Prevalence of Pulmonary Hypertension in Myelofibrosis

Abstract

Background.

Pulmonary hypertension (PH) has been described in myelofibrosis (MF), but it is rare and typically found in advanced disease. Although the etiology of PH in MF is unclear, early predictors may be detected by echocardiogram. The goals of our study were to evaluate the prevalence of PH as determined by echocardiography in a cohort of MF patients and to identify clinical risk factors for PH.

Methods.

We performed a retrospective review of MF patients from October 2015 to May 2017 at MD Anderson Cancer Center in the ambulatory clinic, and those with echocardiogram were included. Clinical, echocardiographic and laboratory data were reviewed. Patients with and without PH were compared using a chi-square or Fisher exact test, and logistic regression was performed with an outcome variable of PH.

Results.

There were 143 patients with MF who underwent echocardiogram, and 20(14%) had echocardiographic findings consistent with PH. Older age, male gender, hypertension, hyperlipidemia, coronary artery disease, dyspnea, hematocrit, brain natriuretic peptide(BNP) and N-terminal-pro hormone BNP(NT-proBNP) were significantly different between those without PH and those with PH(p<0.05). Female gender was protective (OR 0.21, 95% CI: 0.049–0.90, p=0.035) and NT-proBNP was a significant clinical predictor of PH(OR 1.07, CI: 1.02=1.12, p=0.006).

Conclusions.

PH in MF is lower than previously reported in our MF cohort, but many patients had cardiac comorbidities. PH due to left-sided heart disease may be underestimated in MF. Evaluation of respiratory symptoms and elevated NT-proBNP should prompt a baseline echocardiogram. Early detection of PH with a multidisciplinary approach may allow treatment of reversible etiologies.

INTRODUCTION

Pulmonary hypertension (PH) is a rare complication of myeloproliferative neoplasms (MPN). Reports of prevalence range from 5 to 48%, but these are based primarily on case reports and small series.(1–6) Studies to date have been limited by variable definitions of PH with different diagnostic modalities and data from heterogeneous groups of MPN. Echocardiography is the standard screening test for PH, but multiple other processes, such as acute pulmonary embolism, heart failure, chronic hemolytic anemia, chronic lung disease or obstructive sleep apnea, can result in elevated pulmonary pressures.(7) In many of these conditions, PH may either completely or partially resolve with treatment of the underlying etiology. In those with persistent PH or with an unclear etiology, a right heart catheterization (RHC) is indicated to confirm the diagnosis and identify if PH is primary or secondary to a heart or lung process. Hemodynamics and vasoreactivity allows further classification, since the World Health Organization (WHO) categorizes PH into 5 groups based on treatment.(8) Unfortunately, systematic evaluation for PH has been lacking in this population, and it is often diagnosed in advanced stages of disease with significant symptom burden.

Myelofibrosis (MF) associated with PH has been identified in many reports. MF may be primary or secondary to either essential thrombocytosis (ET) or polycythemia vera (PV). It is a disease with a median age at diagnosis of 65, with a slightly increased prevalence in men.(9) The evolution of bone marrow fibrosis central to this disease is complex and poorly understood, but it is thought to represent, in part, reaction to several cytokines.(10, 11) Bone marrow fibrosis resulting in inefficient extramedullary hematopoiesis has been postulated to contribute to the development of PH in MF; however portopulmonary hypertension related to organomegaly, acute or chronic pulmonary emboli, and congestion of pulmonary vascular bed due to hematologic aberrancies are other potential contributors.(10, 12) Both improvement and exacerbation of PH have also been reported with agents such as ruxolitinib, a JAK-1 and JAK-2 inhibitor.(11, 13) Given the advanced age of presentation in MF, other cardiac comorbid conditions may also result in or contribute to PH. The purpose of our study was to evaluate the prevalence of PH as determined by echocardiography in a cohort of MF patients, and secondarily to identify clinical risk factors for PH in this cohort.

METHODS

We performed a retrospective evaluation of MF patients seen in outpatient Leukemia clinic at the University of Texas MD Anderson Cancer Center from October 1, 2015 to May 20, 2017. Patients were included if they had the following performed on the same date of evaluation: clinical evaluation and physical examination by a hematology/oncology physician; a two dimensional echocardiogram; routine laboratory data including complete blood count with differential, creatinine, brain natriuretic peptide (BNP) and N-terminal-pro hormone brain natriuretic peptide (NT-pro-BNP). Malignancy characteristics including type of myelofibrosis, presence of JAK2 mutation, World Health Organization (WHO) bone marrow myelofibrosis grade, and dynamic international prognostic scoring system (DIPSS), from baseline evaluation at our center. The study was conducted in accordance with the ethical rules of the Helsinki Declaration and approved by the by the institutional review board (DR07–0468).

Echocardiography

Comprehensive echocardiographic examinations were performed using multiple commercially available equipment (GE Healthcare, Milwaukee, WI; Philips, Amsterdam, The Netherlands) with 3.5-MHz ultrasound probes. Standard views were acquired carefully to avoid foreshortening. From the apical 4-chamber view, pulsed wave Doppler was used to record mitral inflows for 3 to 5 cardiac cycles at the level of the mitral annulus and mitral leaflet tips. Guided by color Doppler, pulmonary venous flow was recorded from one accessible pulmonary vein. Tissue Doppler was used to register mitral annular velocities at the septal and lateral aspects of the annulus. The mitral annular velocities by pulsed wave Doppler were recorded for 3 to 5 cardiac cycles at a sweep speed of 100 mm/s. Tricuspid regurgitation (TR) velocities were recorded by continuous wave Doppler from multiple windows and the highest velocity was considered. The tricuspid annular plane excursion (TAPSE) was obtained using the m-mode acquisition of the lateral tricuspid annulus at the free right ventricle (RV) wall in the 4 chamber view plane. Saline contrast was used when tricuspid signal was insufficient to determine tricuspid velocities. Inferior vena caval diameter and its collapse was obtained in the substernal window. Linear and volumetric measurements were performed following the American Society of Echocardiography (ASE) chamber quantification, diastolic assessment and right heart assessment guidelines (14–16) in an offline workstation by three board certified cardiologists with Core Cardiology Training Symposium (COCATS) level 3 competence in echocardiography with minimal inter-observer variability.(17, 18) Right ventricular systolic pressure (RVSP) was determined by Doppler using the peak velocity (V) of a tricuspid insufficiency if available, using the following formula: RVSP= 4V2 + right atrial pressure. Right atrial pressure was estimated by using the inferior vena cava collapsibility in respiration, and an RVSP > 35mmHg was defined as PH.(16) Left ventricular filling pressures were estimated using the ASE left ventricular diastolic assessment guidelines.(15, 19). Assessment of filling pressures was derived from the mitral leaflets tips pulsed wave Doppler measurements and tissue Doppler imaging to calculate the ratio E/e’.(15, 20) WHO Group classification was determined as group II (post-capillary) if there was evidence of an RVSP >35 mmHg accompanied by elevated filling pressures and non-group II (pre-capillary) if the RVSP>35 mmHg in the absence of elevated filling pressures, as it has been previously shown to be feasible.(21)

Statistics

Demographic and clinical characteristics of all patients were summarized with descriptive statistics. Categorical variables were compared by those with and without pulmonary hypertension using a chi-square test or Fisher exact test. Continuous variables were compared using a t-test or Wilcoxon rank-sum (Mann Whitney) test depending on the underlying distribution of the data. P-values less than 0.05 were considered to be significant, and all tests were two-sided. A secondary analysis to determine the clinical risk factors for PH was performed. Univariate and multivariable logistic regression was performed with the outcome variable of PH. Variables with a p-value of less than 0.20 on univariate analysis were considered candidate variables for a multivariable regression model. The full model was then reduced via backward selection, with a p-value of less than 0.05 to be inclusion criteria for including in the final model. Overall survival was estimated using the methods of Kaplan and Meier. Overall survival was calculated from the time of MF diagnosis to date of last follow up or death. Statistical software used was Stata® version 15.1 (College Station, Texas).

Study data were collected and managed using REDCap electronic data capture hosted at The University of Texas at M.D. Anderson Cancer Center.(22) REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedure for importing data from external sources.

RESULTS

Of the 151 patients identified, 6 did not meet criteria for MF, and 2 did not have an echocardiogram performed. In all patients, time from diagnosis of MF to our assessment ranged from 21 days to 20 years with a median time of 3.6 years. In those with primary MF, time from diagnosis to our assessment ranged from 23 days to 20 years with median time of 3.4 years, in those with history of ET ranged from 21 days to 10.1 years with a median of 3.8 years and in those with history of PV ranged from 7.5 months to 16.7 years with median time of 4.4 years.

Demographic and clinical characteristics are displayed in Table 1. Echocardiographic assessment identified PH in 20 (14%) patients. In the group without PH, eleven patients had thromboembolic disease (9%), one had autoimmune disease (0.8%), three patients had obstructive sleep apnea (2.4%), and four had undergone a splenectomy (3.1%). No patients had human immunodeficiency virus (HIV). A few patients reported lower extremity edema (7.0%) and palpitations (1.4%), but there was no significant difference between the two groups. There were no complaints of chest pain or syncope. Age, gender, hypertension, hyperlipidemia, coronary artery disease, and dyspnea were significantly different between those without PH and those with PH.

Table 1.

Patient characteristics

	Without PH	With PH	P value
	n= 123 (%)	n=20 (%)
Age (years)			0.019
Mean ± SD	66.8 ± 9.7	71.8 ± 6.7
Median (range)	68 (18–86)	73.5 (61–83)
Gender			0.048
Male	63 (51)	15 (75)
Female	60 (49)	5 (25)
Time (days) from MF diagnosis to ECHO			0.518
Mean ± SD	1547.5 + 1120.3	1836.7 ± 1578.1
Median (range)	1294 (21 – 6092)	1760 (251 – 7311)
MF type			0.470
PMF	72 (59)	12 (60)
Post-ET MF	21 (17)	5 (25)
Post-PV MF	30 (24)	3 (15)
JAK2 mutation present	67 (54)	11(55)	0.965
WHO grading myelofibrosis*			0.932
MF-1	16 (14)	2 (13)
MF-2	49 (43)	8 (50)
MF-3	50 (44)	6 (38)
DIPSS^			0.731
Low risk (0)	5 (4)	-
Intermediate-1 risk (1 to 2)	49 (40)	8 (40)
Intermediate-2 risk (3 to 4)	53 (43)	8 (40)
High risk (5 to 6)	15 (12)	4 (20)
Active therapy for MF	51 (41)	8 (40)	0.902
Co-morbid conditions
Hypertension	65 (53)	16 (80)	0.028
Hyperlipidemia	25 (20)	9 (45)	0.016
Coronary artery disease	10 (8)	6 (30)	0.004
Atrial fibrillation	5 (4)	1 (5)	≥0.999
Hypothyroidism	28 (23)	7 (35)	0.238
Diabetes Mellitus	11 (9)	1 (5)	≥0.999
COPD	5 (4)	1 (5)	≥0.999
Clinical
Dyspnea	13 (11)	7 (35)	0.003
ECOG performance status			0.845
0	48 (39)	6 (30)
1	65 (53)	13 (65)
2	8 (7)	1 (5)
≥3	2 (2)	-
Splenomegaly	76 (62)	16 (80)	0.137
Hepatomegaly	19 (15)	6 (30)	0.112
Active treatment	51 (41)	8 (40)	0.902

^*Data not available in *10 and

^{^}1 patient

PH, pulmonary hypertension; MF, myelofibrosis; ECHO, echocardiogram; PMF, primary myelofibrosis; Post-ET, myelofibrosis post-essential thrombocytopenia; Post-PV, myelofibrosis post-polycythemia vera; WHO, World Health Organization; DIPSS, dynamic international prognostic scoring system; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group

Echocardiographic and laboratory data are detailed in Table 2. TR velocity ranged from 1.73 to 2.83 m/s in 81 patients without PH and 2.78 to 3.84 m/s in 20 patients with PH. TAPSE ranged from 1.5 m/s to 3.8 m/s in 107 patients without PH and 1.5 m/s to 4.0 m/s in 17 patient with PH. In those with PH, elevated filling pressures were present in 12 (63%) which suggests PH related to left-sided heart disease (WHO Group II). Normal filling pressures were found in 6 (32%), and this may suggest precapillary PH. None of the patient had clinical or echocardiographic findings of severe PH or right-sided heart failure, and no patients underwent RHC. Echocardiographic parameters of left ventricular end-diastolic volume, left ventricular end-systolic volume, left atrial volume size, E/e’, filling pressure and RVSP and laboratory values for hematocrit, BNP, and NT-proBNP were significantly different between those without PH and those with PH. There were 48 patients (34%) in our cohort for which the RVSP by TR could not be quantified due to poor quality Doppler tracing or insufficient TR.

Table 2.

Echocardiographic and laboratory data

	Without PH		With PH		P value
	N		N
Echocardiographic variables Mean ± standard deviation
LV ejection Fraction (%)	123	59.3 ± 5.6	20	56.8 ± 8.8	0.279
LV end-Diastolic Volume (mL)	122	119.4 ± 41.4	20	148.4 ± 51.8	0.016
LV end-Systolic Volume (mL)	122	49.1 ± 21.8	20	67.8 ± 39.1	0.020
E/e’ average	115	10.4 ± 4.4	19	14.8 ± 8.1	0.005
LA volume index (mL/m²)	115	30.5 + 9.4	20	39.9 + 15.2	0.002
LV mass index (g/m²)	121	86.2 ± 25.5	20	97.8 ± 27.5	0.118
RVSP	81	27.3 ± 4.9	20	48.0 ± 8.9	<0.001
RV size	116	3.55 ± 0.5	19	3.92 ± 0.7	0.006
Presence of valvular disease (n, %)	123	5 (4)	20	3 (15)	0.083
Filling pressure (n, %)	116		19		<0.001
Normal		95 (82)		6 (32)
Elevated		13 (11)		12 (63)
Indeterminate		8 (7)		1 (5)
Hematologic parameters Mean ± standard deviation
WBC (K/μL)	123	14.2 ±22.9	20	16.8 ± 16.7	0.182
Hemoglobin (g/dL)	123	10.24 ± 1.8	20	9.6 ± 2.1	0.125
Hematocrit	123	34.9 ± 22.0	20	29.9 ± 6.3	0.048
Platelet count (K/μL)	123	182.8 ± 153.5	20	136.7 ± 94.7	0.383
BNP	117	69.8 ± 75.3	17	276.4 ± 412.5	0.003
NT-ProBNP (pg/mL)	114	356.2 ± 689.1	17	4999.1 ± 11614.4	0.018

PH, pulmonary hypertension; LV, left ventricular; LA, left atrial; RVSP, right ventricular systolic pressure; RV, right ventricular; WBC, white blood cell count; BNP, brain natriuretic peptide; NT-ProBNP, N-terminal-pro hormone brain natriuretic peptide

Univariate logistic regression for clinical prognostic factors of pulmonary hypertension with a p-value < 0.20 included age, gender, hypertension, hyperlipidemia, coronary artery disease, dyspnea, splenomegaly, hepatomegaly, hemoglobin, hematocrit, BNP and NT-proBNP. Due to high collinearity between BNP and NT-proBNP, only NT-proBNP was used in the full multivariable model. Multivariate model with backward selection yielded significant association only with female gender (OR 0.21, 95% CI: 0.049–0.90, p=0.035) and NT-pro-BNP (OR 1.07, CI: 1.02=1.12, p=0.006). The median follow up time for all subjects was 5.3 years (range: 0.4 – 20.2).

Discussion

PH was found in 14% of our MF cohort, and the majority of these had elevated filling pressures suggestive of a post-capillary PH consistent with left-sided heart disease. Diastolic dysfunction was the culprit in the majority of these patients. Dyspnea, older age, male gender, hypertension, hyperlipidemia and coronary artery disease were more common in the PH group. Male gender and NT-proBNP were significant clinical predictors of PH in MF. RHC was not performed in our study, but NT-proBNP and early echocardiographic findings did confirm abnormalities in those with PH.

Our study detected a lower prevalence of PH based on echocardiogram compared to previous data. A few other prospective studies support our findings. Brabrand and colleagues used both a screening echocardiogram and confirmatory RHC to identify 3.8% PH in a cohort of 158 MPN patients.(23) The majority of their cohort included PV with only 24 (15%) patients with MF. Interestingly, half of those with confirmed PH had left-sided heart disease. Chebrek’s group screened 103 MPN patients with echocardiogram and concluded an prevalence of 4.8%, but they only included 15 patients with MF of which 2 had PH.(5) In comparison, our cohort includes only MF, and there was no correlation with degree of fibrosis, anemia, type of MF or DIPSS. Other co-morbid conditions including chronic obstructive pulmonary disease, obstructive sleep apnea, HIV, autoimmune disease and thromboembolic disease were systematically assessed and excluded as potential etiologies of PH, so we conclude our cases of PH were primarily related to left-sided heart disease (WHO Group II). Our results are different than previous investigations that have attributed the PH primarily to the underlying MF and the inflammatory milieu. Interestingly, data in patients with PAH (WHO Group I) on pulmonary vasodilator therapy without cancer may have indolent myeloid abnormalities, such as polyclonal myelofibrosis.(24) In animal models, hematopoietic myeloid progenitors from patients with PAH induces endothelial injury, vascular remodeling and PAH, so some have postulated that a myelopulmonary pathophysiologic link may exist in patients with PAH and MF.(25, 26) Others have proposed that the development of PAH in MF is due to pro-angiogenic state. In a small study of 36 primary MF patients, Cortelezzi and associates uses echocardiogram to detect PH and simultaneously assessed peripheral blood levels of endothelial progenitor cells, circulating endothelial cells, vascular endothelial growth factor (VEGF) and bone marrow microvessel density.(4) In the 12 (36%) of their patients with PH, they found higher levels of VEGF and bone marrow microvessel density, but a negative correlation between endothelial progenitor cells and RVSP. Their conclusions were limited due to small sample size, but their data suggested a potential distinct phenotype for those that develop PAH in MF. Thus although PAH (WHO Group I) and PH related to unclear mechanisms such as extramedullary hematopoiesis (WHO Group V) have been described in MF, we suspect these etiologies for PH are rare, and PH due to left-sided heart disease may be far more common.(27, 28) It is important to note that as in many other disease states, there may be different phenotypes of PH (or WHO Groups) associated with MF.

Cardiovascular complications have been reported in 12 to 50% of MF patients with coronary atherosclerosis and high-output cardiac failure.(2, 29–31) Since MF occurs in older individuals, they are at risk for the development of hypertension, coronary atherosclerosis and Heart Failure with preserved Ejection Fraction (HFpEF).(32) Along with other risk factors of hypertension and coronary atherosclerosis, HFpEF is defined as development of clinical heart failure despite a left ventricular ejection fraction of greater than 50%, mainly due to left ventricular stiffening.(32) This may also result from infiltrative disorders such as hemochromatosis or amyloidosis, thus frequent transfusions or transfusion-dependency in MF could also predispose these patients to infiltrative disease due to iron overload.(32) In our study, the group with PH were older, had more men, and comorbid conditions of hypertension, hyperlipidemia and coronary artery disease were significantly more present. In the general population, left-sided heart disease is the most common cause of PH, and the incidence of diastolic dysfunction increases with age.(33, 34) Given the advanced age, comorbidities and increased incidence of PH WHO Group II in MF patients, they might be susceptible to develop HFpEF, so a baseline echocardiogram could provide valuable information including left ventricular function, left atrial volume, diastolic function assessment and right ventricular function and size. In those with significant symptoms of dyspnea and right heart failure, both clinical assessment and echocardiogram fail to discern between PAH (WHO Group I) from PH related to left-sided heart disease (WHO Group II) or CTEPH (WHO Group IV), and RHC might be necessary since treatment differs greatly in all three. However, screening echocardiogram could provide valuable information about the etiology of PH especially if it is related to valvular disease or diastolic dysfunction. It is unclear how many of the cases related to PH may have a component or have started with some degree of left-sided cardiac dysfunction, but prospective evaluation may help elucidate the true pathophysiology further.

Although signs of right heart failure, syncope, and dyspnea at rest heighten the suspicion for possible PH, mild PH symptoms such as dyspnea with exertion or fatigue may be non-specific, and these may be discounted to anemia or underlying MF. Despite previous reports of leukocytosis and thrombocytosis in MPN with PH, there was no difference in the group with PH or sustained effect in our analysis. However, both BNP and NT-proBNP were significantly different in the PH group (Table 2), and in our multivariate analysis, NT-proBNP and gender were clinical predictors of PH (Table 3). Natriuretic peptides are a family of hormones that are released by the myocardium in response to wall stress.(35) They essentially function as protective hormones that antagonize the pathophysiology of heart failure, but their levels are increased with conditions that results in heart strain including heart failure, pulmonary hypertension, atrial fibrillation, pulmonary embolism and some non-cardiovascular conditions such as renal failure.(36) Both BNP and NT-proBNP are used in the workup of dyspnea, and along with clinical assessment and tools, normal levels suggest a non-cardiac etiology. These biomarkers also provide risk stratification and treatment guidance for heart failure and pulmonary hypertension. In another oncologic condition, NT-proBNP has been used as a surrogate endpoint in studies, since it predicts cardiac involvement and prognosis in patients with AL amyloidosis.(37) The levels of BNP and NT-proBNP correlate but are not interchangeable, for they have different half-lives, different modes of degradation and distinct ranges for normal values.(35) In left ventricular dysfunction, NT-proBNP rises approximately four-fold higher than BNP, and thus may detect heart failure earlier.(38) We would recommend obtaining and NT-proBNP for MF patients at baseline, and in those with respiratory symptoms or other cardiac comorbidities, a baseline echocardiogram should be obtained. In our institution, we have a multidisciplinary team to evaluate patients with suspected pulmonary hypertension. A systematic approach to evaluate other causes of dyspnea including chest imaging, pulmonary function testing, walk test and natriuretic peptides is carried out in those with an abnormal echocardiogram. In those with mild PH and symptoms suggestive of obstructive sleep apnea, polysomnography is ordered. Finally in a clear etiology is not identified, RHC is indicated to confirm PH, assess hemodynamics and vasoreactivity, and guide further management.

Table 3.

Univariate and multivariate logistic regression for clinical predictors of pulmonary hypertension

		Univariate			Multivariable
Characteristic	OR	95% CI	p-value	OR	95% CI	p-value
Age	1.08	1.01–1.16	0.027
Female gender	0.35	0.12–1.02	0.055	0.21	0.05–0.90	0.035
Time from MF diagnosis to ECHO	1.00	1.00–1.00	0.317
MF type
Primary MF	1.00	1.00–1.00	.
Post-ET MF	1.43	0.45–4.52	0.544
Post-PV MF	0.60	0.16–2.28	0.453
JAK2 mutation present	1.02	0.40–2.62	0.965
WHO grading MF
MF-1	1.00	1.00–1.00	.
MF-2	1.31	0.25–6.79	0.751
MF-3	0.96	0.18–5.24	0.962
DIPSS
Low and intermediate risk	1.02	0.36–2.91	0.972
High risk	1.80	0.48–6.80	0.386
Active therapy	0.94	0.36–2.47	0.902
Hypertension	3.57	1.13–11.29	0.030
Hyperlipidemia	3.21	1.20–8.58	0.020
Coronary artery disease	4.84	1.53–15.36	0.007
Atrial fibrillation	1.24	0.14–11.22	0.847
Hypothyroidism	1.83	0.66–5.02	0.243
Diabetes mellitus	0.54	0.07–4.39	0.561
COPD	1.24	0.14–11.22	0.847
Dyspnea	4.56	1.54–13.47	0.006
Splenomegaly	2.47	0.78–7.85	0.124
Hepatomegaly	2.35	0.80–6.87	0.120
ECOG Performance Status
0 to 1	1.60	0.57–4.51	0.374
2 to 4	0.80	0.086–7.39	0.844
WBC	1.00	0.99–1.02	0.623
Hemoglobin	0.81	0.61–1.07	0.134
Hematocrit	0.91	0.83–1.00	0.048
Platelets	1.00	0.99–1.00	0.200
BNP * ^	1.87	1.16–3.02	0.010
NT-proBNP ^	1.07	1.02–1.12	0.008	1.07	1.02–1.12	0.006

^*BNP was not used in the multivariate model to avoid collinearity with NT-proBNP

^{^}Value were divided by 100

PH, pulmonary hypertension; MF, myelofibrosis; ECHO, echocardiogram; Post-ET, myelofibrosis post-essential thrombocytopenia; Post-PV, myelofibrosis post-polycythemia vera; WHO, World Health Organization; DIPSS, dynamic international prognostic scoring system; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cell count; BNP, brain natriuretic peptide; NT-ProBNP, N-terminal-pro hormone brain natriuretic peptide

There are limitations inherent to retrospective studies. Our sample size only included a quarter of the patients with MF seen during this time period, and selection bias exists since only patients that had echocardiogram and laboratory data on the same day of clinical evaluation were included. Although all patients had MF, there was a disparity in our cohort, since PH was assessed at varying times from the initial myelofibrosis diagnosis and patients had different disease severities. Although an electronic medical record and echocardiographic videos ensured minimal loss of patient data, some cardiac variables could not be obtained either due to lack of image quality from inadequate acoustic windows, or complicated by concomitant arrhythmias, concomitant mitral valve disorders, or other technical difficulties. In addition, although echocardiography is routinely used as a screening tool for PH, RHC remains the gold standard. It is well established that limitation of assessment of left ventricular filling pressures by echocardiogram and overestimation of systolic pulmonary pressures by using the TR velocities via Doppler method exist.(20, 39) Cases evaluated with echocardiogram that were deemed to be unexplained by having normal left ventricular filling pressures and PH could had been misinterpreted if they fell in the “gray zone” between E/e’ average 9 to 13.(15) However, we meticulously reviewed medical histories of each patient to identify other risk factors for PH including thromboembolic disease, autoimmune disease, chronic lung disease, and obstructive sleep apnea, and we included these in our analysis. Our study is the largest prospective evaluation for PH in MF using echocardiogram, and provide insight into the potential pathophysiology of pulmonary vascular disease in MF.

Our data reports a prevalence of PH lower than that reported in other studies. The PH patients in our cohort were older and had multiple cardiovascular risk factors. In those with PH, the majority had echocardiographic findings of left-sided dysfunction, and given the advanced age of MF patients, cardiac etiology or WHO Group II disease may be the initial insult resulting in PH. Gender and NT-proBNP were significant clinical predictors of PH. Evaluation of respiratory symptoms followed by serum NT-proBNP is recommended, for elevated NT-proBNP is a reliable, easily measurable and reproducible continuous measure of heart strain. In those with symptoms or abnormal natriuretic peptide, baseline echocardiogram would be indicated. Systematic evaluation of other etiologies of PH should be carried out, and in those without a clear etiology, RHC would be the next step. A multidisciplinary approach and early proactive testing will help to identify those PH and MF earlier.