Background & Aims-Hepatopulmonary syndrome (HPS) affects 10%-30% of patients with cirrhosis and portal hypertension, but the impact on functional status, quality of life, and survival is poorly defined. We assessed the impact of HPS in patients evaluated for liver transplantation.

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Portopulmonary hypertension affects up to 6% of patients with advanced liver disease, but the predictors and biologic mechanism for the development of this complication are unknown. We sought to determine the clinical risk factors for portopulmonary hypertension in patients with advanced liver disease. We performed a multicenter case-control study nested within a prospective cohort of patients with portal hypertension recruited from tertiary care centers. Cases had a mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes ⅐ second ⅐ cm ؊5 , and pulmonary capillary wedge pressure < 15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimable) and normal right-sided cardiac morphology by transthoracic echocardiography. The study sample included 34 cases and 141 controls. Female sex was associated with a higher risk of portopulmonary hypertension than male sex (adjusted odds ratio ‫؍‬ 2.90, 95% confidence interval 1.20-7.01, P ‫؍‬ 0.018). Autoimmune hepatitis was associated with an increased risk (adjusted odds ratio ‫؍‬ 4.02, 95% confidence interval 1.14-14.23, P ‫؍‬ 0.031), and hepatitis C infection was associated with a decreased risk (adjusted odds ratio ‫؍‬ 0.24, 95% confidence interval 0.09-0.65, P ‫؍‬ 0.005) of portopulmonary hypertension. The severity of liver disease was not related to the risk of portopulmonary hypertension. Conclusion: Female sex and autoimmune hepatitis were associated with an increased risk of portopulmonary hypertension, whereas hepatitis C infection was associated with a decreased risk in patients with advanced liver disease. Hormonal and immunologic factors may therefore be integral to the development of portopulmonary hypertension. (HEPATOLOGY 2008;48:196-203.) See Editorial on Page 13 P ulmonary arterial hypertension (PAH) is a progressive disease which is characterized by elevated pulmonary vascular resistance, right heart failure, exercise limitation, and an increased risk of death. Histopathologic examination reveals intimal proliferation, medial hypertrophy, and adventitial fibrosis in the small muscular pulmonary arteries. Plexiform lesions and in situ thrombosis are also commonly seen. Most commonly idiopathic, PAH may also be associated with portal hypertension, termed portopulmonary hypertension (PPHTN

Rationale: Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood. Objectives: To identify genetic risk factors for PPHTN in patients with advanced liver disease. Methods: We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure .25 mm Hg, pulmonary vascular resistance .240 dynesÁs 21 Ácm 25 , and pulmonary capillary wedge pressure <15 mm Hg. Controls had a right ventricular systolic pressure , 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient. Measurements and Main Results: The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P , 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels. Conclusions: Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease.Keywords: genetic polymorphism; portal hypertension; hypertension, pulmonary Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery pressure and pulmonary vascular resistance, right heart failure, exercise limitation, and an increased risk of death. Histopathologic examination reveals intimal proliferation, medial hypertrophy, and adventitial fibrosis in the small muscular pulmonary arteries. Plexiform lesions and in situ thrombosis are also seen. Most commonly idiopathic, PAH may also be associated with portal hypertension, termed portopulmonary hypertension (PPHTN). McDonnell and colleagues showed a prevalence of histopathologic changes of PAH of 0.61% in autopsies of patients with cirrhosis, and PPHTN was the third most common form of PAH in a population-based epidemiologic study in France (1, 2). Recent cohort studies showed that the prevalence of PPHTN in patients presenting for liver transplant evaluation is between 5 and 6% (3-5). Patients with PPHTN have an increased risk of death, even with specific PAH treatment (4, 6-8). In many cases, PPHTN greatly complicates or precludes liver transplantation, significantly affecting the course of hepatic failure in these patients (6,9,10).The etiology of PAH in patients with portal hypertension (characterized by systemic vasodilatation) is unclear. We have shown that female sex and type of liver disease are associated with the risk of PPHTN (11). Although germline mutations in the gene that codes for bone morphogenetic protein receptor type II (BMPR2) have been associate...

OBJECTIVES The purpose of this study was to determine the predictors of mortality in patients with pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF). BACKGROUND PH is commonly associated with HFpEF. The predictors of mortality for patients with these conditions are not well characterized. METHODS In a prospective cohort of patients with right heart catheterization, we identified 73 adult patients who had pulmonary hypertension due to left heart disease (PH-LHD) associated with HFpEF (left ventricular ejection fraction ≥50% by echocardiography); hemodynamically defined as a mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure >15 mm Hg. PH severity was classified according to the diastolic pressure gradient (DPG). Cox proportional hazards ratios were used to estimate the associations between clinical variables and mortality. Receiver-operating characteristic curves were used to evaluate the ability of hemodynamic measurements to predict mortality. RESULTS The mean age for study subjects was 69 ± 12 years and 74% were female. Patients classified as having combined post-capillary PH and pre-capillary PH (DPG ≥7) were not at increased risk of death as compared to patients with isolated post-capillary PH (DPG <7). A baseline pulmonary arterial capacitance (PAC) of <1.1 ml/mm Hg was 91% sensitive in predicting mortality, with better discriminatory ability than DPG, transpulmonary gradient, or pulmonary vascular resistance (area under the curve of 0.73, 0.50, 0.45, and 0.37, respectively). Fifty-seven subjects underwent acute vasoreactivity testing with inhaled nitric oxide. Acute vasodilator response by the Rich or Sitbon criteria was not associated with improved survival. CONCLUSIONS PAC is the best predictor of mortality in our cohort and may be useful in describing phenotypic subgroups among those with PH-LHD associated with HFpEF. Acute vasodilator testing did not predict outcome in our cohort but needs to be further investigated.

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The aim of the present study was to determine if patients with both pulmonary arterial hypertension (PAH), due to pulmonary vascular obstructive disease, and congenital heart defects (CHD), have mutations in the gene encoding bone morphogenetic protein receptor (BMPR)-2.The BMPR2 gene was screened in two cohorts: 40 adults and 66 children with PAH/ CHD. CHDs were patent ductus arteriosus, atrial and ventricular septal defects, partial anomalous pulmonary venous return, transposition of the great arteries, atrioventicular canal, and rare lesions with systemic-to-pulmonary shunts.Six novel missense BMPR2 mutations were found in three out of four adults with complete type C atrioventricular canals and in three children. One child had an atrial septal defect and patent ductus arteriosus; one had an atrial septal defect, patent ductus arteriosus and partial anomalous pulmonary venous return; and one had an aortopulmonary window and a ventricular septal defect.Bone morphogenetic protein receptor 2 mutations were found in 6% of a mixed cohort of adults and children with pulmonary arterial hypertension/congenital heart defects. The current findings compliment recent reports in mouse models implicating members of the bone morphogenetic protein/transforming growth factor-b pathway inducing cardiac anomalies analogous to human atrioventricular canals, septal defects and conotruncal congenital heart defects. The small number of patients studied and the ascertainment bias inherent in selecting for pulmonary arterial hypertension require further investigation.

Rationale: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men.Objectives: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men.Methods: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age-and body mass index-matched men without clinical cardiovascular disease.Measurements and Main Results: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH.Conclusions: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.