b Fractional shortening (FS%) on Day 14 or Day 56 in WT and PKG LZ mutant mice treated with vehicle, valsartan, or sacubitri/valsartan. and vasculopathy has been the subject of extensive study in pre-clinical animal models, in vascular studies in patients, and in large human cohort studies. Intravascular hemolysis releases cell-free hemoglobin into the plasma, which can scavenge NO and generate reactive oxygen species, impairing redox balance and leading to proliferative systemic and pulmonary vasculopathy. Pre-clinical studies also suggest that sGC may be oxidized in sickle cell disease, and responsive to sGC activator therapy. It has also been recently appreciated that Fumonisin B1 products released from the red cell during hemolysis, including heme released from hemoglobin, can be considered danger associated molecular pattern molecules or erythrocyte DAMPs (eDAMPs). Large screening studies of patients with sickle cell disease (SCD) for the presence of pulmonary hypertension (PH) have been performed using non-invasive Doppler-echocardiography, screening biomarkers such as N-terminal brain natriuretic peptide and right heart catheterization. These studies have reported a high prevalence of PH in this population, a significant association of increasing pulmonary pressures with more severe hemolytic anemia, cutaneous leg ulcerations, systemic systolic hypertension and renal dysfunction, and a high prospective associated risk of death. These studies support a more general pathological role for intravascular hemolysis and cell-free hemoglobin in various human diseases and in transfusion medicine. ReferencesAtaga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, Orringer EP. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol. 2006;134:109C15. De Castro LM, Jonassaint JC, Graham FL, Ashley-Koch A and Telen MJ. Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am J Hematol. 2008;83:19C25. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O and Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350:886C95. Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ, Taveira-DaSilva AM, Ballas SK, Blackwelder W, Xu X, Hunter L, Barton B, Waclawiw M, Castro O and Gladwin MT. N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA. 2006;296:310C8. Mehari A, Alam S, Tian X, Cuttica MJ, Barnett CF, Miles G, Xu D, Seamon C, Adams-Graves P, Castro OL, Minniti CP, Sachdev V, Taylor JGt, Kato GJ, Machado RF. Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med. 2013;187:840C7. Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA. 2012;307:1254C6. Fonseca GH, Souza R, Salemi VM, Jardim CV, Gualandro SF. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J. 2012;39:112C8. Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, Habibi A, Bennani S, Savale L, Adnot S, Maitre B, Yaici A, Hajji L, OCallaghan DS, Clerson P, Girot R, Galacteros F, Simonneau G. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl Fumonisin B1 J Fumonisin B1 Med. 2011;365:44C53. Pax6 Caughey MC, Poole C, Ataga KI, Hinderliter AL. Estimated pulmonary artery systolic pressure Fumonisin B1 and sickle cell disease: a meta-analysis and systematic review. Br J Haematol. 2015;170:416C24. Gladwin MT. Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 2016;387:2565C74. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO, III, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002;8:1383C1389. Rother RP, Bell.
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