Hereditary Pulmonary Arterial Hypertension Research Articles

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

Possible Hereditary Pulmonary Arterial Hypertension: from Clinical to Genetic Investigation in Precision Medicine Era

Background: Pulmonary Hypertension is a life-threatening disease characterized by a progressive increase of pulmonary vascular resistance that often leads to right ventricular (RV) failure and death. Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). At least 6% of all PAH cases are familial in origin known as Familial Pulmonary Arterial Hypertension (FPAH) and display autosomal dominant inheritance with incomplete penetrance. While early diagnosis is associated with improved long-term survival, however at present, most patients are diagnosed at a very advanced stage of HPAH indicating that the early screening for HPAH is crucial. In this regard, genetic testing is an effective strategy for the early diagnosis and management of PAH, specifically Hereditary Pulmonary Arterial Hypertension (HPAH). We present two cases of Familial Pulmonary Arterial Hypertension and in-depth analysis of diagnostic cascade to allow an earlier and more reliable diagnosis of possible Hereditary Pulmonary Arterial Hypertension (HPAH). Case Illustration: Familial cases, a 44-years old man and his son a 17-years old boy, came with chief complaint of dyspnea. His daughter or his sister passed away when 4 years old due to PH. Both patients had been subsequently diagnosed with PAH with possible HPAH after the exclusion of primary and secondary heart anomalies using electrocardiography, echocardiography, and cardiac marker test. Both patients subsequently were performed right heart catheterization (RHC). Conclusions: We describe familial cases of pulmonary hypertension with clinically presenting right-sided heart failure. Diagnostic investigation was performed according to recent guideline to rule out and rule in all the possible cause of pulmonary hypertension. However, the final assessment showed unknown cause of pre-capillary pulmonary hypertension. Therefore, genetic investigation should be performed in precision medicine era due to high possibility of hereditary pulmonary arterial hypertension.

Transition from Intravenous Epoprostenol to Treprostinil Due to Intolerable Side Effects in Patients With Pulmonary Arterial Hypertension

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, it has side effects. Reviewing the side effects associated with epoprostenol and treprostinil is essential for improving the long-term treatment strategies for PAH. This retrospective review included patients with PAH who transitioned from intravenous epoprostenol to intravenous treprostinil owing to intolerable side effects, including high cardiac output symptoms, ascites, and thrombocytopenia. Of the 85 patients who received epoprostenol at our hospital between 2013 and 2021, 16 (11 women), with a median age of 33 (range 26 to 40) years (including 12 with idiopathic PAH, 3 with hereditary PAH, and 1 with connective tissue disease pulmonary hypertension), had to switch from intravenous epoprostenol to treprostinil owing to the side effects. After transitioning, epoprostenol-associated intolerable side effects, such as high cardiac output symptoms, ascites, and thrombocytopenia, were ameliorated. In conclusion, for patients with PAHwho have intolerable side effects fromepoprostenol and have difficulty in continuing treatment, switching from epoprostenol to treprostinil may be an option. Switching treatment leads to better adherence and improved long-term prostacyclin therapy.

Hereditary pulmonary arterial hypertension burden in pediatrics: A single referral center experience.

Hereditary pulmonary arterial hypertension (HPAH) is a rare yet serious type of pulmonary arterial hypertension (PAH). The burden in the pediatric population remains high yet underreported. The objective of this study is to describe the distribution of mutations found on targeted PAH panel testing at a large pediatric referral center. Children with PAH panel administered by the John Welsh Cardiovascular Diagnostic Laboratory at Texas Children's Hospital and Baylor College of Medicine in Houston, Texas between October 2012 to August 2021 were included into this study. Medical records were retrospectively reviewed for clinical correlation. Sixty-six children with PAH underwent PAH genetic testing. Among those, 9 (14%) children were found to have pathogenic mutations, 16 (24%) children with variant of unknown significance and 41 (62%) children with polymorphism (classified as likely benign and benign). BMPR2 mutation was the most common pathogenic mutation, seen in 6 of the 9 children with detected mutations. Hemodynamic studies showed higher pulmonary vascular resistance among those with pathogenic mutations than those without (17.4 vs. 4.6 Wood units). All children with pathogenic mutations had severe PAH requiring triple therapy. There were tendencies for higher lung transplantation rate but lower mortality among those with pathogenic mutations. Abnormalities on genetic testing are not uncommon among children with PAH, although majority are of unclear significance. However, children with pathogenic mutations tended to present with more severe PAH requiring aggressive medical and surgical therapies. Genetic testing should be routinely considered due to consequences for treatment and prognostic implications. Larger scale population studies and registries are warranted to characterize the burden of HPAH in the pediatric population specifically.

Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension.

Paediatric-onset idiopathic/hereditary pulmonary arterial hypertension (IPAH/HPAH) is partially linked to genetic factors that may also affect treatment response and outcome. The relation between clinical characteristics and pathogenicity of gene variants in childhood IPAH/HPAH is still not well understood. We retrospectively analyzed IPAH/HPAH paediatric patients aged between 3 months and 18 years under follow-up at a large tertiary referral center. Whole-exome sequencing focused on PAH high-risk genes was performed in all patients. Pathogenicity grading of gene variant sites was assessed using ClinVar and population frequencies. The association between gene variants and death was studied using Cox proportional multivariate models. Overall, 129 patients (54.3% females; 91.5% on PAH therapy) with a median age at diagnosis of 6.8 (IQR 3.4-10.7) years were included. A relevant PAH gene variant was detected in 95 patients (73.6%). The most common variants were in the BMPR2 (n = 43, 3%) gene. Over a median follow-up period of 27.6 months, 26 children died. The presence of a likely pathogenic genetic variant was significantly associated with survival (HR: 3.56, p = 0.005) on multivariable Cox analysis. The number of PAH-specific drugs at presentation was associated with better survival in the cohort with pathogenic variants (p = 0.02). Pathogenic/likely pathogenic genetic variants are prevalent in children with PAH and are related to a worse prognosis irrespective of other recognized risk factors in this population. Combination PAH therapy was associated with superior prognosis in children with pathogenic variants or BMPR2 variants. Therefore, proactive medical therapy should be employed in this population.

Vascular stiffening in aging females with a hypertension-induced HIF2A gain-of-function mutation.

Pulmonary arterial hypertension (PAH) is more prevalent in females than males; the causes of this sex difference have not been adequately explored. Gain-of-function (GOF) mutations in hypoxia-inducible factor 2α (HIF2A) lead to PAH and thrombotic consequences in patients and mice. Additionally, multiple emerging studies suggest that elevated systemic arterial stiffening (SAS) occurs in PAH; this could have critical prognostic value. Here, we utilized a HIF2A GOF mouse model to determine how SAS can be used as a prognosticator in sex-divergent PAH. We analyzed survival, vascular mechanics, and vascular phenotypes in young adult (8-16 weeks) and middle age (9-12 months) Hif2a GOF mice. We find that Hif2a heterozygous (HT) female mice, but not Hif2a HT male mice, exhibit poor survival, SAS upon aging, and decreased ability to withstand repeated physiological strain. Hif2a HT female mice also display thickening of the adventitial intima and increased collagen I and collagen III in all layers of the thoracic aorta. Our findings demonstrate differing PAH progression in female and male Hif2a GOF mice. Specifically, alterations in extracellular matrix (ECM) content led to vascular stiffening in aged females, resulting in poor survival. Moreover, we show that SAS emerges early in mice with PAH by coupling studies of vascular mechanics and analyzing vascular structure and composition. Importantly, we present a model for assessing sex differences in hereditary PAH progression and sex-specific prognosis, proposing that aortic stiffening can be used to prognosticate future poor outcomes in PAH.

Mitochondrial Respiration in Peripheral Blood Mononuclear Cells Negatively Correlates with Disease Severity in Pulmonary Arterial Hypertension.

Mitochondrial and immune cell dysfunction contributes to the development of pulmonary arterial hypertension (PAH). We thus aimed to investigate mitochondrial respiration and mitochondrial gene expression patterns in the peripheral blood mononuclear cells (PBMC) of patients with idiopathic and hereditary PAH and their correlation to disease parameters. Mitochondrial respiration determined using high-resolution respirometry was not significantly different in PBMC when comparing an outpatient cohort of PAH patients with healthy controls. However, when directly comparing mitochondrial respiration to the hemodynamic parameters of an inpatient PAH cohort, mitochondrial respiration negatively correlated with pulmonary vascular resistance (PVR) and positively correlated with the cardiac index (CI). Furthermore, microarray analysis shows upregulation of mitochondrial erythroid-specific 5-aminolevulinate synthase 2 (ALAS2), as well as the regulation of genes involved in iron and heme metabolism, in the PBMC of patients with PAH, with ALAS2 upregulation in PAH patients being confirmed on the protein level. Multiple regression analysis with age and gender as confounders showed that both PVR and hemoglobin content negatively correlated with maximal respiration. Therefore, we conclude that mitochondrial function in the PBMC of PAH patients is affected by disease severity. However, further studies to investigate cell-type-specific alterations and functional consequences are necessary.

A Novel BMPR2 Variant Gene in Relation with Hereditary Pulmonary Arterial Hypertension Combined with Pulmonary Arteriovenous Malformations.

A Novel BMPR2 Variant Gene in Relation with Hereditary Pulmonary Arterial Hypertension Combined with Pulmonary Arteriovenous Malformations.

A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension.

RationaleThe blood is a rich source of potential biomarkers for the diagnosis of idiopathic and hereditary pulmonary arterial hypertension (iPAH and hPAH, referred to as “PAH”). While a lot of biomarkers have been identified for PAH, the clinical utility of these biomarkers often remains unclear. Here, we performed an unbiased meta-analysis of published biomarkers to identify biomarkers with the highest performance for detection of PAH.MethodsA literature search (in PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and Wiley/Cochrane Library) was performed up to 28 January 2021. Primary end points were blood biomarker levels in PAH versus asymptomatic controls or patients suspected of pulmonary hypertension (PH) with proven normal haemodynamic profiles.Results149 articles were identified by the literature search. Meta-analysis of 26 biomarkers yielded 17 biomarkers that were differentially expressed in PAH and non-PH control subjects. Red cell distribution width, low density lipid-cholesterol, d-dimer, N-terminal prohormone of brain natriuretic protein (NT-proBNP), interleukin-6 (IL-6) and uric acid were biomarkers with the largest observed differences, largest sample sizes and a low risk of publication bias. Receiver operating characteristic curves and sensitivity/specificity analyses demonstrated that NT-proBNP had a high sensitivity, but low specificity for PAH. For the other biomarkers, insufficient data on diagnostic accuracy with receiver operating characteristic curves were available for meta-analysis.ConclusionThis meta-analysis validates NT-proBNP as a biomarker with high sensitivity for PAH, albeit with low specificity. The majority of biomarkers evaluated in this meta-analysis lacked either external validation or data on diagnostic accuracy. Further validation studies are required as well as studies that test combinations of biomarkers to improve specificity.

Pulmonary arterial hypertension in hereditary hemorrhagic telangiectasia associated with ACVRL1 mutation: a case report

IntroductionHereditary hemorrhagic telangiectasia is an autosomal dominant condition with an estimated prevalence of 1 in 5000. It is characterized by the presence of abnormalities of vascular structures, and may affect many organ systems, including the lungs, brain, spinal cord, gastrointestinal tract, and liver. A causative mutation is identified in approximately 97% of patients with definite hereditary hemorrhagic telangiectasia in one of three genes including a mutation in endoglin, a mutation in a locus mapped to chromosome 5, and an activin receptor-like kinase-1 (ACVRL1) mutation that is associated with an increased incidence of primary pulmonary hypertension. Pulmonary arterial hypertension is a rare (15–25 cases per million people) but severe vascular disorder. Heritable pulmonary arterial hypertension is associated with several gene mutations, with 75% having a mutation in the bone morphogenetic protein receptor 2 (BMPR2). However, the remaining 25% of patients have other associated genetic mutations including ACVLR1, which is also associated with hereditary hemorrhagic telangiectasia. Pulmonary arterial hypertension is a rare complication in patients with hereditary hemorrhagic telangiectasia (< 1% of the hereditary hemorrhagic telangiectasia population). We describe a case report with this rare occurrence.Case presentationA 70-year-old white/caucasian Irish male presented for screening for hereditary hemorrhagic telangiectasia due to a history of recurrent epistaxis (once/week) and a family history suggestive of pulmonary hypertension. Genetic testing confirmed an ACVRL1 mutation, while an echocardiogram and right heart catheterization confirmed pulmonary arterial hypertension. On examination, he had several mucocutaneous telangiectasia across his face. He was commenced on tadalafil and macitentan. However, this led to increased iron deficiency anemia and pedal edema. Selexipag was also added to his drug regime. He continues to require intermittent admissions for diuresis and blood transfusions.ConclusionThe association of hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension is rare (< 1%). Here we describe a case of hereditary hemorrhagic telangiectasia complicated with pulmonary arterial hypertension as a result of an ACVRL1 mutation. We also describe the clinical challenges of treating these two conditions together, as treatment options for pulmonary arterial hypertension tend to worsen hereditary hemorrhagic telangiectasia symptoms.

Impact of Pulmonary Arterial Hypertension on Employment, Work Productivity, and Quality of Life - Results of a Cross-Sectional Multi-Center Study

IntroductionData on burden of pulmonary arterial hypertension (PAH) are mostly limited to physical and clinical endpoints as well as quality of life. Research on employment, work productivity, and educational background is scarce. The aim of this study was to assess the impact of PAH on employment status and work productivity in Germany.Materials and MethodsIn a multicenter cross-sectional survey, patients with PAH were surveyed in two large pulmonary hypertension referral centers in Germany. The survey contained questions on education, employment, work productivity and impairment (WPAI, also at the time of diagnosis), quality of life, and socioeconomic status. Additional data was assessed using clinical research database for 6-min walk distance (6MWD), WHO functional class, and N-terminal fragment of pro-brain natriuretic peptide. All patients provided written informed consent, and the institutional review board approved this study.ResultsIn total, 212 patients were surveyed (72% female; median, 57 years) approximately 6 years after initial PAH diagnosis. A total of 76% had an idiopathic PAH followed by hereditary and associated PAH (10% each). Employment at the time of diagnosis was 48% (34% full-time, 14% part-time), with productivity measured by a WPAI score of 6 points and decreased to 29% (21% full-time, 8% part-time) at the time of the survey (with a WPAI score of 2 points, p < 0.001). Logistic regression showed education and 6MWD as predictors for employment. Patients in moderate or high educational category had a 3.6- or 5.6-fold chance, respectively, of being employed (p = 0.025 and p = 0.019), and per 50-m increase of 6MWD, the odds of being employed were 1.2, p = 0.042.ConclusionPatients with PAH had a reduced employment rate, which was influenced by education and 6MWD. There was a considerable loss of employment over the course of the disease. Employment should be one possible treatment goal in patients with PAH to provide social participation to this patient group.

Channelopathy Genes in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The underlying pathogenetic mechanisms are heterogeneous and current therapies aim to decrease pulmonary vascular resistance but no curative treatments are available. Causal genetic variants can be identified in ~13% of adults and 43% of children with PAH. Knowledge of genetic diagnoses can inform clinical management of PAH, including multimodal medical treatment, surgical intervention and transplantation decisions, and screening for associated conditions, as well as risk stratification for family members. Roles for rare variants in three channelopathy genes—ABCC8, ATP13A3, and KCNK3—have been validated in multiple PAH cohorts, and in aggregate explain ~2.7% of PAH cases. Complete or partial loss of function has been demonstrated for PAH-associated variants in ABCC8 and KCNK3. Channels can be excellent targets for drugs, and knowledge of mechanisms for channel mutations may provide an opportunity for the development of PAH biomarkers and novel therapeutics for patients with hereditary PAH but also potentially more broadly for all patients with PAH.

PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

REAL-WORLD CLINICAL PRESENTATION OF PATIENTS WITH PORTOPULMONARY HYPERTENSION IN COMPARISON WITH IDIOPATHIC/HEREDITARY PULMONARY ARTERIAL HYPERTENSION IN THE USA

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: Portopulmonary hypertension (PoPH) is pulmonary arterial hypertension (PAH) associated with portal hypertension. The diagnosis of PoPH can be challenging due to overlapping symptoms of decompensated liver disease, other types of PAH, and the paucity of available epidemiological and real-world evidence. We compared the clinical presentation of PoPH with idiopathic or hereditary PAH (I/HPAH) patients in a real-world US-based clinical practice setting. METHODS: This is a descriptive analysis of the Adelphi PAH Disease Specific Programme, a point-in-time physician survey providing data on patient and disease characteristics among PAH patients visiting pulmonologists, cardiologists and internists for routine care in the USA. Data collection was completed July-October 2019, with a PoPH oversample collected May-June 2020. RESULTS: A total of 90 PoPH patients from 44 physicians and 255 I/HPAH patients (233 IPAH, 22 HPAH) from 68 physicians were included in this study. 51.1% of PoPH and 45.1% of I/HPAH patients were male, with a mean age of 56.8 and 55.3 years, respectively. Prior to PAH treatment, physicians classified 65.6% of PoPH patients as functional class III or IV compared with 50.2% of I/HPAH patients. Most patients (60.0% PoPH, 56.1% I/HPAH) were reported by physicians as having "stable” PAH disease, with 18.9% of PoPH and 17.3% of I/IPAH patients considered to be "deteriorating", at the time of data collection. Physicians reported ascites, symptoms of abdomen distension and pain in 5.6%, 14.4% and 7.8% of PoPH patients and 3.1%, 7.5% and 4.3% of I/HPAH patients, respectively. Dyspnea following exertion (32.2% PoPH, 42.4% I/HPAH) and chest pressure/tightness (13.3% PoPH, 22.4% I/HPAH) were reported in a higher proportion of I/HPAH patients compared with PoPH patients. The mean Charlson Comorbidity Index score was 1.5 in PoPH and 0.4 in I/HPAH patients, indicating a poorer prognosis for patients with PoPH. Comorbid anxiety was reported in 17.8% of PoPH and 11.8% I/HPAH patients, depression in 16.7% and 12.9%, and obesity in 15.6% and 10.6% of patients, respectively. CONCLUSIONS: This study showed differences in disease severity prior to treatment as well as symptoms of PoPH compared with I/HPAH, with a higher proportion of PoPH patients with ascites, abdominal distension and pain, but a lower proportion with chest pain and dyspnea following exertion. The results also suggested a greater comorbidity burden among PoPH vs I/HPAH patients, particularly related to mental health. CLINICAL IMPLICATIONS: Our findings add to the understanding of clinical presentation of PoPH in a real-world setting, and highlight previously unreported differences in disease severity, symptoms, and comorbidity burden between PoPH and I/HPAH. DISCLOSURES: Employee relationship with Janssen Pharmaceuticals Please note: June 16, 2017 to now Added 04/26/2021 by Peter Agron, source=Web Response, value=Salary Consultant relationship with Janssen Please note: 2020-2021 Added 04/26/2021 by Hilary Dubrock, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Janssen Please note: 2020 Added 04/26/2021 by Hilary Dubrock, source=Web Response, value=Honoraria Advisory Committee Member relationship with United Therapeutics Please note: 2021 Added 04/26/2021 by Hilary Dubrock, source=Web Response, value=Honorariaunknown relationship with Anumana Please note: Ongoing Added 04/26/2021 by Hilary Dubrock, source=Web Response, value=Intellectual property rights Removed 04/26/2021 by Hilary Dubrock, source=Web Response No relevant relationships by Julia Harley, source=Web Response Employee relationship with Janssen Please note: May 2020 to present Added 04/21/2021 by Sumeet Panjabi, source=Web Response, value=Salary Employee relationship with Janssen Please note: May 2020 to present Added 04/21/2021 by Sumeet Panjabi, source=Web Response, value=Ownership interest No relevant relationships by Megan Scott, source=Web Response No relevant relationships by Mark Small, source=Web Response Employee relationship with Janssen Scientific Affairs, LLC Please note: 2015 to present Added 04/20/2021 by Yuen Tsang, source=Web Response, value=Salary Employee relationship with Janssen Scientific Affairs, LLC Please note: 2015 to present Added 04/20/2021 by Yuen Tsang, source=Web Response, value=Stock

A DOUBLE HIT: PULMONARY ARTERIAL HYPERTENSION, BMPR2 MUTATION, AND EXPOSURE TO PRESCRIPTION AMPHETAMINES

TOPIC: Pulmonary Vascular Disease TYPE: Fellow Case Reports INTRODUCTION: Pulmonary arterial hypertension (PAH) management during pregnancy is challenging. We present a case of PAH diagnosed during 3rd trimester of pregnancy, in a patient with familial history of PAH and exposure to prescription-amphetamines. CASE PRESENTATION: 30-year-old primigravid female at 30 weeks of gestation was referred to our Pulmonary Hypertension program for evaluation of rapidly progressive dyspnea, lightheadedness and echocardiogram revealing increased pulmonary pressures. She had a history of Attention-deficit/hyperactivity disorder, treated with dextroamphetamine/amphetamine (Adderall®) and lisdexamfetamine (Vyvanse®) for several years. Her mother had died of pulmonary hypertension at the age of 30. She had functional class III symptoms. An echo showed an estimated right ventricular systolic pressure of 69mm Hg, with right ventricular dilation and dysfunction, as well as interventricular septal flattening. A right heart catheterization (RHC) showed a mPAP of 34 mmHg, PAWP 10 mmHg, cardiac output 3.96 L/min, cardiac index of 2.08 L/min/m2 and PVR of 6.1 WU. She was admitted for expedited work-up and treatment of pulmonary hypertension. Investigational studies were negative for alternative etiologies of pulmonary hypertension, there was no evidence of chronic thromboembolic disease. She was started on a rapid titration with intravenous treprostinil. Once at a dose of 40 ng/kg/min, a repeated RHC showed mPAP of 28 mmHg, PAWP 6 mmHg, cardiac output 5.8 L/min, cardiac index of 3.1 L/min/m2 and PVR of 5.1 WU. A multidisciplinary discussion with high-risk OB, cardiac anesthesia, neonatology and our Pulmonary Hypertension program recommended for C-section under epidural anesthesia with VA-ECMO on stand-by, which was performed at 32 weeks of gestation. Her post-op course was uneventful and she was discharged home on triple therapy with sildenafil, ambrisentan and intravenous treprostinil. She was found to have the BMPR2 mutation. At follow-up, she is functional class II, six-minute walk distance is 530 meters and BNP values are 17 ?g/mL. DISCUSSION: Studies report 75% prevalence of BMPR2 mutations in cases of hereditary PAH, with an autosomal dominant mode of inheritance and incomplete penetrance. It is hypothesized that a "two-hit” phenomenon with environmental influencers like drugs, toxins or infection known to cause pulmonary hypertension may have a role in providing the "second hit” leading to development of the disease. We wonder if the exposure to prescription-amphetamines could have been a second hit, on top of her genetic background. PAH in pregnant females poses a very high risk of maternal and fetal mortality. Aggressive counseling focusing of avoiding pregnancy and early termination should be instituted in all patients. In cases where pregnancy is continued, care at centers with expertise in pulmonary hypertension and ECMO/transplant capability is recommended. CONCLUSIONS: . REFERENCE #1: Geraci MW, Bull TM, Tuder RM. Genomics of pulmonary arterial hypertension: implications for therapy. Heart failure clinics. 2010 Jan 1;6(1):101-14. DISCLOSURES: No relevant relationships by Roberto Bernardo, source=Web Response No relevant relationships by HUZAIFA JALIAWALA, source=Web Response No relevant relationships by Katherine Summers, source=Web Response

Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial

Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH. We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18-75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02234141. Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm5. Change in pulmonary vascular resistance was 6·0 dyn·s/cm5 (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm5 (n=35; p=0·21 vs placebo) for 2 mg selonsertib, -28·0 (30·2) dyn·s/cm5 (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and -21·0 (37·9) dyn·s/cm5 (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo. Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1-p38 pathway in PAH is warranted. Gilead Sciences.

Application of [18F]FLT-PET in pulmonary arterial hypertension: a clinical study in pulmonary arterial hypertension patients and unaffected bone morphogenetic protein receptor type 2mutation carriers.

Pulmonary arterial hypertension is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3′-deoxy-3′-[18F]-fluorothymidine (18FLT) positron emission tomography (PET) scanning was increased in pulmonary arterial hypertension patients, hence providing a possible biomarker for pulmonary arterial hypertension as it reflects vascular cell hyperproliferation in the lung. This study sought to validate 18FLT-PET in an expanded cohort of pulmonary arterial hypertension patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 mutation carriers. 18FLT-PET scanning was performed in 21 pulmonary arterial hypertension patients (15 hereditary pulmonary arterial hypertension and 6 idiopathic pulmonary arterial hypertension), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung 18FLT k3 phosphorylation among pulmonary arterial hypertension patients, unaffected bone morphogenetic protein receptor type 2 mutation carriers and healthy controls. Lung 18FLT uptake did not correlate with haemodynamic or clinical parameters in pulmonary arterial hypertension patients. Sequential 18FLT-PET scanning in three patients demonstrated uneven regional distribution in 18FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. We did not detect significantly increased lung 18FLT uptake in pulmonary arterial hypertension patients, nor in the unaffected bone morphogenetic protein receptor type 2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human 18FLT report may be explained by a small sample size previously and we observed large variation of lung 18FLT signals between patients, challenging the application of 18FLT-PET as a biomarker in the pulmonary arterial hypertension clinic.

KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models.

Loss of function KCNK3 mutation is one of the gene variants driving hereditary pulmonary arterial hypertension (PAH). KCNK3 is expressed in several cell and tissue types on both membrane and endoplasmic reticulum and potentially plays a role in multiple pathological process associated with PAH. However, the role of various stressors driving the susceptibility of KCNK3 mutation to PAH is unknown. Hence, we exposed kcnk3fl/fl animals to hypoxia, metabolic diet and low dose lipopolysaccharide (LPS) and performed molecular characterization of their tissue. We also used tissue samples from KCNK3 patients (skin fibroblast derived inducible pluripotent stem cells, blood, lungs, peripheral blood mononuclear cells) and performed microarray, immunohistochemistry (IHC) and mass cytometry time of flight (CyTOF) experiments. Although a hypoxic insult did not alter vascular tone in kcnk3fl/fl mice, RNASeq study of these lungs implied that inflammatory and metabolic factors were altered, and the follow-up diet study demonstrated a dysregulation of bone marrow cells in kcnk3fl/fl mice. Finally, a low dose LPS study clearly showed that inflammation could be a possible second hit driving PAH in kcnk3fl/fl mice. Multiplex, IHC and CyTOF immunophenotyping studies on human samples confirmed the mouse data and strongly indicated that cell mediated, and innate immune responses may drive PAH susceptibility in these patients. In conclusion, loss of function KCNK3 mutation alters various physiological processes from vascular tone to metabolic diet through inflammation. Our data suggests that altered circulating immune cells may drive PAH susceptibility in patients with KCNK3 mutation.

Transient Left Bundle Branch Block Associated with Septal Edema after Orthotopic Heart and Lung Transplant

<h3>Introduction</h3> The development of left bundle branch block (LBBB) after orthotopic heart transplant is uncommon. We present a case of transient left bundle branch block associated with septal edema after orthotopic heart and lung transplant. <h3>Case Report</h3> A 47-year-old female with hereditary pulmonary arterial hypertension is on 4L oxygen despite the use of sildenafil, macitentan, and intravenous epoprostenol. She had severe right ventricular, right atrial, and pulmonary artery dilation with severe pulmonic and tricuspid insufficiency on echocardiogram (TTE). Right heart catheterization revealed PVR of 10.1 wood units. Patient underwent uncomplicated dual heart and lung transplantation (CBT 225 minutes, DIT 130 minutes, basiliximab induction). Donor was a 40-year-old female with ejection fraction 50%, septal wall (IVS) 1.45 cm, CI 6.6 L/min/m². On post-op day 1 (POD#1) patient was in sinus tachycardia with a new LBBB on electrocardiogram (ECG). QRS interval increased from 94 ms to 154 ms. TTE showed preserved left ventricular function with no wall motion abnormality but significant IVS edema measuring 1.7 cm. Immunosuppression regimen was tacrolimus 1 mg twice daily, mycophenolate mofetil 1 g twice daily, and prednisone 10 mg daily. QRS interval remained stable over the next few days and normalized to 98 ms on POD#5. Repeat TTE showed decrease in IVS thickness to 1.5 cm. Patient had an uneventful remainder of hospital stay and was discharged home two weeks later. Her IVS on TTE three months post-transplant decreased to 1.1 cm and she continues to do well. <h3>Summary</h3> The development of LBBB acutely after orthotopic heart transplant is uncommon and the clinical significance is unknown. We highlight a case of a 47-year-old female who underwent heart and lung transplantation complicated by the acute onset of LBBB due to significant post-operative septal edema. Serial ECGs demonstrated stable QRS interval and spontaneous resolution of LBBB with improvement of septal edema on day 5 after transplant.

Autoimmune hypophysitis as a cause of adrenocorticotropic hormone deficiency in pulmonary arterial hypertension: a case report

Background Severe pulmonary arterial hypertension (PAH) is generally treated with multiple PAH-specific vasodilators. If these agents are unsuccessful, additional treatment options are scarce, and the prognosis is poor due to right-sided heart failure. Some of these severe cases are also accompanied by endocrinological side effects. The most common side effect of prostacyclin is thyroid dysfunction, but in very few cases, adrenocorticotropic hormone (ACTH) deficiency may occur.Case summary A 35-year-old woman was diagnosed with hereditary PAH 2 years ago. Since her mean pulmonary arterial pressure was high, combination therapy of vasodilators, including prostacyclin, was introduced. Several months later, she was hospitalized with a persistent fever. Laboratory tests showed no findings suggestive of infection. However, hypereosinophilia and decreased secretion of ACTH and cortisol were noted, which led to the diagnosis of ACTH deficiency. A multimodal diagnostic approach, including pituitary magnetic resonance imaging and axillary lymph node biopsy, indicated that the aetiology of the ACTH deficiency was likely autoimmune hypophysitis. She was treated with hydrocortisone supplementation, which significantly relieved her condition.Discussion Endocrinological side effects in PAH patients using prostacyclin should be carefully addressed. If right-sided heart failure worsens during the administration of prostacyclin, it is essential to determine whether it is due to progression of pulmonary hypertension or endocrinological side effects. Careful diagnosis and treatment are important for managing the haemodynamics and symptoms of PAH patients given prostacyclin.