N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease.

CONTEXT Thirty percent of patients with sickle cell disease (SCD) develop pulmonary hypertension, a major risk factor for death in this population. A validated blood biomarker of pulmonary hypertension in SCD could provide important prognostic and diagnostic information and allow the exploration of the prevalence of pulmonary hypertension in participants in the 1996 Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Patients' Follow-up Study. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) provide such information in patients with idiopathic pulmonary arterial hypertension. OBJECTIVE To determine the relationship between NT-proBNP levels and severity of pulmonary hypertension and prospective mortality in patients with SCD. DESIGN, SETTING, AND PARTICIPANTS NT-proBNP levels were measured in 230 participants in the National Institutes of Health (NIH) Sickle Cell Disease-Pulmonary Hypertension Screening Study (enrollment between February 2001 and March 2005) and in 121 samples from patients enrolled starting in 1996 in the MSH Patients' Follow-up Study. A threshold level predictive of high pulmonary artery pressure and mortality was identified in the NIH Sickle Cell Disease-Pulmonary Hypertension Screening Study and used to define an a priori analytical plan to determine the prevalence and associated mortality of pulmonary hypertension in the MSH follow-up study. MAIN OUTCOME MEASURES Severity of pulmonary hypertension and risk of all-cause mortality. RESULTS NT-proBNP levels were higher in patients with sickle cell pulmonary hypertension and correlated directly with tricuspid regurgitant jet velocity in the NIH cohort (R = 0.50, P<.001). An NT-proBNP level of 160 pg/mL or greater had a 78% positive predictive value for the diagnosis of pulmonary hypertension and was an independent predictor of mortality (21 deaths at 31 months' median follow-up; risk ratio, 5.1; 95% confidence interval, 2.1-12.5; P<.001; 19.5% absolute increase in risk of death). In the MSH cohort, 30% of patients had an NT-proBNP level of 160 pg/mL or greater. An NT-proBNP level of 160 pg/mL or greater in the MSH cohort was independently associated with mortality by Cox proportional hazards regression analysis (24 deaths at 47 months' median follow-up; risk ratio, 2.87; 95% confidence interval, 1.2-6.6; P = .02; 11.9% absolute increase in risk of death). CONCLUSIONS Pulmonary hypertension, as indicated by an NT-proBNP level of 160 pg/mL or greater, was very common in patients in the NIH study and in the MSH cohort. The MSH analysis suggests that rates of vaso-occlusive pain episodes in these patients were unrelated to risk of death; this risk was largely determined by occult hemolytic anemia-associated pulmonary hypertension.

[1]  F. Barton,et al.  Erythropoietic activity in patients with sickle cell anaemia before and after treatment with hydroxyurea , 1999, British journal of haematology.

[2]  E. Antman,et al.  Prognostic value of N-terminal pro-atrial and pro-brain natriuretic peptide in patients with acute coronary syndromes. , 2002, The American journal of cardiology.

[3]  R. Califf,et al.  N‐Terminal Pro‐Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients With Unstable Coronary Artery Disease: A Global Utilization of Strategies To Open occluded arteries (GUSTO)‐IV Substudy , 2003, Circulation.

[4]  J. Herlitz,et al.  N-Terminal ProB – Type Natriuretic Peptide and Long-Term Mortality in Acute Coronary Syndromes , 2002 .

[5]  J. Eaton,et al.  Spontaneous oxygen radical generation by sickle erythrocytes. , 1982, The Journal of clinical investigation.

[6]  M. Fischer,et al.  BNP as a marker of diastolic dysfunction in the general population: Importance of left ventricular hypertrophy , 2005, European journal of heart failure.

[7]  G. Eknoyan,et al.  National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification , 2003, Annals of Internal Medicine.

[8]  D J Weatherall,et al.  Inherited haemoglobin disorders: an increasing global health problem. , 2001, Bulletin of the World Health Organization.

[9]  J. Herlitz,et al.  N-Terminal Pro-B-Type Natriuretic Peptide and Long-Term Mortality in Acute Coronary Syndromes , 2002, Circulation.

[10]  M. Gladwin,et al.  Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  David R. Cox.  The analysis of binary data , 1970 .

[12]  M. Gladwin,et al.  Biological activity of nitric oxide in the plasmatic compartment. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Loscalzo,et al.  Effects of nitric oxide/EDRF on platelet surface glycoproteins. , 1996, The American journal of physiology.

[14]  M. Gladwin,et al.  The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. , 2005, JAMA.

[15]  A. Duits,et al.  Evidence for a metabolic shift of arginine metabolism in sickle cell disease , 2004, Annals of Hematology.

[16]  Pedro Lozano.  Natriuretic peptides. , 2020, The Journal of the Arkansas Medical Society.

[17]  C. B. Alexander,et al.  Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease , 2003, The Journal of Biological Chemistry.

[18]  K. Kangawa,et al.  Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. , 2000, Circulation.

[19]  S. Kuribayashi,et al.  Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. , 1998, Journal of the American College of Cardiology.

[20]  R. Califf,et al.  Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. , 2005, JAMA.

[21]  M. Gladwin,et al.  The Perfusion Paradox and Vascular Instability in Sickle Cell Disease , 2004, Microcirculation.

[22]  M. Vogeser,et al.  Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. , 2004, Journal of the American College of Cardiology.

[23]  F. Ofosu,et al.  Plasma factor VII and thrombin–antithrombin III levels indicate increased tissue factor activity in sickle cell patients , 1992, British journal of haematology.

[24]  M. Vogeser,et al.  Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. , 2004, American journal of respiratory and critical care medicine.

[25]  T. Omland,et al.  B-type natriuretic peptide and long-term survival in patients with stable coronary artery disease. , 2005, The American journal of cardiology.

[26]  M. Gladwin,et al.  Divergent Nitric Oxide Bioavailability in Men and Women With Sickle Cell Disease , 2003, Circulation.

[27]  S. Moncada,et al.  Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. , 1993, Cardiovascular research.

[28]  M. Cairo,et al.  Pulmonary hypertension in sickle cell disease. , 2007, Clinical advances in hematology & oncology : H&O.

[29]  C. B. Alexander,et al.  Nitric oxide-dependent generation of reactive species in sickle cell disease. Actin tyrosine induces defective cytoskeletal polymerization. , 2003, The Journal of biological chemistry.

[30]  L. Farrer,et al.  Hemolysis-associated Priapism in Sickle Cell Disease , 2005 .

[31]  R. T. Lie,et al.  Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. , 1996, Circulation.

[32]  David W. Hosmer,et al.  Applied Logistic Regression , 1991 .

[33]  O. Platt,et al.  Mortality in sickle cell disease. Life expectancy and risk factors for early death. , 1994, The New England journal of medicine.

[34]  R. Nagel,et al.  Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice. , 2004, The Journal of clinical investigation.

[35]  M. Gladwin,et al.  Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. , 2002 .

[36]  N. Nagelkerke,et al.  A note on a general definition of the coefficient of determination , 1991 .

[37]  Judith D. Goldberg,et al.  Applied Survival Analysis , 1999, Technometrics.

[38]  O. Castro,et al.  Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. , 2003, Blood.

[39]  H. Gerlach,et al.  Reduction of Platelet Trapping in Membrane Oxygenators by Transmembraneous Application of Gaseous Nitric Oxide , 1996, The International journal of artificial organs.

[40]  M. Gladwin,et al.  Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. , 2005, The Journal of clinical investigation.

[41]  K. Kangawa,et al.  Secretion patterns of brain natriuretic peptide and atrial natriuretic peptide in patients with or without pulmonary hypertension complicating atrial septal defect. , 1998, American heart journal.

[42]  M L Terrin,et al.  Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. , 1995, The New England journal of medicine.

[43]  L. Morrison,et al.  B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. , 2002, Annals of emergency medicine.

[44]  David W. Hosmer,et al.  Applied Survival Analysis: Regression Modeling of Time-to-Event Data , 2008 .

[45]  D. Fukai,et al.  Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. , 1997, Circulation.

[46]  L. Køber,et al.  N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. , 2005, The New England journal of medicine.

[47]  S. Moncada,et al.  ENDOGENOUS NITRIC OXIDE INHIBITS HUMAN PLATELET ADHESION TO VASCULAR ENDOTHELIUM , 1987, The Lancet.

[48]  D. Samson,et al.  Changes in coagulation and fibrinolysis in patients with sickle cell disease compared with healthy Black controls , 1995, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[49]  C. Pegelow,et al.  Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. , 2003, JAMA.

[50]  A. Ashley-Koch,et al.  Pulmonary Hypertension in SS, SC and Sβ Thalassemia: Prevalence, Associated Clinical Syndromes, and Mortality. , 2004 .

[51]  C. Hall.  Essential biochemistry and physiology of (NT‐pro)BNP , 2004, European journal of heart failure.

[52]  W. Travis,et al.  Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis. , 2003, American journal of respiratory and critical care medicine.

[53]  B. Lämmle,et al.  Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. , 2005, Blood.

[54]  Daniel Levy,et al.  Plasma natriuretic peptide levels and the risk of cardiovascular events and death. , 2004, The New England journal of medicine.

[55]  Stanley L Hazen,et al.  Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. , 2005, JAMA.

[56]  Eric R. Ziegel,et al.  Analysis of Binary Data (2nd ed.) , 1991 .

[57]  Mark T Gladwin,et al.  Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. , 2005, Blood.

[58]  A. Levey,et al.  A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation , 1999, Annals of Internal Medicine.

[59]  L. Magee,et al.  R 2 Measures Based on Wald and Likelihood Ratio Joint Significance Tests , 1990 .

[60]  D. Mccrory,et al.  Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. , 2004, Chest.

[61]  B. Plaat,et al.  Enhanced thrombin generation in children with sickle cell disease. , 1994, Thrombosis and haemostasis.

[62]  J. Krishnan,et al.  Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. , 2004, The New England journal of medicine.

[63]  D. Farmakis,et al.  Cardiac involvement in thalassemia intermedia: a multicenter study. , 2001, Blood.