Diagnostic Work-up of Pulmonary Hypertension in Non Transfusion Dependent Thalassemia Patients: Pathophysiologichal Mechanisms and Clinical Implications
Authors: Mancarella Marta , Motta Irene , Rota Irene , Migone De Amicis Margherita , Marcon Alessia , Ferraresi Marta , Giuditta Marianna , Graziadei Giovanna , Cappellini Maria Domenica , Vicenzi Marco 
Published: November 2020

INTRODUCTION: Pulmonary hypertension (PH) is a well documented clinical complication in Non-Transfusion Dependent Thalassemia (NTDT) patients, and it is associated with poor outcome [1]. PH prevalence is extremely variable among studied cohorts, ranging from 4.8% to 59% [2, 3]. Nevertheless, in the majority of the studies, the diagnosis is based on echocardiography, whereas the gold standard for PH definition is right heart catheterization (RHC). Thus, PH real prevalence, its pathophysiological mechanisms and risk factors still need to be elucidated.
AIM:The aim of this study is to define the prevalence of PH in a cohort of NTDT patients through the application of the PH diagnostic work-up of the European Society of Cardiology Guidelines (ESC) [4]. We also aimed to investigate the involved pathophysiological mechanisms, to define risk factors, and to identify a potential role for cardiopulmonary exercise testing (CPET) in the risk stratification.
MATERIALS AND METHODS: We planned a screening program for all NTDT patients referring to Rare Disease Center, in collaboration with the Dyspnea Lab of the Cardiology Unit, at Fondazione IRCCS Ca' Granda Policlinico in Milan. Following the systematic approach of ESC PH algorithm, together with an echocardiogram and cardiological evaluation, our patients underwent cardiopulmonary exercise testing (CPET) and the dosage of NT-proBNP. Patients were stratified according to PH probability (low vs intermediate-high) and further investigations (including V/Q lung scan and RHC) to confirm PH were performed in those with intermediate-high risk.
RESULTS AND DISCUSSION:48 NTDT patients (18 females and 30 males) were consecutively enrolled over a period of 10 months. The mean age at enrollment was 46±12 years (median 45, range 25-72 years) and a wide spectrum of thalassemia genotypes was observed. 38 out of 48 (79%) had a low PH probability according to NYHA class and echocardiogram, thus they were addressed to regular follow-up. 10 patients presented intermediate-high PH probability and underwent further tests. So far, 6 out of 10 intermediate-high risk underwent RHC: PH was confirmed in 5 cases, allowing to identify 2 post-capillary PH, 1 pre-capillary PH (due to pulmonary embolism detected with V/Q scan) and 2 forms of PH due to high cardiac output (CO). The sixth patient showed a condition of high CO but with a mean arterial pulmonary pressure just below the value needed to diagnose PH. Thus, PH was confirmed in 5 out of 48 patients, with a prevalence of 10.4%. The four remaining patients with high PH probability are planned to be tested. Comparing those with high and low PH probability, the first were older (58.4 ±8.9 vs 42.6 ±10.7 years, p=0.0002) and presented higher NT-proBNP (450±442 vs 92±99 ng/mL, p=0.0001). Hemoglobin, erythroblasts, and platelet count were similar. Patients with high PH probability on CPET reached a lower maximal workload (87.9 W ±32.1 vs 126.9 ±41.6W) and lower O2 consumption (1207.7 ±284.5 vs 1594 ±454.8 mL/min), together with worse ventilation efficiency (VE/VCO2 slope 40.9 ±6.9 vs 29.4 ±3.85).
CONCLUSIONS: In our cohort, according to these preliminary data, PH prevalence in NTDT is 10.4% and older patients seem to be at higher risk. Thus, cardiac evaluation programs are required, considering the increased life span. RHC is mandatory to confirm the diagnosis, to identify the underlying mechanisms and consequently a proper treatment. CPET may have an essential role in detecting predictive and prognostic parameters of PH and in defining different hemodynamic mechanisms (pre- or post-capillary) to select patients requiring RHC. Together with pulmonary embolism, which needs to be excluded with imaging, high CO due to chronic anemia seems to play an important role. This hypothesis could have significant treatment implications, giving more importance to increase Hb levels, either with blood transfusions or new therapies.
Sleiman J, Int J Mol Sci 2018 2 Derchi G, Circulation 2014 3 Aessopos E., Blood 2001 4 Galiè N, Eur Heart J 2016

Disclosures
Motta: Sanofi Genzyme:Honoraria.Cappellini:Genzyme/Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees;CRISPR Therapeutics, Novartis, Vifor Pharma:Membership on an entity's Board of Directors or advisory committees;BMS:Honoraria.