were investigated with a complete blood count, renal chemistry, hemolytic parameters including LDH, haptoglobin, liver function tests, coagulation studies, HPLC studies including HbS and HbF level estimations, X ray Chest, ECG, ABG, Pulmonary function tests, Pulse oximetry, and Serum NT pro-BNP levels. Results In the evaluable patient cohort of 116 subjects [63 females, 53-males], the prevalence of PH was 5.2%. No statistically significant differences were detected in Hb levels, ECG, chest radiography, pulmonary function tests between patients with and without PH. However, plasma NT pro-BNP levels were significantly correlated with PAH [r=0.934, p<0.000], TRV jet [r=.671, p<0.000], Abnormal ECHO [r=0.672, p<0.000], and direct Bilirubin levels [r=0.278,p<0.009] in SCD patients. Furthermore, in SCD patients with PH, there was a statistically significant increase in plasma NT pro-BNP levels [ p<0.001], ALT [p<0.02], S. Creatinine [p=0.045] and Total bilirubin [p<0.0001] and direct Bilirubin levels [p<0.0001][Table]. Conclusions Serum NT pro-BNP is a strong indicator of PH in SCD patients. Doppler ultrasound echocardiography is a useful initial screen for PH in SCD patients. The correlation between PH and hemolytic markers suggests an implication in the pathogenesis of PH. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 5010-5020 ◽  
Author(s):  
Kori L. Wallace ◽  
Joel Linden
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Nk Cells ◽  
Natural Killer ◽  
Sickle Cell ◽  
Pulmonary Injury ◽  
Cell Disease ◽  
Inkt Cells ◽  
Adenosine A2a ◽  
Hypoxia Reoxygenation

Abstract We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A2A receptor (A2AR) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A2AR agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1−/− mice reduced pulmonary injury that was restored by adoptive transfer of 106 purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A2AR alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ϵ]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A2ARs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation–induced exacerbation of pulmonary injury. A2A agonists have promise for treating diseases associated with iNKT or NK cell activation.

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