TAPSE powerfully reflects RV function and prognosis in PAH.

Pregnancy outcomes in patients with pulmonary hypertension remain poor despite advanced therapies. Although consensus guidelines recommend against pregnancy in pulmonary hypertension, it may nonetheless occasionally occur. This guideline document sought to discuss the state of knowledge of pregnancy effects on pulmonary vascular disease and to define usual practice in avoidance of pregnancy and pregnancy management. This guideline is based on systematic review of peer-reviewed, published literature identified with MEDLINE. The strength of the literature was graded, and when it was inadequate to support high-level recommendations, consensus-based recommendations were formed according to prespecified criteria. There was no literature that met standards for high-level recommendations for pregnancy management in pulmonary hypertension. We drafted 38 consensus-based recommendations on pregnancy avoidance and management. Further, we identified the current state of knowledge on the effects of sex hormones during pregnancy on the pulmonary vasculature and right heart and suggested areas for future study. There is currently limited evidence-based knowledge about both the basic molecular effects of sex hormones and pregnancy on the pulmonary vasculature and the best practices in contraception and pregnancy management in pulmonary hypertension. We have drafted 38 consensus-based recommendations to guide clinicians in these challenging topics, but further research is needed in this area to define best practices and improve patient outcomes.

The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.

This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

Background Pulmonary hypertension (PH) is a common and morbid complication of left heart disease with 2 subtypes: isolated post-capillary PH (Ipc-PH) and combined post-capillary and pre-capillary PH (Cpc-PH). Little is known about the clinical or physiological characteristics that distinguish these 2 subphenotypes, and if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH). Objectives We sought to test the hypothesis that the hemodynamic and genetic profile of Cpc-PH would more closely resemble PAH than Ipc-PH. Methods We used Vanderbilt’s electronic medical record linked to a DNA biorepository to extract demographics, clinical data, invasive hemodynamics, echocardiography, and vital status for all patients referred for right heart catheterization between 1998 and 2014. We identified shared genetic variants between PAH and Cpc-PH compared with Ipc-PH using pre-existing single-nucleotide polymorphism data. Results We identified 2,817 patients with PH (13% Cpc-PH, 52% Ipc-PH, and 20% PAH). Cpc-PH patients were on average 6 years younger, with more severe pulmonary vascular disease than Ipc-PH patients, despite similar comorbidities and prevalence, severity, and chronicity of left heart disease. After adjusting for relevant covariates, the risk of death was similar between Cpc-PH and Ipc-PH (HR: 1.14, 95% CI: 0.96 to 1.35, p = 0.15) when defined by diastolic pressure gradient. We identified 75 shared exonic single-nucleotide polymorphisms between Cpc-PH and PAH enriched in pathways involving cell structure, extracellular matrix, and immune function. These genes are expressed, on average, 32% higher in lungs relative to other tissues. Conclusions Cpc-PH patients develop pulmonary vascular disease similar to PAH patients, despite younger age and similar prevalence of obesity, diabetes mellitus, and left heart disease compared with Ipc-PH patients. An exploratory genetic analysis in Cpc-PH identified genes and biological pathways in the lung known to contribute to PAH pathophysiology, suggesting that Cpc-PH may be a distinct and highly morbid PH subphenotype.

R ight ventricular (RV) failure is the predominant cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapies exist because the underlying mechanisms are poorly understood. Abnormalities of glucose homeostasis and insulin resistance are well described in PAH, 1-4 but less is known about lipid metabolism despite the interrelated nature of glucose and lipid homeostasis. Abnormalities in fatty acid metabolism have been described in experimental models of PAH, 5,6 but systemic and myocardial fatty acid metabolism have not been studied in human PAH. Clinical Perspective on p 1944Given the heart's preference for fatty acids (FAs) as an energy source, 7 understanding FA metabolism may be particularly relevant to understanding RV adaptation to elevated afterload in PAH. We recently showed that RV failure is associated with myocardial steatosis and accumulation of the lipotoxic and proapoptotic mediator ceramide in human heritable PAH because of mutation in bone morphogenetic protein receptor type II (BMPR2). 8 Others and we have also shown indirect evidence of abnormal fatty acid oxidation (FAO) in experimental models of PAH. [9][10][11] The generalizability of these abnormalities in FA metabolism to idiopathic PAH and whether they are a systemic feature in human PAH are unknown.We hypothesized that reduced FA metabolism is ubiquitous in PAH and associated with lipotoxic cardiac steatosis in the RV. We tested this hypothesis by studying blood, RV Background-The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH. Methods and Results-We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls ( Sample Collection and AnalysisFasting peripheral blood samples were obtained at the time of clinic visits or at the Vanderbilt General Clinical Research Center. Plasma samples were collected into ethylenediaminetetraacetic acid plasma tubes. Ethylenediaminetetraacetic acid tubes were centrifuged within 45 minutes at 4000 rpm and the plasma fraction immediately aliquoted as 20-µL aliquots and stored at -80ºC. Plasma acylcarnitine samples were analyzed as described previously. 13 The Hormone Assay Core of the Mouse Metabolic Phenotypic Center at Vanderbilt University quantified plasma-free fatty acids by using standard enzymatic reactions. RV Gene Expression ArrayRNA isolation and Microarray techniques have been described previously. 8 All array results...

Rationale: Shorter survival in heritable pulmonary arterial hypertension (HPAH), often due to BMPR2 mutation, has been described in association with impaired right ventricle (RV) compensation. HPAH animal models are insulin resistant, and cells with BMPR2 mutation have impaired fatty acid oxidation, but whether these findings affect the RV in HPAH is unknown.Objectives: To test the hypothesis that BMPR2 mutation impairs RV hypertrophic responses in association with lipid deposition.Methods: RV hypertrophy was assessed in two models of mutant Bmpr2 expression, smooth muscle-specific ( Sm22 R899X ) and universal expression (Rosa26 R899X ). Littermate control mice underwent the same stress using pulmonary artery banding (Low-PAB). Lipid content was assessed in rodent and human HPAH RVs and in Rosa26 R899X mice after metformin administration. RV microarrays were performed using human HPAH and control subjects. Conclusions: These data demonstrate that Bmpr2 mutation affects RV stress responses in a transgenic rodent model. Impaired RV hypertrophy and triglyceride and ceramide deposition are present as a function of RV mutant Bmpr2 in mice; fatty acid oxidation impairment in human HPAH RVs may underlie this finding. Further study of how BMPR2 mediates RV lipotoxicity is warranted.