Echocardiography and Cardiopulmonary Exercise Testing for Early Detection of Pulmonary Hypertension in Primary Myelofibrosis
Authors: Iurlo Alessandra , Sciumè Mariarita , Mattiello Veronica , Cattaneo Daniele , Orofino Nicola , Cortinovis Ivan , Gianelli Umberto , Pierini Alberto , Cortelezzi Agostino 
Published: October 2019

Abstract
Introduction
Pulmonary Hypertension (PH) is a frequently under-recognized complication of primary myelofibrosis (PMF) which is included in PH with unclear multifactorial mechanisms (group 5, acc. WHO 2008). Multiple pathophysiologic mechanisms have been implicated in its development in MF, including pulmonary myeloid metaplasia, pulmonary vessels obstruction by megakaryocytes or platelets, smooth muscle hyperplasia and thrombotic occlusion of the pulmonary vasculature. At present, there are no specific and noninvasive screening tools; transthoracic echocardiography frequently over- or understimates Pulmonary Arterial Pressures (PAPs). Right heart catheterization remains the gold standard for PH diagnosis and quantification, but as an invasive procedure it is not suitable for screening. Cardiopulmonary Exercise Testing (CPET) is a non-invasive, dynamic method that allows an integrated evaluation of both the patient's functional capacity and the severity of PH, as well as the course of its development. Our aim was to identify CPET parameters useful to earlier PH detection in PMF.
Methods
Patients (pts) with diagnosis of PMF (acc. WHO 2008), age >18 years and fit to perform CPET were included. Main exclusion criteria were concurrent pulmonary chronic disease, portal hypertension or cardiac comorbidities and clinical history of PH. At enrollment (t0) pts underwent echocardiography, CPET, global spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) analysis; echocardiographic assessment was repeated after 6 months (t1). During CPET we monitored ECG and beat-to-beat arterial pressure; we also used ventilatory expired-gas and transcutaneous PCO2/PO2 analyzer. Statistics was performed using T-test unpaired, T-test paired and Pearson's correlation.
Results
Twenty-eight pts (male/female=14/14) were compared to age and gender-matched controls. The median age was 68 years (range 37-79); 12 (43%) pts carried JAK2 V617F mutation, 14 (50%) a CARL mutation (9 type-1, 5 type-2), 2 were triple-negative. At the time of CPET, the mean platelet count was 451x109/L; mean hemoglobin level was 12.5 g/dl and mean white blood cell count was 8.27 x109/L. DIPSS was low in 11 (39%) pts, intermediate-1 in 15 (54%) pts, intermediate-2 or high in one patient, respectively. Twenty (71%) pts had a prefibrotic-stage MF, while 8 (29%) had grade 2-3 bone-marrow fibrosis. Seventeen (61%) pts were receiving hydroxyurea and 20 (71%) antiplatelet drugs. During CPET PMF compared to controls demonstrated raised minute ventilation−carbon dioxide production relationship at anaerobic threshold (AT) (35.2+5.3 vs 27.6+1.7; p 0.01), high difference between artery and tele-expiratory CO2-pressure [deltaP(a-et)CO2] at rest (11.2+3.7 vs 7.2+0.9; p 0.01) and at AT (+4.1+2.2 vs -7.8+2.3 mmHg; p 0.001). By echocardiography PMF showed short Pulmonic Valve Acceleration Time (PVAccTime) (109.6+23.6 vs 122+9 msec; p<0.01), while PAPs were not significantly elevated (24.6+6.5 vs 23+4.5 mmHg; p>0.05). Global spirometry and DLCO analysis showed normal values. At t1 PMF demonstrated a significant increase of PAPs and reduction of PVAccTime when compared with t0 (33.2+ 6.35 vs 24.6+6.5 mmHg; 90.8+15.6 vs 109.6+23.6 msec; p 0.000). A positive relationship between deltaP(a-et)CO2 at AT and both deltaPAPs and deltaPVAccTime was identified (Rsquared 0.367 and 0.964; p 0.007 and 0.000). DeltaP(a-et)CO2 at AT also showed a positive correlation with ventilation/perfusion ratio at peak exercise (R 0.17; p 0.04). No correlation was found between hematological parameters and deltaP(a-et)CO2 at AT, deltaPAPs or deltaPVAccTime.
Conclusions
CPET was able to identify a pulmonary perfusion defect during exercise in asymptomatic PMF pts with no severe alterations to the baseline echocardiography. This study defines deltaP(a-et)CO2 as predictor of pulmonary circulation impairment; this variable was significantly linked to subsequent increase of resistance (PAPs) and impedance (PVaccTime) of the circulatory system of the lungs. Our results underline how CPET should be considered as a part of initial assessment in PMF pts in order to early detect PH before appearance of clinical symptoms when available therapies might be ineffective. CPET might be a non-invasive useful tool to identify a cohort of PMF pts most at risk of developing clinically significant PH, requiring a proper echocardiographic follow-up.

Disclosures
No relevant conflicts of interest to declare.