Cardiopulmonary and Laboratory Profiling of Patients with Thalassemia At Risk for Pulmonary Hypertension: Report From the Thalassemia Clinical Research Network.
Authors: Morris Claudia R. , Kim Hae-Young , Wood John C , Trachtenberg Felicia , Klings Elizabeth S , Porter John B. , Sweeters Nancy , Olivieri Nancy F , Kwiatkowski Janet L. , Singer Sylvia Titi , Taher Ali T , Neufeld Ellis J. , Thompson Alexis A. , Larkin Sandra K , Suh Jung H , Vichinsky Elliott , Kuypers Frans A 
Published: October 2019

Abstract
Abstract 2122

Introduction:
Pulmonary hypertension (PH) commonly develops in thalassemia syndromes, but is poorly characterized. Since limited data are available we set out to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassemia at-risk for PH.

Methods:
We designed a case-control study of thalassemia patients at-risk for PH, defined by a tricuspid-regurgitant-jet velocity (TRV)≥2.5m/s on Doppler-echocardiography (echo) compared to those with low PH-risk, define by a TRV<2.5m/s, similar in age, gender, ethnicity and transfusion dependence. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including echo, 6-minute-walk-test (6MWT), Borg Dyspnea Score, New York Heart Association (NYHA) functional class, cardiac MRI, pulmonary function testing, laboratory analyses and biomarkers of hemolysis, inflammation, coagulation and adhesion, compared in thalassemia patients at high vs. low PH-risk.

Results:
Twenty-seven thalassemia patients with a mean TRV=2.5±0.6m/s (range:1.0–4.9m/s) were evaluated, 14 with a TRV≥2.5m/s. Mean age was 35±12 years, 70% were male, 74% were splenectomized, and 67% had thalassemia major (TM). Patients with PH-risk (mean TRV=3.1±0.7m/s) had a significantly higher frequency of splenectomy (OR:11.1 [95% CI: 1.11–112.0], p=0.04), higher NYHA functional class, Borg Dyspnea Score after 6MWT, and significantly larger right atrial size, left atrial volume, and left septal-wall thickness on echo and/or MRI, with elevated biomarkers of coagulation abnormalities, lactate dehydrogenase (LDH) levels, arginase concentration (5.7±7 vs. 78.7±108 ng/ml, p=0.003) and arginase activity, and lower arginine-bioavailability compared to low-risk patients (mean TRV=2.1±0.4m/s). Arginase concentration and activity correlated significantly to several echo/MRI parameters of cardiovascular function including cardiac index (r=0.75, p<0.0001), in addition to white blood cell count, several adhesion biomarkers, global-arginine-bioavailability and biomarkers of hemolytic rate, including LDH, hemoglobin and bilirubin. Arginase activity, but not concentration, correlated strongly to brain natriuretic factor (r =0.45, p=0.03). Diffusion capacity for carbon monoxide (DLCO) was generally low in our cohort (mean % predicted: 68.2±16.3 (range 45–115), however other measurements of pulmonary function were within the normal range, and together with DLCO, did not differ significantly by TRV. No significant difference was found in 6MWT in cases vs. controls, however the 6MWT paradoxically trended higher in patients with a TRV≥2.5m/s and may not be an ideal PH biomarker in thalassemia. The 6MWT was significantly worse in TM patients compared to patients with thalassemia intermedia (460±106 vs. 539±66 m, p=0.05), despite similar TRVs, was a poor predictor of echo/MRI parameters, and paradoxically correlated to increased right atrial size (r =0.42, p=0.03). A strong correlation of 6MWT to DLCO (r =0.51, p=0.008) may indicate a pulmonary contribution to 6MWT in this cohort as an additional confounding factor.

Conclusions:
Thalassemia patients with a TRV≥2.5m/s have additional echo and MRI parameters suggestive of PH-risk. Dysregulation of the arginine metabolome and the consequences of excess plasma arginase are associated with cardiopulmonary complications in thalassemia and warrants further study.

Disclosures:
Taher: Novartis: Research Funding, Speakers Bureau.