Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p \u3c 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p \u3c 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p \u3c 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization

The Liver-Lung Connection in Portopulmonary Hypertension

Portopulmonary hypertension, a subtype of World Health Organization Group 1 pulmonary arterial hypertension (PAH) that develops in the setting of portal hypertension, is the third most common cause of associated PAH and affects approximately 5-6% of patients evaluated for liver transplant. POPH is pathologically indistinct from idiopathic PAH(1), but is associated with a significantly lower 5-year survival of 40%(2). POPH can complicate or preclude liver transplantation due to an elevated risk of perioperative death(8). Because of this increased risk, patients on the liver transplant list undergo yearly echocardiograms to screen for POPH, and patients with a known diagnosis of POPH undergo repeated right heart catheterizations every 3 months to ensure hemodynamics are acceptable for transplant(9, 10). Since 2006, patients with treated POPH who meet certain hemodynamic criteria have been eligible to receive MELD exception points, or waitlist priority upgrades, in order to expedite liver transplant(10, 11), but potentially important factors, such as severity of liver disease and POPH, are not included in the score and may affect survival. The pathogenesis of POPH, characterized by pulmonary vasoconstriction and vascular remodeling, is poorly understood. There is no association between the presence of POPH and severity of liver disease or portal hypertension(3-5), but an increased prevalence of spontaneous portosystemic shunts in patients with POPH(6) as well as the development of POPH in patients with congenital portosystemic shunts with normal liver function(7) suggests that vasoactive factors from the splanchnic circulation contribute to disease pathogenesis. Identification of these factors and improved understanding of the role of the liver in the pathogenesis of POPH could lead to novel targeted therapies for this disease. The overall goal of my research is to define the liver-lung connection in POPH and to determine the role of the portal circulation in disease pathogenesis and the role of liver transplant in the management of POPH. To address these goals, we have performed two studies. First, we performed a prospective multicenter case-control study in patients with liver disease to identify novel biomarkers of POPH and to compare biomarker gradients across the systemic and pulmonary circulation. We identified higher levels of macrophage migration inhibitory factor (MIF), a pleiotropic inflammatory cytokine, in both the systemic and pulmonary circulation of patients with POPH and found that MIF was correlated with POPH disease severity. Additionally, MIF in conjunction with echocardiogram could improve the screening of patients with liver disease for POPH. In the second study, we performed a retrospective analysis of the United Network for Organ Sharing (UNOS) national database to identify significant predictors of waitlist mortality in patients with POPH. We characterized waitlist and post-transplant outcomes in patients with POPH and identified both initial MELD score and pulmonary vascular resistance as significant predictors of waitlist mortality. Future directions will include prospective study to identify the short-term and long-term effects of liver transplant on pulmonary hemodynamics in patients with POPH

High-sensitivity C-reactive protein in heart failure with preserved ejection fraction.

BACKGROUND:Microvascular inflammation may contribute to the pathogenesis of both heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH). We investigated whether the inflammation biomarker C-reactive protein (CRP) was associated with clinical characteristics, disease severity or PH in HFpEF. METHODS:Patients in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart failure (RELAX) trial had baseline high-sensitivity CRP levels measured (n = 214). Clinical characteristics, exercise performance, echocardiographic variables and biomarkers of neurohumoral activation, fibrosis and myocardial necrosis were assessed. Patients with normal (≤3mg/L) versus high (>3mg/L) CRP levels were compared. RESULTS:The median CRP level was 3.69mg/L. CRP was elevated in 57% of patients. High CRP levels were associated with younger age, higher body mass index (BMI), chronic obstructive pulmonary disease (COPD), lower peak oxygen consumption and higher endothelin-1 and aldosterone levels. CRP increased progressively with the number of comorbidities (0.7mg/L per increment in comorbidity number, P = 0.02). Adjusting for age, BMI and statin use, high CRP levels were additionally associated with atrial fibrillation, right ventricular dysfunction, and higher N-terminal pro-B-type natriuretic peptide levels (P<0.05 for all). CRP was not associated with PH or left ventricular function. CRP did not identify responders to sildenafil(P-value for interaction 0.13). CONCLUSIONS:In HFpEF, high CRP is associated with greater comorbidity burden and some markers of disease severity but CRP was normal in 40% of patients. These findings support the presence of comorbidity-driven systemic inflammation in HFpEF but also the need to study other biomarkers which may better reflect the presence of systemic inflammation

Bezold–Jarisch reflex mediated syncope in pulmonary arterial hypertension: An illustrative case series

Abstract We present a novel description of Bezold–Jarisch Reflex (BJR) during cardiopulmonary exercise testing (CPET) in three young female patients with Group 1 pulmonary arterial hypertension (PAH). These three cases presented within 26 months, representing only 0.8% of 11,387 tests on patients with PAH undergoing CPET during this time frame

Pulmonary Vessel Cross-sectional Area before and after Liver Transplantation: Quantification with Computed Tomography

Rationale and Objectives: Pulmonary vascular complications of liver disease have a substantial impact on morbidity and mortality in patients who undergo liver transplant. The effect of liver transplantation on the pulmonary vasculature in patients without pulmonary vascular disease, however, has not been described. This study was undertaken to characterize the regional effect of liver transplant on the cross-sectional area (CSA) of pulmonary vessels. Materials and Methods: We performed a single-center, retrospective, cohort study of patients who had a liver transplant between 2002 and 2012 and who had chest computed tomography scans within 1 year before and after transplant. Using ImageJ software, we measured the CSA of small pulmonary vessels (0-5mm2) and the total lung CSA to calculate the percent CSA of pulmonary vessels <5mm (%CSA<5) at the level of the aortic arch, carina, and right inferior pulmonary vein (RIPV). Pretransplant and posttransplant, %CSA<5 were compared, and associations of pretransplant %CSA<5 with clinical parameters were measured. Results: There was a significant decrease in %CSA<5 at the level of the RIPV (0.19% [interquartile range IQR, 0.15-0.26] before vs. 0.15% [IQR, 0.12-0.21] after; P=0003), with a median change of -16.2% (IQR, -39.3 to 3.9) posttransplant. Changes at the level of the aortic arch and carina were not significant. Pretransplant RIPV %CSA<5 was not significantly correlated with severity of liver disease or oxygenation but was inversely correlated with percent change in %CSA<5 (r=-0.39; P=0039). Conclusions: This is the first study to describe a significant regional change in the pulmonary vessels of patients without known pulmonary vascular disease who undergo liver transplant

Pulmonary Vessel Cross-Sectional Area Before And After Liver Transplantation: Quantification With Computed Tomography

Rationale: Pulmonary vascular complications of liver disease are poorly understood but contribute significantly to morbidity and mortality. While Model for End-stage Liver Disease (MELD) exception points are sometimes given for these entities to expedite liver transplantation, the effect of liver transplantation on pulmonary vascular disease is variable. This study was undertaken to further characterize the effect of liver transplantation on the cross-sectional area (CSA) of small pulmonary vessels. Methods: We performed a retrospective review of all patients who had undergone a liver transplantation at our institution from 2002 to 2012. Medical records were reviewed to identify subjects with clinical evidence of portal hypertension that had a computed tomography (CT) scan of the chest during both the year prior and the year after liver transplantation. Using Image J software, we measured the CSA of small pulmonary vessels (0-5mm) and the total lung CSA at three anatomical levels of each CT scan: the aortic arch, carina, and the right inferior pulmonary vein. We then calculated the percentage of small vessel cross-sectional area (%CSA<5) compared to the total CSA, and compared pre and post transplantation values using a two-tailed paired t-test. Results: We identified 109 subjects who had CT scans of the chest before and after liver transplantation. 34 subjects were excluded due to lack of similar chest imaging for comparison (ie. contrast vs non-contrast studies) and 13 subjects were excluded due to the presence of parenchymal abnormalities or large effusions that precluded reliable CSA calculations. At this time, CT scans have been analyzed for 37 subjects. Characteristics of the study population are detailed in Table 1. Overall, there was a decrease in mean %CSA<5 after liver transplantation (0.23+0.14% pre-transplant vs 0.20+0.07% post-transplant, p=0.139) at all three anatomical levels which was significantly different at the level of the right inferior pulmonary vein (0.22+0.14% pre-transplant vs 0.17+0.07% post-transplant, p=0.012). Conclusions: The CT method presented in this study helps to characterize regional changes in pulmonary vasculature that occur after liver transplantation. We found that the percentage of small pulmonary vessel cross-sectional area decreases after liver transplantation, and that the lower lung vessels significantly contribute to this decrease. Ongoing data analysis in the patients not yet included will allow us to further analyze the relationship between pulmonary vessel cross-sectional area and other characteristics such as the MELD score and the etiology of liver disease

Portopulmonary Hypertension: A Survey of Practice Patterns and Provider Attitudes

Background: The role of liver transplantation (LT) in the management of portopulmonary hypertension (POPH) is poorly understood. The aim of this study was to better understand provider attitudes and practice patterns regarding the management of patients with POPH and to assess the concordance between clinical practice and current guidelines. Methods: We performed a multicenter survey study of hepatologists and pulmonary hypertension (PH) physicians at US LT centers that performed \u3e50 transplants per year. Survey responses are summarized as number (%). Associations were assessed using a Wilcoxon-rank sum, chi-square, or Fisher exact test, as appropriate. Results: Seventy-four providers from 35 centers were included. There was marked variability regarding screening practices, management, and attitudes. Forty-two percent responded that POPH nearly always or often improves with LT, and 15.5% reported that POPH rarely or never improves. In contrast to current guidelines, 50.7% agreed that treated POPH should be an indication for LT in patients with compensated cirrhosis. Hepatologists were more likely than PH physicians to agree that POPH should be an indication for LT (P = 0.02). Forty-nine percent of respondents thought that the current POPH Model for End-stage Liver Disease exception criteria should be modified, and management of patients with an elevated mean pulmonary arterial pressure and normal pulmonary vascular resistance differed from current policies. Conclusions: There is marked variability in provider attitudes and practice patterns regarding the management of POPH. This study highlights the need for prospective studies to inform practice and for improved implementation of practice guidelines in order to standardize care

Predictors of Waitlist Mortality in Portopulmonary Hypertension

BACKGROUND: The current Organ Procurement Transplantation Network policy grants Model for End-Stage Liver Disease (MELD) exception points to patients with portopulmonary hypertension (POPH), but potentially important factors, such as severity of liver disease and pulmonary hypertension, are not included in the exception score, and may affect survival. The purpose of this study was to identify significant predictors of waitlist mortality in patients with POPH. METHODS: We performed a retrospective cohort study of patients in the Organ Procurement and Transplantation Network database with hemodynamics consistent with POPH (defined as mean pulmonary arterial pressure \u3e25 mm Hg and pulmonary vascular resistance [PVR] ≥240 dynes·s·cm) who were approved for a POPH MELD exception between 2006 and 2014. Using a Cox proportional hazards model, we identified predictors of waitlist mortality (or removal for clinical deterioration). RESULTS: One hundred ninety adults were included. Age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.00-1.08; P = 0.0499), initial native MELD score (HR, 1.11; 95% CI, 1.05-1.17; P \u3c 0.001), and initial PVR (HR, 1.12 per 100 dynes·s·cm; 95% CI, 1.02-1.23; P = 0.02) were the only significant univariate predictors of waitlist mortality and remained significant predictors in a multivariate model, which had a c-statistic of 0.71. PVR and mean pulmonary arterial pressure were not significant predictors of posttransplant mortality. CONCLUSIONS: Both the severity of liver disease and POPH (as assessed by MELD and PVR, respectively) were significantly associated with waitlist, but not posttransplant, mortality in patients with approved MELD exceptions for POPH. Both factors should potentially be included in the POPH MELD exception score to more accurately reflect waitlist mortality risk