Abstract

Pulmonary hypertension (PHT) is associated with high mortality rate and is a leading factor in heart failure and death in thalassemia (Thal) intermedia. However, data on PHT and Thal major is limited. While there are several risk factors for PHT in Thal major, ongoing chronic hemolysis, despite transfusion, supports the development of hemolysis-associated PHT. Recently, we reported in sickle cell disease a novel paradigm whereby hemolysis liberates vasoactive hemoglobin and erythrocyte arginase, resulting in impaired NO bioavailability, endothelial dysfunction, PHT and death. Since arginase activity is also elevated in Thal red cells, we hypothesize that elevated arginase contributes to dysregulated arginine (Arg) metabolism in Thal. Pilot data was analyzed from transfused Thal patients (8 Thal-major, 4 E-beta Thal, 2 Hb H alpha Thal). Echocardiogram were performed in steady state in 10 of the patients; 70% (7/10) demonstrated PHT (tricuspid regurgitant jet velocity ≥ 2.5 m/s). Plasma Arg trended lower in patients with Thal (19.5 to 122mM, median 50 mM) compared to controls. Ornithine (Orn) levels were higher, and Arg/Orn ratio was lower in Thal vs. contrls. Plasma arginase activity was significantly elevated (median 0.83 mmol/cc/hr, range 0.06 – 1.17). Proline, a downstream metabolite of arginase causing pulmonary vascular remodeling was also elevated. Exhaled nitric oxide (NO) levels are significantly elevated in Thal vs. controls (49±41 parts per billion vs.18±8 ppb, p=0.02), suggesting upregulation of NO synthase in the lungs in addition to higher plasma arginase activity. Recent findings indicate diverse origins of PHT share similar pathophysiologic abnormalities, particularly decreased Arg bioavailability and a shift of metabolism towards ornithine-dependent pathways. Hemolysis is most likely a trigger for these pathologic pathyways in hemoglobinopathies. Therapies that maximize Arg and NO bioavailability may benefit patients with thalassemia.

Variable NL Control (n=36) Thalassemia (n=14) p* 
Arginine (μM) 67±18 57±26 (50) 0.15 
Ornithine (μM) 62±22 85±68 0.05 
Arg/Orn ratio 1.2±0.5 0.79±0.4 <0.01 
Proline (μM) 161±48 258±116 <0.001 
Citrulline (μM) 25±11 42±17 <0.001 
Arginase (μmol/cc/hr) 0.33±0.2 (n=45) 0.71±0.3 <0.001 
Variable NL Control (n=36) Thalassemia (n=14) p* 
Arginine (μM) 67±18 57±26 (50) 0.15 
Ornithine (μM) 62±22 85±68 0.05 
Arg/Orn ratio 1.2±0.5 0.79±0.4 <0.01 
Proline (μM) 161±48 258±116 <0.001 
Citrulline (μM) 25±11 42±17 <0.001 
Arginase (μmol/cc/hr) 0.33±0.2 (n=45) 0.71±0.3 <0.001 

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