Early detection of pulmonary hypertension in primary myelofibrosis: The role of echocardiography, cardiopulmonary exercise testing, and biomarkers
Authors: Mariarita Sciumè, Veronica Mattiello, Daniele Cattaneo, Cristina Bucelli, Nicola Orofino, Lisa Gandolfi, Loredana Pettine, Silvia Lonati, Umberto Gianelli, Alberto Pierini, Agostino Cortelezzi, Alessandra Iurlo
Journal: American Journal of Hematology (2017)

Primary myelofibrosis (PMF) is the most aggressive of the classic BCR-ABL1-negative myeloproliferative neoplasms.1 Its clinical course can be complicated by pulmonary hypertension (PH) in approximately a third of cases.2 PH in PMF patients is now categorized as PH with unclear multi-factorial mechanisms (group 5), according to WHO 2008 classification.3 Its pathophysiology is not clarified and no definitive therapies have been established; recently, it has been suggested the role of a persistent activation of STAT3 in pulmonary artery endothelial cells through aberrant Janus kinase (JAK) signaling.4 Initial PH symptoms are non-specific and typically induced by exertion. This frequently results in a considerable delay of PH diagnosis meaning that PH is rarely suspected until it reaches an advanced stage when prognosis becomes poor.2, 3 At present, there are no specific and non-invasive screening tools; Doppler transthoracic echocardiography (TTE) frequently over- or underestimates systolic pulmonary arterial pressure (SPAP).3 Right heart catheterization remains the gold standard for PH diagnosis and quantification, but as an invasive procedure it is not suitable for screening.3 Cardiopulmonary exercise testing (CPET) is a non-invasive, dynamic method for an integrated evaluation of the patients' lung and heart functional capacity during the performance of physical exercise.3, 5 For its properties, CPET has been used in PH to estimates the severity of disease, patients' prognosis, and response to therapy, but its use has been limited to experienced centers and restricted group of patients.3, 5 Together with the instrumental investigations, a variety of plasmatic biomarkers has been proposed for the optimization of PH management; current guidelines recommend the use of either brain natriuretic peptide (BNP) or the N-terminal fragment of pro-BNP (NT-proBNP) as biomarkers for mortality risk stratification.3, 6 Our aim was to describe cardiopulmonary function and exercise tolerance in PMF patients without PH symptoms to detect early signs of pulmonary perfusion defects. Forty patients with a diagnosis of PMF and sufficiently fit to perform CPET were included in the study. Main exclusion criteria were concurrent pulmonary or cardiac disease, portal hypertension, clinical history of PH, or a previous splenectomy. At enrollment (t0) patients underwent TTE, CPET, global spirometry, diffusing capacity of lung for carbon monoxide analysis (DLCO), and PH serum biomarkers measurement [NT-proBNP, D-dimer, von Willebrand Factor antigen (vWF:Ag), and ristocetin-cofactor activity (vWF:RCo)]. During CPET, we continuously monitored electrocardiogram, beat-to-beat arterial pressure, impedenzometry-assessed cardiac output. We also used ventilatory expired gas analysis breath-by-breath and transcutaneous PCO2 and PO2 gas analyzer. Biomarkers and TTE were repeated after 12 months (t1). The patients were matched by age and gender to a control group consisting of 40 healthy volunteers (HV). The characteristics of the cohort (Supporting Information) reflect the heterogeneity of epidemiologic and clinical features that are found in the routine clinical practice of PMF patients. Most relevant echocardiographic and CPET parameters are listed in Table 1. The basal echocardiographic evaluation demonstrated normal myocardial mass, global ejection fraction, systolic and diastolic function. At t0 resistance (SPAP) and impedance of pulmonary circulation [pulmonic valve acceleration time (PVAccTime)] were not abnormal, although significantly different when compared to HV (P < .01). Global spirometry and DLCO analysis showed normal values. During CPET the patient cohort performed an adequate exercise, but a ventilatory inefficiency emerged from a raised minute ventilation-carbon dioxide production relationship (VE/VCO2) at anaerobic threshold (AT) (34.8 ± 5.9 vs 27.5 ± 1.6; P < .001) and a raised VE/VCO2 slope (29.3 ± 5.9 vs 23.9 ± 1.2; P < .01). Increased dead-space ventilation also led to a high difference between artery and tele-expiratory CO2-pressure [deltaP(a-et)CO2] at rest (9.3 ± 3.5 vs 7.04 ± 0.8; P < .01), and a further widening at AT (13.1 ± 4.9 vs −7.9 ± 2.2 mmHg; P < .001). After a 12 months follow-up, SPAP, PVaccTime, and pulmonary distensibility (SPAP/PVaccTime) significantly changed (P < .001). A significantly positive correlation was found between VE/VCO2 slope and both PVaccTime/SPAP (P = .009) and SPAP at t1 (P = .004). Serum biomarkers showed values within normal reference ranges (Table 1). At t0 NT-proBNP and vWF:Ag positively correlated with SPAP and DIPSS risk stratification (P = .005, P = .001, and P < .001, P = .047, respectively). No correlation was found with mutational status of JAK2, CALR, or MPL genes. Based on these results, the present study suggests a pulmonary perfusion defect during exercise in patients affected by PMF that we expressly selected without PH symptoms or limitations in their ordinary physical activity. So far, CPET has been applied to evaluate respiratory function in the field of hematological diseases, in particular chronic hemolytic anemia, while it has not been widely utilized concerning hematological malignancies.3, 5 To the best of our knowledge, this is the first study investigating CPET in a series of PMF patients. In this patient population, CPET demonstrated a significant increase of VE/VCO2 and deltaP(a-et)CO2, underlining the over-ventilation of alveoli with insufficient perfusion during physical effort. This study benefits from a 12-month follow-up; VE/VCO2 slope showed to own a strong predictive value for subsequent increase of resistance (SPAP) and impedance (PVaccTime/SPAP) of the pulmonary circulatory system. In conclusion, our study highlights the existence of an altered pulmonary perfusion/ventilation matching during exercise in asymptomatic PMF patients with no severe echocardiographic alteration. Cardiopulmonary exercise testing could be used as a part of a non-invasive PMF assessment to early recognize patients most at risk of developing clinically significant PH and requiring a proper cardiological surveillance. Nothing to report. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.