Prognostic Implications of Pulmonary Hypertension in Myeloproliferative Neoplasms and Predictors of Hematologic Progression
Authors: Leiva Orly , Soo Steven , Smilowitz Nathaniel , Reynolds Harmony , Shah Binita , Bernard Samuel , Lee Michelle Hyunju , How Chi-Joan , Hobbs Gabriela S. 
Published: December 2024

Introduction:
Myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of disorders of clonal hematopoiesis associated with increased risk of cardiovascular disease (CVD), including pulmonary hypertension (PH). In a prior study of patients with MPN and established CVD, PH was associated with increased risk of hematologic progression to secondary MF or acute leukemia and major adverse cardiovascular events (MACE). However, the prognostic implication of PH among patients with MPN regardless of prior CVD status is unclear. Furthermore, transthoracic echocardiographic (TTE) characterization of risk of hematologic progression among those with PH has not been well studied.
Methods:
This was a multicenter retrospective cohort study of MPN patients with ≥ 1 TTE after diagnosis of MPN at New York University Langone Health and Massachusetts General Hospital from 2010 to 2023. PH was defined as estimated pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on first TTE after MPN diagnosis. The primary outcome was a composite hematologic outcome of progression to secondary MF, acute leukemia, or death from MPN. Secondary outcome was MACE, a composite of arterial or venous thrombosis, heart failure (HF) hospitalization, or CV death. Given the competing risk of death, multivariable Fine-Gray competing-risk regression was used to estimate subhazard ratio (SHR) of the primary and secondary outcomes, and were adjusted for age at first TTE, MPN type, driver mutation, any non-driver mutation status, time from MPN to TTE, hemoglobin and WBC concentration, and spleen size. The association between PH and MACE was further adjusted for treatment for the MPN, left ventricular ejection fraction (LVEF), prior CVD, indication/setting of TTE, diastolic dysfunction, anti-thrombotic use, statin use, and creatinine. Hemodynamic predictors of the composite hematologic outcome among patients with PH was assessed using univariate competing-risk regression. Variables that were significantly different between groups (p &lt; 0.05) were adjusted for age, time from MPN to TTE, driver and non-driver mutations, and spleen size.
Results:
Of the 555 patients included, 42.7% had PV, 41.1% ET, and 16.2% had MF at time of TTE, 48.5% were male and 86.8% were White race. PH was diagnosed in 195 patients (35.1%). The median time from MPN diagnosis to TTE was 39 months. Patients with PH were older (median age 71 vs 66 years, p &lt;0.001), more likely to have MF (25.6% vs 11.1%, p &lt;0.001), and higher VAF of driver MPN mutation (median 50% vs 40%, p = 0.002) and larger spleen sizes at time of TTE (median 13.7 vs 12.0 cm, p &lt;0.001). Patients with PH had a higher rate of prior HF (15.4% vs 3.3%, p &lt;0.001), hypertension (69.7% vs 56.7%, p= 0.003), and AF (29.7% vs 15.6%, p &lt;0.001). After a median follow-up of 51 months, the composite hematologic outcome (23.6% vs 10.3%, p &lt;0.001) and MACE (41.5% vs 19.2%, p &lt;0.001) were more common among patients with PH. After multivariable competing-risk regression, PH was associated with increased risk of hematologic outcome (aSHR 1.79, 95% CI 1.10-2.92) and MACE (aSHR 1.67, 95% CI 1.10-2.56). Among patients with PH, 46 (23.6%) had hematologic outcome. After adjustment, atrial enlargement (aSHR 0.42, 95% CI 0.20-0.90) and valvular regurgitation (aSHR 0.30, 95% CI 0.16-0.57) were associated with decreased risk of hematologic outcome. Tricuspid annular plane systolic excursion (TAPSE, aSHR 2.44, 95% CI 1.27-4.69), a marker of right ventricular (RV) function, and estimated cardiac output (CO, aSHR 1.33, 95% CI 1.40-1.70) were associated with increased risk of hematologic outcome.
Conclusions:
Among patients with MPN, PH was associated with increased risk of hematologic progression and MACE. Our study also sheds some light on the pathophysiology behind PH and MPN progression given the association between preserved RV function and higher CO and MPN progression. MPN progression may lead to increased catabolic demand and cell turnover that may increase CO and may in part explain the association of preserved RV function and increased CO among patients with PH and MPN progression. However, further studies are needed to better understand the physiology of PH in MPN, characterize PH phenotypes and their associations with outcomes, and to assess the utility of TTE for screening for PH and surveillance of MPN progression.