Correlations Between Cytokines and Elevated Tricuspid Regurgitant Jet Velocity in Children and Adolescents with Sickle Cell Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2484-2484
Author(s):  
Xiaomei Niu ◽  
Mehdi Nouraie ◽  
Caterina Minniti ◽  
Craig Sable ◽  
Andrew Campbell ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Children And Adolescents ◽  
Sickle Cell ◽  
Plasma Concentrations ◽  
Interferon Γ ◽  
Cell Disease ◽  
Jet Velocity ◽  
Factor Α

Abstract Background:The pathogenesis of pulmonary hypertension in sickle cell disease is not fully defined. We have found independent associations of hemolysis and hemoglobin oxygen desaturation with elevated tricuspid regurgitant jet velocity in a prospective multicenter study of 310 children and adolescents with sickle cell disease. The present report includes a subset of these patients in whom we investigated the association with jet velocity of an array of cytokines and biomediators that have previously been associated with vasculopathy and primary or secondary hypertension. Methods:Jet velocity was prospectively determined by Doppler echocardiograph in 237 children and adolescents with sickle cell disease at steady state. Elevated jet velocity was defined as ≥2.6 m/sec based on the mean + 2 SD in control subjects matched by age, sex and ethnicity to every sixth patient. Plasma concentrations of interleukins-6, 8 and10, interferon-γ, tumor necrosis factor-α, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB (PDGF-BB) and Regulated upon Activation Normal T-cell Expressed and Secreted (RANTES) were determined by a multiplex cytokine kit and the Bio-Plex suspension array system (Bio-Rad, Hercules, CA). Plasma concentrations of endothelin-1 and serum concentrations of erythropoietin were analyzed by ELISA (R&D Systems, Minneapolis, MN). Levels of significance were adjusted for multiple comparisons. A hemolytic index was derived by principle component analysis of reticulocyte count, aspartate aminotransferase, total bilirubin and lactate dehydrogenase. Oxygen saturation of hemoglobin was determined by pulse oximetry. Results:Interleukins-8 and 10, VEGF and erythropoietin were significantly increased in sickle cell disease patients compared with controls while RANTES was significantly decreased. Among patients with sickle cell disease, interleukins-6 and 8, interferon-γ, tumor necrosis factor-α, PDGF-bb, erythropoietin and RANTES had significant positive correlations with jet velocity in bivariate analyses. Of these, only interleukin-8 and erythropoietin correlated significantly with the hemolytic index in bivariate analyses. By logistic regression, interleukin-6 (p = 0.020) and PDGF-bb (P = 0.003) were independently associated with increased odds of elevated jet velocity while VEGF was independently associated with decreased odds (P = 0.004). These associations persisted after adjustment either for the degree of hemolysis or for hemoglobin oxygen saturation. Conclusion: Similar to observations in primary and experimental pulmonary hypertension, altered expression of interleukin-6, PDGF-bb and VEGF may be associated with the development of pulmonary hypertension in children with sickle cell disease. At least some of these effects may be additive to those of hemolysis and hypoxia. Further investigations of these pathways may be appropriate in the search for new therapeutic modalities.

scholarly journals High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension

Blood ◽  
2010 ◽  
Vol 116 (1) ◽  
pp. 109-112 ◽  
Author(s):  
Nambirajan Sundaram ◽  
Anitaben Tailor ◽  
Laurel Mendelsohn ◽  
Janaka Wansapura ◽  
Xunde Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Right Ventricle ◽  
Sickle Cell ◽  
Angiogenic Factor ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Endothelin 1 ◽  
Erythroid Hyperplasia

Abstract Pulmonary hypertension is associated with reduced nitric oxide bioavailability and early mortality in sickle cell disease (SCD). We previously demonstrated that placenta growth factor (PlGF), an angiogenic factor produced by erythroid cells, induces hypoxia-independent expression of the pulmonary vasoconstrictor endothelin-1 in pulmonary endothelial cells. Using a lentivirus vector, we simulated erythroid expression of PlGF in normal mice up to the levels seen in sickle mice. Consequently, endothelin-1 production increased, right ventricle pressures increased, and right ventricle hypertrophy and pulmonary changes occurred in the mice within 8 weeks. These findings were corroborated in 123 patients with SCD, in whom plasma PlGF levels were significantly associated with anemia, endothelin-1, and tricuspid regurgitant velocity; the latter is reflective of peak pulmonary artery pressure. These results illuminate a novel mechanistic pathway linking hemolysis and erythroid hyperplasia to increased PlGF, endothelin-1, and pulmonary hypertension in SCD, and suggest that strategies that block PlGF signaling may be therapeutically beneficial. This trial was registered at http://clinicaltrials.gov as #NCT00011648.

Elevation of tricuspid regurgitant jet velocity, a marker for pulmonary hypertension in children with sickle cell disease

2006 ◽  
Vol 47 (7) ◽  
pp. 907-913 ◽  
Author(s):  
Steven J. Ambrusko ◽  
Sriya Gunawardena ◽  
Allison Sakara ◽  
Beth Windsor ◽  
Lizabeth Lanford ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Jet Velocity ◽  
Hypertension In Children ◽  
Tricuspid Regurgitant Jet Velocity

Tricuspid Regurgitant Jet Velocity Is Significantly Associated with Hemolysis in the Evaluation of Pulmonary Hypertension in Children and Young Adults with Sickle Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1211-1211
Author(s):  
Robert I. Liem ◽  
Nichele M. Willingham ◽  
Luciana T. Young ◽  
Alexis A. Thompson
Keyword(s):  
Pulmonary Hypertension ◽  
Young Adults ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Reticulocyte Count ◽  
Cell Disease ◽  
Significant Difference ◽  
Children And Young Adults ◽  
Jet Velocity ◽  
Tricuspid Regurgitant Jet Velocity

Abstract Pulmonary hypertension (PHT) has emerged as a frequent cause of increased morbidity and mortality in adults with sickle cell disease (SCD). However, the incidence, prevalence and etiology of PHT in children with SCD are currently unknown. An elevated tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/sec on Doppler echocardiogram (ECHO) in adults may predict PHT usually diagnosed by traditional cardiac catheterization. We hypothesized that routinely measuring TRJV in children and young adults with SCD was feasible and that TRJV correlated with degree of baseline hemolysis. Methods Using a standard protocol, we prospectively measured steady state TRJV in a convenience, cross-sectional sample of 43 patients (mean age 14.2±2.8 years, range 10 to 20) with hemoglobin (Hb) SS, SC or S-β0 thalassemia at our institution as part of a PHT screening initiative beginning December 2005. Patients on chronic transfusions were excluded. The relationship between TRJV and same day laboratory studies and clinical data obtained from patient charts was examined. Results TRJV was not measurable in 5 of 43 (12%) patients, due presumably to normal pulmonary artery systolic pressures. Neither right ventricular hypertrophy nor decreased septal wall motion, both suggestive of PHT, was present when TRJV could not be determined. In the remaining 38 studies in which TRJV could be quantified (mean 2.34 m/sec±0.44), TRJV was ≥ 2.5 m/sec in 13 patients. Using Pearson’s correlation coefficient, we found a significant correlation between TRJV and LDH (r=0.54, p=0.01), with higher TRJV associated with higher LDH. There were also significant, though more modest, positive correlations between TRJV and WBC (r=0.37, p=0.05) and reticulocyte count (r=0.40, p=0.05) and a significant negative correlation between TRJV and Hb (r= -0.46, p=0.01). Using t-test for independent samples, we found a significant difference in mean LDH (458 IU/L±192 vs. 338 IU/L±144, p=0.037), Hb (8.7 g/dL±1.3 vs. 10.2 g/dL±1.6, p=0.008) and reticulocyte count (17.3%±10.3 vs. 10.7%±6.9, p=0.027) between patients with TRJV ≥ 2.5 and <2.5 m/sec. A difference approaching significance in total WBC (11.4 x103/μL±5.3 vs. 8.3 x103/μL ±3.2, p=0.075) was also observed between the two groups. We found neither a significant difference in mean values between the two groups nor significant relationships with TRJV when we examined platelet count, plasma free Hb, percent fetal Hb or total bilirubin. Using Fisher’s Exact Test, we did not demonstrate in our small cohort a difference in the proportion of patients with TRJV ≥ 2.5 or < 2.5 m/sec who had a history of hydroxyurea use, acute chest syndrome, frequent pain, asthma, splenectomy, gallstones, priapism, exchange transfusion, heart disease or tonsilloadenoidectomy. Conclusions We conclude that TRJV by ECHO is quantifiable in most children and young adults being evaluated for PHT and that a higher LDH and reticulocyte count and a lower Hb at baseline are observed more frequently with elevated TRJV. Larger cohort studies are needed to test the predictive value of one or more of these markers of hemolysis. Although long term outcomes associated with elevated TRJV, as an indication of PHT, in children with SCD remains unclear, decreasing hemolysis in this population may represent an early therapeutic target in the prevention of future clinically significant PHT.

Pulmonary Hypertension in Sickle Cell Disease: Cardiopulmonary Evaluation and Response to Chronic Phosphodiesterase 5 Inhibitor Therapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 235-235 ◽  
Author(s):  
Roberto F. Machado ◽  
Sabrina E. Martyr ◽  
Anastasia Anthi ◽  
Gregory J. Kato ◽  
Lori A. Hunter ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Functional Capacity ◽  
Cell Disease ◽  
Walk Distance ◽  
Jet Velocity ◽  
Minute Walk Distance ◽  
Minute Walk ◽  
Tricuspid Regurgitant Jet Velocity

Abstract Pulmonary hypertension (PH) is a risk factor for mortality in Sickle Cell Disease, but it is unclear whether pulmonary hypertension is a marker or a direct cause of mortality. To better understand the pathophysiology of pulmonary hypertension in patients with sickle cell disease we performed evaluations of cardiopulmonary function in sickle cell disease patients with pulmonary hypertension (n= 15, mean age = 41 ± 2.4 years, males = 7, HbSS = 15, mean Hb = 8.3 ± 0.2 g/dl, mean tricuspid regurgitant jet velocity = 3.2 ± 0.11 m/s) compared to matched controls with sickle cell disease without pulmonary hypertension (n=11, mean age=40.2 ± 2.5 years, males=4, HbSS=11, mean Hb=8.5 ± 0.3 g/dl, mean tricuspid regurgitant jet velocity = 2.28 ± 0.07 m/s). To evaluate if specific therapy for pulmonary hypertension has any impact on systolic pulmonary artery pressure (PAP), estimated by tricuspid regurgitant jet velocity (TRJ), and functional capacity, measured by six-minute walk test (a well validated surrogate of functional capacity and response to therapy in patients with other causes of pulmonary hypertension), we treated 14 patients with sickle cell disease and pulmonary hypertension (mean age = 40 ± 2.5 years, males = 3, HbSS = 14, mean Hb = 8.8 ± 0.6 g/dl, mean TRJ = 3.4 ± 0.1 m/s) with sildenafil for at least three months. When compared to controls pulmonary hypertension patients had lower maximal oxygen consumption (VO2 max (% predicted), +PH: 44 ± 4, −PH: 55 ± 4; P=0.41), walked shorter six-minute walk distance (meters, +PH: 308.5 ± 53.8, −PH: 427.1 ± 44.6; P=0.03), demonstrated greater degree of interstitial lung disease by chest CT (P < 0.05), and more perfusion impairments measured by ventilation perfusion scan (P < 0.05). Six-minute walk distance correlated directly with maximal oxygen consumption (R=0.6; P=0.01), and inversely with mean pulmonary arterial pressure (R= −0.5; P=0.03) and tricuspid regurgitant jet velocity (R= −0.6;P=0.002), suggesting that the test is an adequate surrogate of functional capacity and response to therapy in pulmonary hypertension patients with sickle cell disease. Chronic treatment with sildenafil (up to 100 mg TID) decreased pulmonary arterial pressure (PAP mmHg, baseline: 50 ± 4.4, sildenafil: 41 ± 2.5; P=0.04) and increased six-minute walk distance (meters, baseline: 394 ± 31, sildenafil: 476 ± 26: P= 0.02). Sildenafil was well tolerated with only 2 patients stopping the drug due to headaches. We also observed 3 episodes of transient eyelid edema not requiring discontinuation of drug. Priapism was not observed in the 3 males treated (2 on exchange transfusion therapy, 1 with erectile dysfunction). In conclusion, we find that in patients with sickle cell disease, 1) pulmonary hypertension, though relatively mild, is associated with severe impairments in cardiopulmonary function, 2) traditional markers of functional capacity such as six-minute walk test can be utilized in this population as a therapeutic endpoint for clinical trials, 3) and therapy with sildenafil seems to have a favorable impact on pulmonary pressures and functional capacity.

Role of Hypoxia Induced Factor (HIF-1 alpha) in Pulmonary Hypertension in Sickle Cell Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2493-2493
Author(s):  
Mukta Kumar ◽  
Xuhui Zhu ◽  
Shilpa Buch
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Target Genes ◽  
Rna Isolation ◽  
Rna Expression ◽  
Cell Disease ◽  
Control Groups

Abstract Background. Pulmonary hypertension is a leading cause of mortality in sickle cell disease (SCD), however, the mechanisms leading to the development of pulmonary hypertension remain poorly understood. The pathogenesis of SCD revolves around chronic hypoxia and hypoxic events that are mediated through the upregulation of hypoxia-inducible factor-1alpha (HIF-1alpha), a transcriptional factor, that is involved in regulation of several redox sensitive genes including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and ApoE. The objective of this study was to examine the role of HIF-1 and its target genes in SCD-associated pulmonary lung disease. Methods. In this study, 3 groups of age-matched homo and hemizygous sickle and control C57/Bl6 mice (Jackson Labs) were sacrificed and organs harvested for RNA isolation in Trizol. Using quantitative RT-PCR we assessed the RNA expression of HIF-1 and its target genes, VEGF and PDGF-B from the lungs of homozygous sickle mice and compared these with the C57/BL6 and the hemizygous sickle controls. HPRT was used as the housekeeping gene control. Results. Homozygous sickle mice demonstrated an upregulation of HIF-1 alpha RNA (almost 2.3 fold) compared with the hemizygous sickle and the C57/Bl6 controls. VEGF RNA expression was elevated ~8.3 to 10.9 fold in sickle mice compared to the two control groups. Interestingly there was a down regulation of PDGF-B expression (0.3 fold) in the sickle mice group compared to the control groups. In contrast, expression of all the HIF-related genes tested was down-regulated in the spleens and brains of sickle mice compared with the respective control tissues. Discussion. These findings support the possibility that complex molecular pathways, including dysregulation of HIF pathway, may contribute to the development of pulmonary hypertension in sickle cell disease and underscore role of oxidative stress pathways in the onset of disease pathogenesis.

Placental Growth Factor Is Elevated in Patients with Sickle Cell Disease and Associated with Pulmonary Hypertension, Hemolysis, Inflammation, Iron Overload, and Hepatic Dysfunction.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1531-1531
Author(s):  
Laurel Mendelsohn ◽  
Anitaben Tailor ◽  
Gregory J Kato
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Hepatic Dysfunction ◽  
Transferrin Saturation ◽  
Placental Growth Factor ◽  
Cell Disease ◽  
Pulmonary Pressure

Abstract Abstract 1531 Poster Board I-554 Placental Growth Factor (PlGF) is a functional cytokine in the vascular endothelial growth factor (VEGF) family that generally promotes angiogenesis, depending on the specific context, and can also promote atherogenesis. Produced in erythroid cells, its level in patients with sickle cell disease (SCD) has been previously related to the rate of erythropoiesis. We evaluated PlGF plasma levels in SCD patients by ELISA, and related it to biomarkers of pulmonary hypertension (PH), an emerging and serious complication of SCD linked to early mortality. We find that PlGF levels are significantly higher in SCD (n=95) than healthy African American control subjects (n=19) (median 16.6 vs. 2.1 pg/mL, p<0.001). PlGF levels were higher in SCD patients with elevated pulmonary pressure (normal pulmonary pressure vs. mildly elevated vs. highly elevated: medians 13.7 vs. 16.7 vs. 19.8 pg/mL, p<0.0001). Supporting a linkage to rate of hemolysis, PlGF correlated with LDH (p=0.001) and inversely with hemoglobin level (p<0.0001). Suggesting a link to inflammation, PlGF correlated significantly with C-reactive protein (p=0.001) and erythrocyte sedimentation rate (p<0.001). PlGF correlated with markers of iron overload, including ferritin, transferrin saturation and inversely with transferrin (all p<0.001). Finally, PlGF correlated with markers of hepatic dysfunction, including low albumin and high direct bilirubin (p<0.001). We found significantly higher PlGF levels in SCD patients taking hydroxyurea compared to those not taking it (median 17.4 vs. 14.0 pg/ml, p<0.01). Confirming that hydroxyurea increases PlGF levels, in a separate cohort of seven patients, PlGF levels rose significantly from their baseline values after initiating hydroxyurea (median approx 22 vs. 27, p<0.05). Our data suggest that elevated PlGF level is associated with PH in patients with SCD, and PlGF is correlated with severity of hemolysis, inflammation, iron overload and hepatic dysfunction. Considering the variable evidence in the literature for either stimulating or inhibiting angiogenesis, it is not clear whether pathologic elevation of PlGF may be mediating pulmonary hypertension, or perhaps conversely providing an adaptive response to vascular damage. It has been suggested by Perelman et al. that PlGF may mediate leukocyte activation that might promote disease severity in SCD. However, hydroxyurea, which tends to ameliorate SCD complications, stimulates PlGF level in an unexpected manner, possibly related to the ability of hydroxyurea to stimulate erythropoietin production, which might in turn induce PlGF. Further research is needed to reconcile the role of PlGF in PH in SCD. Disclosures Tailor: Mesoscale: Employment.

Acute on Chronic Pulmonary Hypertension in Patients with Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1669-1669 ◽  
Author(s):  
Gregory J. Kato ◽  
Sabrina Martyr ◽  
Roberto Machado ◽  
Vandana Sachdev ◽  
Inez Ernst ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Mortality Rate ◽  
Sickle Cell ◽  
Hemoglobin Concentration ◽  
Cell Disease ◽  
Marked Rise ◽  
Jet Velocity ◽  
Tricuspid Regurgitant Jet Velocity

Abstract Secondary pulmonary hypertension (PHT), defined as a tricuspid regurgitant jet velocity (TRV) > 2.4 meters/second at rest, has been identified as an emerging complication in patients with sickle cell disease, with 32% prevalence. Patients with sickle cell pulmonary hypertension tend to have a higher mortality rate than patients with primary PHT at comparable pulmonary artery pressures (PAP). We analyzed prospectively obtained Doppler echocardiography measurements from 11 patients in steady-state and during vaso-occlusive crisis episodes or during exercise to determine whether pulmonary pressures became further elevated during stress. We found that tricuspid regurgitant jet velocity is significantly further elevated during vaso-occlusive crisis (2.61 ± 0.03 vs. 2.81 ± 0.06 m/sec (mean ± SEM), p = 0.01)(Fig. A). We assessed other laboratory parameters and found associated significant decreases in hemoglobin concentration (9.3 ± 0.3 vs. 8.4 ± 0.3 gm/dL, p = 0.02)(Fig. B), and significant elevations in lactate dehydrogenase (381 ± 39 vs. 442 ± 49 IU/L, p = 0.02)(Fig. C). These data are consistent with increased hemolysis during vaso-occlusive crisis, and the association of increased hemolysis with acute exacerbation of PHT in patients with SCD. In three patients at steady state, exercise echocardiograms were performed, showing acute marked rise in TRV during exercise (2.80 ± 0.12 vs. 3.37 ± 0.17 m/sec, p = 0.02)(Fig. D). These data bring to light several important points in the clinical assessment of tricuspid regurgitant jet velocity in patients with sickle cell disease. First, the relatively mild steady state PHT in patients with SCD is associated with previously unappreciated acute increases in PAP that may explain the high mortality rate in this population. This might be responsible for sudden death occurring during vaso-occlusive crisis or physical exertion. Second, this acute rise is associated with markers of increased hemolysis, further implicating hemolysis-associated derangement of nitric oxide homeostasis, endothelial function and PHT. Third, exercise measurements of TRV may be indicated in the clinical evaluation of patients with SCD and dyspnea on exertion, since it may unmask otherwise unappreciated PHT. Figure Figure

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