natriuretic-peptide--brain and Hemoglobinuria--Paroxysmal

Pulmonary hypertension (PH) is a common complication of haemolytic anaemia. Intravascular haemolysis leads to nitric oxide (NO) depletion, endothelial and smooth muscle dysregulation, and vasculopathy, characterized by progressive hypertension. PH has been reported in patients with paroxysmal nocturnal haemoglobinuria (PNH), a life-threatening haemolytic disease. We explored the relationship between haemolysis, systemic NO, arginine catabolism and measures of PH in 73 PNH patients enrolled in the placebo-controlled TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study. At baseline, intravascular haemolysis was associated with elevated NO consumption (P < 0.0001) and arginase-1 release (P < 0.0001). Almost half of the patients in the trial had elevated levels (> or =160 pg/ml) of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of pulmonary vascular resistance and right ventricular dysfunction previously shown to indicate PH. Eculizumab treatment significantly reduced haemolysis (P < 0.001), NO depletion (P < 0.001), vasomotor tone (P < 0.05), dyspnoea (P = 0.006) and resulted in a 50% reduction in the proportion of patients with elevated NT-proBNP (P < 0.001) within 2 weeks of treatment. Importantly, the significant improvements in dyspnoea and NT-proBNP levels occurred without significant changes in anaemia. These data demonstrated that intravascular haemolysis in PNH produces a state of NO catabolism leading to signs of PH, including elevated NT pro-BNP and dyspnoea that are significantly improved by treatment with eculizumab.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biomarkers; Blood Pressure; Dyspnea; Female; Hemoglobins; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Nitric Oxide; Peptide Fragments; Treatment Outcome

Pulmonary hypertension is becoming a recognized complication of the hereditary and acquired haemolytic anaemias, associated with a poor prognosis. Recently we reported that patients with paroxysmal nocturnal haemoglobinuria (PNH) have high levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker associated with both right and left ventricular dysfunction and cardiac dysfunction. In the current study we evaluated a cohort of patients (N = 29) with haemolytic PNH for elevated pulmonary artery systolic pressure and cardiac function by Doppler-echocardiography. Of the 29 patients, eight were further studied using cardiac magnetic resonance imaging (MRI), as well as two additional patients (number of patients studied using cardiac MRI = 10). Plasma from the first cohort (N = 29) demonstrated intravascular haemolysis associated with a 12-fold increase in median nitric oxide (NO) consumption when compared with healthy volunteers (P < 0·001). Doppler echocardiography demonstrated normal left ventricular function and elevated pulmonary artery systolic pressure in 41% of patients. Cardiac MRI from the second cohort (N = 10) demonstrated depressed right ventricular function in 80% of PNH patients tested, and 60% had findings suggestive of subclinical small pulmonary emboli. Together, these data suggest a high prevalence of haemolysis-associated NO scavenging, Doppler-estimated systolic pulmonary hypertension, and depressed right ventricular function in patients with PNH.

Topics: Adolescent; Adult; Aged; Echocardiography, Doppler; Heart; Hemoglobinuria, Paroxysmal; Humans; Hypertension, Pulmonary; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Ventricular Function, Right; Young Adult