Elizabeth S Klings

Publications (25)171.15 Total impact

• Article: Sildenafil therapy in thalassemia patients with doppler-defined risk for pulmonary hypertension

  Claudia R. Morris, Hae-Young Kim, John Wood, John B. Porter, Elizabeth S. Klings, Felicia L. Trachtenberg, Nancy Sweeters, Nancy F Olivieri, Janet L Kwiatkowski, Lisa Virzi, Sylvia T. Singer, Ali Taher, Ellis J Neufeld, Alexis A. Thompson, Vandana Sachdev, Sandra Larkin, Jung H. Suh, Frans A. Kuypers, Elliott P. Vichinsky
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  ABSTRACT: Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There is limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We therefore designed a 12-week open-label phase 1/2 pilot-scale proof-of-principle trial of sildenafil therapy in 10 patients with beta-thalassemia and increased risk for pulmonary hypertension based upon an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables measured include Doppler-echocardiography, 6-minute walk distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function testing, and laboratory analyses compared at baseline and after 12 weeks of sildenafil. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0+/-0.7 vs. 2.6+/-0.5m/s, p=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in six-minute walk distance was noted. Sildenafil was well tolerated, although minor anticipated adverse events were commonly reported. Total dose amount of sildenafil (mg) taken strongly correlated with % change in nitric oxide metabolite concentration in the plasma (ρ =0.80, p=0.01). A significant increase in plasma and erythrocyte arginine concentration also occurred. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk for pulmonary hypertension; however efficacy with respect to 6-minute walk distance was not demonstrated. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in beta-thalassemia. (clinicaltrials.gov identifier: NCT00872170).
  Haematologica 04/2013; · 6.42 Impact Factor
• Article: Sildenafil therapy in thalassemia patients with doppler-defined risk for pulmonary hypertension.

  Claudia R Morris, Hae-Young Kim, John C Wood, John B Porter, Elizabeth S Klings, Felicia L Trachtenberg, Nancy Sweeters, Nancy F Olivieri, Janet L Kwiatkowski, Lisa Virzi, Sylvia T Singer, Ali Taher, Ellis J Neufeld, Alexis A Thompson, Vandana Sachdev, Sandra Larkin, Jung H Suh, Frans A Kuypers, Elliott P Vichinsky
  [show abstract] [hide abstract]
  ABSTRACT: Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There is limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We therefore designed a 12-week open-label phase 1/2 pilot-scale proof-of-principle trial of sildenafil therapy in 10 patients with beta-thalassemia and increased risk for pulmonary hypertension based upon an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables measured include Doppler-echocardiography, 6-minute walk distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function testing, and laboratory analyses compared at baseline and after 12 weeks of sildenafil. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0+/-0.7 vs. 2.6+/-0.5m/s, p=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in six-minute walk distance was noted. Sildenafil was well tolerated, although minor anticipated adverse events were commonly reported. Total dose amount of sildenafil (mg) taken strongly correlated with % change in nitric oxide metabolite concentration in the plasma (ρ =0.80, p=0.01). A significant increase in plasma and erythrocyte arginine concentration also occurred. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk for pulmonary hypertension; however efficacy with respect to 6-minute walk distance was not demonstrated. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in beta-thalassemia. (clinicaltrials.gov identifier: NCT00872170).
  Haematologica 04/2013; · 6.42 Impact Factor
• Source

  Available from: Claudia R Morris

  Article: Making it personal: using genomics to predict pulmonary hypertension in sickle cell disease.

  Elizabeth S Klings, Claudia R Morris
  American Journal of Respiratory and Critical Care Medicine 08/2012; 186(4):304-5. · 11.08 Impact Factor
• Article: Monocytes from sickle cell disease patients induce differential pulmonary endothelial gene expression via activation of NF-κB signaling pathway.

  Surinder Safaya, Martin H Steinberg, Elizabeth S Klings
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  ABSTRACT: Monocyte-endothelial interactions play an important role in inflammatory diseases and may modulate vasculopathy in sickle cell disease, a disorder with an important inflammatory component. We co-incubated normal and sickle monocytes, lymphocytes and TNF-α with pulmonary microvascular and arterial endothelial cells and compared the expression of genes coding for adhesion molecules and cytokines that might contribute to sickle vasoocclusion. Monocyte-endothelial cell co-incubation resulted in up-regulation of L-selectin, E-selectin, VCAM-1, ICAM-1, MCP-1, MMP-1, TNF-α, IL-6 and IL-1β and down-regulation of eNOS. Lymphocyte-endothelial cell co-incubations, induced similar effects restricted to pulmonary artery endothelial cells. TNF-α had similar effects on the endothelial cells as monocytes did, however monocyte induced gene expression in endothelial cells was not TNF-α dependent but was regulated through the NF-κB pathway. Sickle monocytes lead to altered expression of L-selectin, MCP-1 and MMP-1 in pulmonary vascular endothelium when compared with normal monocytes. The gene expression changes we observed could reflect pathological events of sickle vasoocclusion.
  Molecular Immunology 02/2012; 50(1-2):117-23. · 2.90 Impact Factor
• Source

  Available from: Pallav Bhatnagar

  Article: A genome-wide association study of total bilirubin and cholelithiasis risk in sickle cell anemia.

  Jacqueline N Milton, Paola Sebastiani, Nadia Solovieff, Stephen W Hartley, Pallav Bhatnagar, Dan E Arking, Daniel A Dworkis, James F Casella, Emily Barron-Casella, Christopher J Bean, W Craig Hooper, Michael R DeBaun, Melanie E Garrett, Karen Soldano, Marilyn J Telen, Allison Ashley-Koch, Mark T Gladwin, Clinton T Baldwin, Martin H Steinberg, Elizabeth S Klings
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  ABSTRACT: Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5 × 10(-8)). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08 × 10(-25)). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15 × 10(-4)). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities.
  PLoS ONE 01/2012; 7(4):e34741. · 4.09 Impact Factor
• Article: Keeping it in the family: three relatives with HbSC disease and simultaneous acute pulmonary emboli.

  Finn Hawkins, Noelle Ebel, George P Sorescu, Lillian McMahon, Philippa Sprinz, Elizabeth S Klings
  American Journal of Hematology 08/2011; 87(1):101-4. · 4.67 Impact Factor
• Article: Ancestry of African Americans with sickle cell disease.

  Nadia Solovieff, Stephen W Hartley, Clinton T Baldwin, Elizabeth S Klings, Mark T Gladwin, James G Taylor, Gregory J Kato, Lindsay A Farrer, Martin H Steinberg, Paola Sebastiani
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  ABSTRACT: The inheritance of genetic disease depends on ancestry that must be considered when interpreting genetic association studies and can provide insights when comparing traits in a population. We compared the genetic profiles of African Americans with sickle cell disease to those of Black Africans and Caucasian populations of European descent and found that they are less genetically admixed than other African Americans and have an ancestry similar to Yorubans, Mandenkas and Bantu.
  Blood Cells Molecules and Diseases 06/2011; 47(1):41-5. · 2.35 Impact Factor
• Article: Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1.

  Daniel A Dworkis, Elizabeth S Klings, Nadia Solovieff, Guihua Li, Jacqueline N Milton, Stephen W Hartley, Efthymia Melista, Jason Parente, Paola Sebastiani, Martin H Steinberg, Clinton T Baldwin
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  ABSTRACT: Sickle cell anemia (SCA, HBB glu6val) is characterized by multiple complications and a high degree of phenotypic variability: some subjects have only sporadic pain crises and few acute hospitalizations, while others experience multiple serious complications, high levels of morbidity, and accelerated mortality [1]. The tumor necrosis factor-α (TNF-α) signaling pathway plays important roles in inflammation and the immune response; variation in this pathway might be expected to modify the overall severity of SCA through the pathway's effects on the vascular endothelium [2,3]. We examined plasma biomarkers of TNF-α activity and endothelial cell activation for associations with SCA severity in 24 adults (12 mild, 12 severe). Two biomarkers, tumor necrosis factor-α receptor-1 (TNF-R1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in subjects with severe SCA. Along with these biomarker differences, we also examined data from a genome-wide association study (GWAS) using SCA severity as a disease phenotype, and found evidence of genetic association between disease severity and a single nucleotide polymorphism (SNP) in VCAM1, which codes for VCAM-1, and several SNPs in ARFGEF2, a gene involved in TNF-R1 release [4].
  American Journal of Hematology 02/2011; 86(2):220-3. · 4.67 Impact Factor
• Article: Severe sickle cell anemia is associated with increased plasma levels of TNF‐R1 and VCAM‐1

  Daniel A. Dworkis, Elizabeth S. Klings, Nadia Solovieff, Guihua Li, Jacqueline N. Milton, Stephen W. Hartley, Efthymia Melista, Jason Parente, Paola Sebastiani, Martin H. Steinberg, Clinton T. Baldwin
  American Journal of Hematology 01/2011; 86(2):220 - 223. · 4.67 Impact Factor
• Article: Sickle cell anemia and vascular dysfunction: the nitric oxide connection.

  Idowu Akinsheye, Elizabeth S Klings
  [show abstract] [hide abstract]
  ABSTRACT: Endothelial dysfunction and impaired nitric oxide bioavailability have been implicated in the pathogenesis of sickle cell anemia. Nitric oxide is a diatomic gas with a role in vascular homeostasis. Hemoglobin polymerization resulting from the HbS mutation produces erythrocyte deformation and hemolysis. Free hemoglobin, released into plasma by hemolysis scavenges on nitric oxide, and leads to reduced nitric oxide bioavailability. Pulmonary hypertension is a known consequence of sickle cell anemia. It occurs in 30-40% of patients with sickle cell anemia, and is associated with increased mortality. Several studies have implicated intravascular hemolysis, and impaired nitric oxide bioavailability in the pathogenesis of pulmonary hypertension. In this review, we summarize the mechanisms of altered nitric oxide bioavailability in sickle cell anemia and its possible role in the pathogenesis of pulmonary hypertension.
  Journal of Cellular Physiology 09/2010; 224(3):620-5. · 3.87 Impact Factor
• Article: Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.

  Paola Sebastiani, Nadia Solovieff, Stephen W Hartley, Jacqueline N Milton, Alberto Riva, Daniel A Dworkis, Efthymia Melista, Elizabeth S Klings, Melanie E Garrett, Marilyn J Telen, Allison Ashley-Koch, Clinton T Baldwin, Martin H Steinberg
  [show abstract] [hide abstract]
  ABSTRACT: We conducted a genome-wide association study (GWAS) to discover single nucleotide polymorphisms (SNPs) associated with the severity of sickle cell anemia in 1,265 patients with either "severe" or "mild" disease based on a network model of disease severity. We analyzed data using single SNP analysis and a novel SNP set enrichment analysis (SSEA) developed to discover clusters of associated SNPs. Single SNP analysis discovered 40 SNPs that were strongly associated with sickle cell severity (odds for association >1,000); of the 32 that we could analyze in an independent set of 163 patients, five replicated, eight showed consistent effects although failed to reach statistical significance, whereas 19 did not show any convincing association. Among the replicated associations are SNPs in KCNK6 a K(+) channel gene. SSEA identified 27 genes with a strong enrichment of significant SNPs (P < 10(-6)); 20 were replicated with varying degrees of confidence. Among the novel findings identified by SSEA is the telomere length regulator gene TNKS. These studies are the first to use GWAS to understand the genetic diversity that accounts the phenotypic heterogeneity sickle cell anemia as estimated by an integrated model of severity. Additional validation, resequencing, and functional studies to understand the biology and reveal mechanisms by which candidate genes might have their effects are the future goals of this work.
  American Journal of Hematology 01/2010; 85(1):29-35. · 4.67 Impact Factor
• Article: Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster.

  Nadia Solovieff, Jacqueline N Milton, Stephen W Hartley, Richard Sherva, Paola Sebastiani, Daniel A Dworkis, Elizabeth S Klings, Lindsay A Farrer, Melanie E Garrett, Allison Ashley-Koch, Marilyn J Telen, Supan Fucharoen, Shau Yin Ha, Chi-Kong Li, David H K Chui, Clinton T Baldwin, Martin H Steinberg
  [show abstract] [hide abstract]
  ABSTRACT: In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or beta thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E-08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E-21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in gamma-globin gene expression.
  Blood 12/2009; 115(9):1815-22. · 9.90 Impact Factor
• Article: Hyperoxia-induced lung injury in gamma-glutamyl transferase deficiency is associated with alterations in nitrosative and nitrative stress.

  Elizabeth S Klings, Matthew H Lowry, Guihua Li, Jyh-Chang Jean, Bernadette O Fernandez, Maria F Garcia-Saura, Martin Feelisch, Martin Joyce-Brady
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  ABSTRACT: gamma-Glutamyl transferase (GGT) regulates glutathione metabolism and cysteine supply. GGT inactivation in GGT(enu1) mice limits cysteine availability causing cellular glutathione deficiency. In lung, the resultant oxidant burden is associated with increased nitric oxide (NO) production, yet GGT(enu1) mice still exhibit higher mortality in hyperoxia. We hypothesized that NO metabolism is altered under severe oxidant stress and contributes to lung cellular injury and death. We compared lung injury, NO synthase (NOS) expression, nitrate/nitrite production, nitroso product formation, peroxynitrite accumulation, and cell death in wild-type and GGT(enu1) mice in normoxia and hyperoxia. The role of NOS activity in cell death was determined by NOS inhibition. Exposure of wild-type mice to hyperoxia caused increased lung injury, altered NO metabolism, and induction of cell death compared with normoxia, which was attenuated by NOS inhibition. Each of these lung injury indices were magnified in hyperoxia-exposed GGT(enu1) mice except nitrosation, which showed a diminished decrease compared with wild-type mice. NOS inhibition attenuated cell death only slightly, likely due to further exacerbation of oxidant stress. Taken together, these data suggest that apoptosis in hyperoxia is partially NO-dependent and reiterate the importance of cellular glutathione in lung antioxidant defense. Therefore, reduced denitrosylation of proteins, possibly resulting in impaired cellular repair, and excessive apoptotic cell death likely contribute to increased lung injury and mortality of GGT(enu1) mice in hyperoxia.
  American Journal Of Pathology 10/2009; 175(6):2309-18. · 4.89 Impact Factor
• Article: Effect of sodium butyrate on lung vascular TNFSF15 (TL1A) expression: differential expression patterns in pulmonary artery and microvascular endothelial cells.

  Surinder Safaya, Elizabeth S Klings, Adam Odhiambo, Guihua Li, Harrison W Farber, Martin H Steinberg
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  ABSTRACT: Vascular endothelial growth inhibitor TNFSF15 (TL1A), a ligand for TNFRSF25 (DR3) and decoy receptor TNFRSF6B (DcR3), is expressed in human pulmonary arterial (HPAEC) and lung microvascular (HMVEC) endothelial cells where it might modulate inflammation and sickle vasculopathy. Pulmonary disease, endothelial abnormalities and inflammation are prominent features of sickle cell disease (SCD). Butyrate has opposing effects on endogenous TNFSF15 expression in pulmonary endothelium, acting as an inhibitor in HPAEC and an inducer in HMVEC. Similar effects were observed with a known cytokine TNF-alpha in these two cell types. Furthermore the TNFSF15 promoter utilized different combinations of cis-elements for its expression in these two cell types. AP1-like and G-rich sequence elements were critical for promoter activity in large vessel HPAEC while AP1-like and NF-kappaB consensus sequence elements were required in small vessel HMVEC. The requirement of an NF-kappaB sequence element by the TNFSF15 promoter in HMVEC but not in HPAEC supported the notion that HMVEC might be a target of inflammation and vasoocclusion in SCD. The dual effects of butyrate-dependant TNFSF15 regulation in lung endothelium may help in identify inflammatory pathways and understand the role of HMVEC in pathogenesis of vasoocclusion in SCD.
  Cytokine 03/2009; 46(1):72-8. · 3.02 Impact Factor
• Article: Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression.

  Elizabeth S Klings, Demedrick Anton Bland, Dara Rosenman, Stephanie Princeton, Adam Odhiambo, Guihua Li, Sheilah A Bernard, Martin H Steinberg, Harrison W Farber
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  ABSTRACT: Pulmonary hypertension (PH), a risk factor for mortality in sickle cell disease (SCD), has pathologic features of both pulmonary arterial hypertension (PAH) and PH related to left-sided heart disease (LHD) suggesting a link between these two entities. We hypothesized that both are characterized by endothelial dysfunction and increased adhesion molecule expression. SCD patients and normal volunteers underwent a screening questionnaire, echocardiogram, and blood donation for preparation of platelet-poor plasma. PAH was defined as a tricuspid regurgitant jet (TRJ) velocity > or =2.5 m/sec and/or the presence of isolated right ventricular hypertrophy or decreased systolic function. LHD was defined as either left-sided systolic/diastolic dysfunction or significant valvular disease. Plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P- and E-selectin, nitric oxide (NO(x)), erythropoietin, and vascular endothelial growth factor (VEGF) levels were assayed by enzyme-linked immunoassay. Forty-three percent of sickle cell anemia (HbSS) and 28% of hemoglobin SC disease (HbSC) disease patients had PAH. Additionally, 10-15% of SCD patients had LHD. VCAM-1 levels were significantly increased in HbSS patients compared with HbSC patients and normal volunteers. VCAM-1 and P-selectin levels correlated positively with TRJ velocity in HbSS patients (r = 0.45, P = 0.03, r = 0.2, P = 0.05, respectively). ICAM-1, E-selectin, NO(x), erythropoietin, and VEGF levels were similar across subject groups. PH is common in SCD and, at times, due to LHD. Increased VCAM-1 and P-selectin expression was associated with TRJ elevation regardless of etiology suggesting a similar effect on endothelial gene expression and possibly providing a pathologic link between PAH and PH related to LHD in SCD.
  American Journal of Hematology 08/2008; 83(7):547-53. · 4.67 Impact Factor
• Article: Pulmonary hypertension of sickle cell disease: more than just another lung disease.

  Elizabeth S Klings
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  ABSTRACT: Pulmonary hypertension (PH) of sickle cell disease (SCD), as defined by a tricuspid regurgitant jet velocity by echocardiogram of >or=2.5 m/sec, occurs in approximately 1/3 of HbSS adults and is an independent risk factor for mortality. Although studies of the past few years have greatly expanded our knowledge of the clinical manifestations and pathogenesis of PH in SCD, many questions remain. Two of the key issues addressed by manuscripts in the issue of the American Journal of Hematology are the prevalence of PH in the large African SCD population and the association of PH with renal disease and systemic hypertension. Because of its high impact on mortality, the assessment of PH in the African population is crucial from a public health standpoint. The association of PH with systemic disease in SCD suggests that a more widespread vasculopathy occurs in these patients that may be one of the mechanisms responsible for the observed increase in mortality. It is through studies such as these that a greater understanding of the pathogenesis and treatment of pulmonary hypertension is sickle cell disease can ve achieved.
  American Journal of Hematology 01/2008; 83(1):4-5. · 4.67 Impact Factor
• Article: Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease.

  Claudia R Morris, Jung H Suh, Ward Hagar, Sandra Larkin, D Anton Bland, Martin H Steinberg, Elliott P Vichinsky, Mark Shigenaga, Bruce Ames, Frans A Kuypers, Elizabeth S Klings
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  ABSTRACT: Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increased hemolysis and oxidative stress, contributes to the pathogenesis of pulmonary hypertension (PH) in sickle cell disease (SCD). We hypothesized that altered glutathione and glutamine metabolism play a role in this process. Total glutathione (and its precursors) and glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than in healthy volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r = -0.62, P < .001), plasma arginase concentration (r = -0.45, P = .002), and plasma-free hemoglobin level (r = -0.41, P = .01), linking erythrocyte glutamine depletion to dysregulation of the arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD.
  Blood 01/2008; 111(1):402-10. · 9.90 Impact Factor
• Article: Identification of oxidative post-translational modification of serum albumin in patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension of sickle cell anemia.

  Adam Odhiambo, David H Perlman, Hua Huang, Catherine E Costello, Harrison W Farber, Martin H Steinberg, Mark E McComb, Elizabeth S Klings
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  ABSTRACT: Pulmonary hypertension (PH) in sickle cell anemia (SCA) is characterized by decreased nitric oxide bioavailability that might, in part, be related to oxidative stress. Oxidative post-translational modifications of plasma proteins may serve as hallmarks of disease severity and could result in altered protein function and structure. We hypothesized that serum albumin in patients with PH of SCA undergoes oxidative post-translational modification and that this modification may reflect important mediators of disease pathogenesis that are common to both idiopathic pulmonary arterial hypertension (IPAH) and PH of SCA. To explore this hypothesis, we studied albumin purified from the plasma of patients in four subject groups: SCA and PH, SCA steady-state without PH, IPAH, and normal volunteers. Purified albumin was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Using MALDI-TOFMS, we identified that an ion corresponding to a malondialdehyde (MDA)-modified albumin peptide was differentially present in patients with IPAH and PH of SCA. These results were confirmed by dot-blotting and Western analysis. We localized the site of MDA modification to albumin residue K159 using LC/MS/MS. Thus, we have identified an MDA modification of serum albumin that appears to be a common link between PH of SCA and IPAH. This finding supports the notion that oxidative stress modulates the pathogenesis of PH of SCA and suggests that this and other post-translational modifications may be important biomarkers of disease.
  Rapid Communications in Mass Spectrometry 02/2007; 21(14):2195-203. · 2.79 Impact Factor
• Article: Abnormal pulmonary function in adults with sickle cell anemia.

  Elizabeth S Klings, Diego F Wyszynski, Vikki G Nolan, Martin H Steinberg
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  ABSTRACT: Pulmonary complications of sickle cell anemia (Hb-SS) commonly cause morbidity, yet few large studies of pulmonary function tests (PFTs) in this population have been reported. PFTs (spirometry, lung volumes, and diffusion capacity for carbon monoxide [DLCO]) from 310 adults with Hb-SS were analyzed to determine the pattern of pulmonary dysfunction and their association with other systemic complications of sickle cell disease. Raw PFT data were compared with predicted values. Each subject was subclassified into one of five groups: obstructive physiology, restrictive physiology, mixed obstructive/restrictive physiology, isolated low DLCO, or normal. The association between laboratory data of patients with decreased DLCO or restrictive physiology and those of normal subjects was assessed by multivariate linear regression. Normal PFTs were present in only 31 of 310 (10%) patients. Overall, adults with Hb-SS were characterized by decreased total lung capacities (70.2 +/- 14.7% predicted) and DLCO (64.5 +/- 19.9%). The most common PFT patterns were restrictive physiology (74%) and isolated low DLCO (13%). Decreased DLCO was associated with thrombocytosis (p = 0.05), with hepatic dysfunction (elevated alanine aminotransferase; p = 0.07), and a trend toward renal dysfunction (elevated blood urea nitrogen and creatinine; p = 0.05 and 0.07, respectively). Pulmonary function is abnormal in 90% of adult patients with Hb-SS. Common abnormalities include restrictive physiology and decreased DLCO. Decreased DLCO may indicate more severe sickle vasculopathy characterized by impaired hepatic and renal function.
  American Journal of Respiratory and Critical Care Medicine 07/2006; 173(11):1264-9. · 11.08 Impact Factor
• Article: Present and future treatment strategies for pulmonary arterial hypertension : focus on phosphodiesterase-5 inhibitors.

  Laura B Kane, Elizabeth S Klings
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  ABSTRACT: Idiopathic pulmonary arterial hypertension (IPAH) is a rare progressive disorder historically associated with mortality in <3 years post-diagnosis. The etiology of PAH is complex, multifactorial, and likely involves the interplay between genetic and environmental factors. These are reviewed with emphasis on the nitric oxide pathway. Use of treatment modalities including vasodilator therapy have resulted in improved symptoms, hemodynamics, and survival in these patients. Vasodilators, including the calcium channel antagonists, prostanoids, and endothelin receptor antagonists, have been used to counteract potential imbalances in vasoactive mediators in PAH patients; all have produced improved long-term symptomatology and hemodynamics. Only the prostanoid epoprostenol has improved survival in IPAH patients. Although these medications have worked well in many patients with PAH, each of them has limitations. The phosphodiesterase-5 (PDE-5) inhibitors are a relatively new form of treatment for PAH. They are designed to potentiate the effects of cyclic guanosine monophosphate, thereby mimicking endogenous nitric oxide within the vasculature. PDE-5 inhibitors are selective pulmonary vasodilators effective in animal models of pulmonary hypertension. The published clinical studies evaluating their use have been small in size to date but appear to demonstrate benefit. The recently completed 12-week randomized placebo-controlled Sildenafil Use in Pulmonary Hypertension (SUPER-1) trial demonstrated improvement in 6-minute walk distance and hemodynamics in patients receiving sildenafil. These data suggest that the PDE-5 inhibitors are effective in treating PAH and that it is likely that their usage will increase over time. The purpose of this review is to present a current view of the pathogenesis and treatment of PAH, with an emphasis on the use of PDE-5 inhibitors in these patients.
  Treatments in Respiratory Medicine 02/2006; 5(4):271-82.