Cause Of Pulmonary Arterial Hypertension Research Articles

ACUTE COR PULMONALE AS THE INITIAL PRESENTATION OF LIMITED SYSTEMIC SCLEROSIS

SESSION TITLE: Medical Student/Resident Pulmonary Vascular Disease 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Acute Cor pulmonale is a common presentation of severe pulmonary arterial hypertension (PAH). PAH affects up to 12% of patients with systemic sclerosis (SS) and associated with a poor prognosis. We present a case of a patient presenting with acute RV failure from severe pulmonary hypertension secondary to limited SS. CASE PRESENTATION: A 63-year-old African American female presented with worsening dyspnea. Past medical history was significant for COPD, severe pulmonary hypertension (PASP of 86 mmHg on previous echocardiogram), obesity and OSA. On arrival to the hospital, patient was tachypneic to 22 breaths/minute with a blood pressure of 92/70. Her oxygen saturation was noted to be 95% on 6L via nasal cannula. She suffered a syncopal episode while walking to the bathroom after being admitted to the hospital, which prompted a rapid response team to be alerted. Her blood pressure was 70/40 mmHg on arrival of the rapid response team (RRT). Pulmonary artery catheterization (PAC) was performed after point-of-care ultrasound suggested significant RV failure. PAC revealed RA 21mmHg, RV 109/20mmHg, PA 115/31 (mean of 62), PCWP 12 mmHg. TTE was performed revealing normal LV function, EF 60-65%. Abnormal septal motion and flat intraventricular septum consistent with RV overload, with an estimated PASP 103mmHg. While in the ICU, patient had continued hypotension requiring vasopressor support with norepinephrine. She was started on furosemide infusion to achieve diuresis. She was also started on intravenous epoprostenol as a pulmonary arterial vasodilator. Given her persistent hypotension and decreased cardiac output, a milrinone infusion was started as well. Despite these efforts, patient continued to deteriorate. The etiology for her decompensation remained unclear, she was noted to have significant worsening of her PASP on review of her previous echocardiography. She was started on a heparin infusion due to concerns for possible pulmonary embolism causing the acute decompensation. Further workup was pursued to evaluate for possible causes of PAH, given the decreased likelihood that her acute worsening was secondary to her history of OSA & COPD. Anti-centromere titers > 8 were revealed suggesting a diagnosis of limited SS. Unfortunately, patient’s clinical status continued to decline and patient expired. DISCUSSION: Acute cor pulmonale from PAH has an in-hospital mortality of 50% when requiring vasopressor and/or inotropic support. PAH affects up to 12% of patients with systemic sclerosis and is the leading cause of death in this patient population. Currently there are no guidelines on appropriate screening tools to identify patients with limited SS complicated by PAH. CONCLUSIONS: Acute cor pulmonale in the setting of SS portends a poor prognosis with associated 50% mortality. More studies are needed to identify strategies for early identification that will improve outcomes in this population. Reference #1: Chaisson et al. Systemic Sclerosis-Associated Pulmonary Arterial Hypertension. Chest. 2013;144(4):1346-1356. doi:10.1378/chest.12-2396. Reference #2: Jentzer et al. Pulmonary Hypertension in the Intensive Care Unit. J Intensive Care Med. 2016 Jul;31(6):369-85. doi: 10.1177/0885066615583652. DISCLOSURES: No relevant relationships by Navneet Kaur, source=Web Response No relevant relationships by Adnan Khalif, source=Web Response

CCL21 as a Potential Serum Biomarker for Pulmonary Arterial Hypertension in Systemic Sclerosis.

Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles for chemokines CCL19 and CCL21 and their receptor CCR7 in lung inflammation leading to PAH. The objective of this study was to assess the chemokine CCL19-CCL21 axis in patients with SSc-related PAH. Serum samples obtained from 2 independent prospective SSc cohorts (n = 326), patients with idiopathic PAH (n = 12), and healthy control subjects (n = 100) were analyzed for CCL19/CCL21 levels, by enzyme-linked immunosorbent assay. The levels were defined as either high or low, using the mean + 2 SD value in controls as the cutoff value. Risk stratification at the time of PAH diagnosis and PAH-related events were performed. Descriptive and Cox regression analyses were conducted. CCL21 levels were higher in patients with SSc compared with controls and were elevated prior to the diagnosis of PAH. PAH was more frequent in patients with high CCL21 levels (≥0.4 ng/ml) than in those with low CCL21 levels (33.3% versus 5.3% [P < 0.001]). In multivariate analyses, CCL21 was associated with PAH (hazard ratio [HR] 5.1, 95% CI 2.39-10.76 [P < 0.001]) and occurrence of PAH-related events (HR 4.7, 95% CI 2.12-10.46, P < 0.001). Risk stratification at the time of PAH diagnosis alone did not predict PAH-related events. However, when risk at diagnosis was combined with high or low CCL21 level, there was a significant predictive effect (HR 1.3, 95% CI 1.03-1.60 [P = 0.027]). A high CCL21 level was associated with decreased survival (P < 0.001). CCL21 appears to be a promising marker for predicting the risk of SSc-related PAH and PAH progression. CCL21 may be part of a dysregulated immune pathway linked to the development of lung vascular damage in SSc.

Favorable Postoperative Evolution after Late Surgical Repair of Truncus Arteriosus Type 1: A Case Report

Abstract Truncus arteriosus communis (TA) is a rare cyanotic congenital heart defect, in which the aorta and the pulmonary artery have not been separated during the normal development of the fetal heart, so a single truncal artery is arising from the base of the heart. Most patients with TA present within the first weeks of life with heart failure. This anomaly is an important cause of pulmonary arterial hypertension. Corrective surgery is indicated in the first 3 months of life, to avoid the development of severe pulmonary arterial hypertension. We report the case of a 12-month-old male infant diagnosed by echocardiography with truncus arteriosus type 1 in whom, based on hemodynamic data, surgical treatment could be performed at the age of 1 year.

Prevalence of primary Sjögren's syndrome in patients undergoing evaluation for pulmonary arterial hypertension.

BackgroundThe prevalence of pulmonary arterial hypertension (PAH) in primary Sjögren’s syndrome (SS) had been reported to be rare. However, recent studies using echocardiography as a screening method showed conflicting results, and the true prevalence is still unclear. Since diagnosing primary SS is difficult because of its heterogeneous nature, a number of patients with primary-SS-associated PAH may be misdiagnosed with idiopathic PAH, losing their chance to undergo immunosuppressive therapy. Therefore, we sought to elucidate the prevalence of primary SS among patients who initially present with PAH.MethodsFrom our prospective institutional PAH database, 40 consecutive patients without any obvious cause of PAH at the time of PAH diagnosis were identified. We retrospectively evaluated the prevalence of primary SS diagnosed during or after the initial assessment of PAH.ResultsDuring the initial assessment, one patient was diagnosed with primary-SS-associated PAH. Among the 25 patients who were initially diagnosed with idiopathic PAH, five were diagnosed with primary SS during their course of the disease. Of the five patients, three had key signs suggesting primary SS and were probably underdiagnosed at the time of initial evaluation. The remaining two patients, who were finally diagnosed with primary SS, did not have any specific signs suggesting primary SS at the time of initial evaluation but showed positive conversion of their autoantibodies during the course of PAH.ConclusionThe prevalence of primary-SS-associated PAH may be relatively high among patients who undergo initial evaluation for PAH. Furthermore, primary-SS-associated PAH may be underdiagnosed with routine evaluation for the primary cause of PAH. Clinicians should pay specific attention and carefully evaluate the possibility of primary SS in patients with PAH.

Role of Multi-Detector Computed Tomography in Assessment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) may be suspected based on the clinical history, physical examination and electrocardiogram findings but imaging is usually central to confirming the diagnosis, establishing a cause and guiding therapy. The diagnostic pathway of PAH involves a variety of complimentary investigations of which computed tomography pulmonary angiography (CTPA) has established a central role both in helping identify an underlying cause for PAH and assessing resulting functional compromise. In particular, CTPA is considered as the gold standard technique for the diagnosis of thromboembolic disease. This article reviews the CTPA evaluation in PAH, describing CTPA techniques, a systematic approach to interpretation and spectrum of key imaging findings.

Pulmonary hypertension spectrum: 16 years of experience from a single center

Pulmonary hypertension (PH) is multidisciplinary disorder that should be diagnosed and treated by specialized centers. Progress in the field of PH diagnosis has led to new classifications of the disease. The aim of this study was to determine the etiological properties of PH diagnosed at one center. A retrospective search of the database of the right heart catheterization laboratory was conducted. All of the patients who underwent right heart catheterization (RHC) and were diagnosed with PH were included in the study and grouped according to etiology. A total of 379 patients with PH (23 female; 53.2±14.7 years) were included in the current research. There were 82 patients classified as having pulmonary arterial hypertension (PAH). The leading cause among the PAH subgroups was congenital heart disease, and valve disease were found to be most the common reason for postcapillary PH. There was a statistically significant difference in the mean and systolic pulmonary artery pressure and left ventricular ejection fraction between the PH groups (p<0.001, p=0.003, p<0.001, respectively). The results of this study indicated that the leading causes of PAH and postcapillary PH were congenital heart disease and valve disease, respectively. Additional research of the etiological properties of PH should be performed by specialized centers in Turkey.

Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension.

Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman’s disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy.

Sildenafil for This Heart Failure With a Preserved Ejection Fraction? Diastolic Dysfunction and Gerbode Defect Induced Combined Precapillary and Postcapillary Pulmonary Hypertension

SESSION TITLE: Pulmonary Vascular Disease SESSION TYPE: Affiliate Case Report Slide PRESENTED ON: Tuesday, October 31, 2017 at 04:30 PM - 05:30 PM INTRODUCTION: A Gerbode defect is a ventricular septal defect (VSD) communicating directly between the left ventricle (LV) and right atrium (RA). The shunt can be either congenital or acquired. Acquired cases are secondary to cardiothoracic surgeries. CASE PRESENTATION: A 66 year-old woman was hospitalized with acute on chronic diastolic heart failure. She had a history of mitral valve papillary muscle rupture replaced with a bioprosthesis and bypass for coronary artery disease. BP was 99/69 (MAP 70), HR 70 bpm, with normoxia at rest and with exertion. Exam showed an internal jugular vein with prominent v-wave, loud holosystolic murmur, right sided heave and 3+ edema. Lab results showed a hemoglobin of 17 mg/dL, creatinine 1.6 mg/dL and BNP 2584 pg/mL. Surface echocardiogram revealed preserved LV function, markedly dilated right ventricle with flattening of the intraventricular septum, severe tricuspid regurgitation (TR), tricuspid annular plane systolic excursion of 1.6 cm, TR peak velocity jet of 3.3 m/sec and a negative bubble study. A transesophageal echocardiogram showed a large left to right communication in the posterior area of the atria with a high velocity systolic flow. Several right heart catherizations showed persistent oxygen step up at the level of the right atrium. DISCUSSION: The presence of the shunt complicated hemodynamic interpretation. This elevated the pulmonary artery saturation falsely increasing the estimated Fick cardiac output (CO). The low CO by thermodilution and renal insufficiency were consistent with a hemodynamic shock state, and improved with furosemide, sildenafil and midodrine. LV-RA shunt correction was not possible in this patient due to severe RV dysfunction and high peri-operative risk. CONCLUSIONS: Gerbode defect is a VSD communicating directly between the LV and RA. Sildenafil has been shown to reduce pulmonary pressures and improve hemodynamics in patients with combined PH. Longstanding hydrostatic pressure within the pulmonary capillaries with persistent high flow produced venulae damage and vascular remodeling similar to other causes of pulmonary artery hypertension. We describe a patient with combined pre and post-capillary PH with progressive right heart failure successfully treated with medical therapy. Reference #1: Opitz CF, Hoeper MM, Gibbs SR, et al. Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. J Am Coll Cardiol 2016 Reference #2: Yuan Shi-Min. A systematic review of acquired left ventricle to right atrium shunt. Hellenic J Cardiol 2015 DISCLOSURE: The following authors have nothing to disclose: Domingo Franco-Palacios, Patrick Kicker, Oksana Shlobin, Qiong Zhao, Mardi Gomberg-Maitland No Product/Research Disclosure Information

Methamphetamine Abuse: Characteristics, Outcomes, Logistics in Pulmonary Hypertension in a Center at Central Valley of California (MEA Culpa II -CVC Study)

SESSION TITLE: Pulmonary Hypertension SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Pulmonary arterial hypertension (PAH) is a life threatening and potentially fatal disorder. The 2013 Nice Edition of PH Classification recognized “Drug & toxin induced PH” as a separate sub-class (1.3) in World Health Organization (WHO) Group I PAH, and highlighted Methamphetamine (ME) as a “likely” cause of PAH. A previous study (Chin et al, Chest 2006) demonstrated Methamphetamine abuse (MEA) in 28.9% of patients with IPAH. Methamphetamine associated PAH (MAPAH) is a growing problem and increasingly recognized in clinical practice and its true incidence, prevalence and characteristics remain unknown. We present phenotypic, social and compliance characteristics of our cohort of MAPAH in this sub-study. METHODS: Single center, retrospective study. We identified patients (n=56) since 2008 from our research database (PHASE) with history of MEA and right heart catheterization (RHC) proven WHO Group-I PAH. RESULTS: Of 56 MAPAH patients - Mean age was 46.5 (SD 8.3), M:F 17:39, 95% of the cohort was White. The breakdown of WHO functional class upon diagnosis was I-0, II-7(12.5%), III-35(62.5%), IV-14(25%). 65.5% had coexistent tobacco use, 28.6% had coexistent alcohol use, 25.0% had marijuana use, 28.6% had coexistent cocaine use. Route of administration was inhalation in 90.5%, intravenous in 8.9% and skin-popping in 1.8%. In 36 of 56 (64.28%) MEA was the only risk factor PAH. Others in the group had additional risk factors such as CHD (11), CTD (7) & HIV (2). 49 of 56 had state regulated Medicaid or no insurance. Only 7 had a private payer source. There was a substantial increase in healthcare burden following the diagnosis of PAH compared to prior to diagnosis as evidenced by a 10-fold increase in ER visits within 12 months post-diagnosis of PAH and doubling of hospitalizations. Subjective assessments of social framework system revealed of the 56 patients, 34 (60.7%) have family support. 11 live alone (19.6%) and 33 (58.9%) live with family or friends. 38 (67.9%) have a stable home and 21 (37.5%) attend clinic with their family. 8 (14.3%) attend PH support group with family. 11 (19.6%) are self-motivated and 24 (42.9%) have problems with transportation. 20 (35.7%) have lack of insight. Only 19/56 were considered compliant. The remaining 37/56 were non or poorly compliant (Compliance was defined as: 1. Complete abstinence from ME based upon results of follow-up urine screens for ME 2. Attendance of > 50% of out patient clinic appointments). There were a total of 12 deaths in this group. CONCLUSIONS: MAPAH demonstrated the following characteristics 1. Female predominant but with higher proportion of males 2. Majority affected were Whites 3. More than a ¼ had concomitant use of other drugs 4. In a clear majority of the cohort (65%), ME was the single risk factor for PAH 5. Substantial increases in healthcare utilization following the diagnosis of PAH 6. Compliance issues were observed in majority (66%) which may explain poor outcomes, higher mortality and increased healthcare utilization CLINICAL IMPLICATIONS: This study elaborates phenotypic and social characteristics of this sub-class of patients with Methamphetamine associated PAH and also identifies unique challenges that may affect their outcomes such as compliance issues and healthcare utilization. DISCLOSURE: The following authors have nothing to disclose: Paymon Ebrahimzadeh, Kirat Gill, Matthew Beutner, Jonathan Tse, Shilpi Gupta, Aysha Khan, Vijay Balasubramanian No Product/Research Disclosure Information

Levoatrial cardinal vein with normal left ventricle: A forgotten cause of pulmonary arterial hypertension.

Levoatrial cardinal vein (LACV) is anomalous connection between left atrium or pulmonary veins and systemic veins such as innominate vein or superior vena cava. This persistence of splanchnic circulation occurs when there is left-sided obstructive cardiac lesions such as hypoplastic left heart or mitral atresia. In this report we present three cases of LACV with well-developed left heart, without any obstructive lesions. All our cases presented with pulmonary arterial hypertension (PAH) and had associated intracardiac shunt such as ventricular/atrial septal defect and supracardiac partial anomalous pulmonary venous connection. Apart from the above shunts, LACV contributed to PAH in these cases. It is important to detect and report LACV as this may require surgical correction along with other defects. If LACV goes undetected during imaging workup, it may cause persistent PAH postoperatively.

Schistosomiasis and pulmonary hypertension

Schistosomiasis is one of the most prevelant parazitic diseases in the world. It is endemic in more than 70 countries, and more than 200 million people worldwide are infected with Schistosoma. Pulmonary hypertension (PHT) is one of the chronic complications of schistosomiasis. The exact pathogenesis of schistosomiasis-associated pulmonary hypertension (S-PHT) remains unclear, although several mechanisms such as parazitic arterial embolisation, pulmonary arteriopathy, and portopulmonary hypertension have been suggested. Pathological pulmonary vascular changes in S-PHT were found similar to those in idiopathic pulmonary arterial hypertension (IPAH). The fact that schistosomiasis is one of the most common causes of pulmonary arterial hypertension (PAH), particularly in the developing countries, underlines the importance of enhancing our knowledge on this disease. Developments in the treatment of PAH have resulted in improved prognosis and significant increase in life expectancy and quality of life in the last two decades, which has enhanced the importance of S-PHT. Schistosomiasis is treated with praziquantel. Nevertheless, there is limited evidence that this treatment is effective for PHT. Although antihelmintic medications do not lead to significant improvement, they have beneficial effects and may slow down disease progression. Using PAH-specific treatments in the patients with schistosomiasis-associated PAH (S-PAH) can improve prognosis. However, inadequate clinical studies and limited sources in the endemic regions restrict extensive usage of these expensive medications. Further studies are required to determine the efficacy of these treatment modalities.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

HIV-Associated Pulmonary Hypertension: A Global Perspective

Human immunodeficiency virus (HIV) infection is a well-recognized cause of pulmonary arterial hypertension (PAH). Worldwide, an estimated 37 million individuals are infected with HIV, and the availability of effective HIV therapy means that more of these patients are living longer and developing cardiovascular complications, including PAH. In European populations, it is estimated that 0.5% of patients with HIV infection develop moderate to severe PAH, so that HIV infection may be one of the most common causes of PAH worldwide. Untreated, the prognosis of HIV-associated PAH is particularly poor, and a large proportion of patients with HIV infection live in resource-poor regions of the world where PAH therapy is not available. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for HIV-associated PAH are summarized.

Device Closure of a Large Atrial Septal Defect in a Patient with Lung Pathology

The incidence of Atrial Septal Defect (ASD) is approximately 3 per 10,000 live births. Ostium secundum ASD is most common type of ASD accounting for 75% of all ASD cases. Patients with irreversible Pulmonary Arterial Hypertension (PAH) are considered ineligible for shunt closure. It is important to ascertain the cause of PAH particularly to rule out pulmonary cause as in present case. A 56-yearold female patient, known case of Ostium secundum ASD presented with NYHA class IV dyspnea and chest infection. A transthoracic echocardiogram revealed 30 mm ASD with bidirectional shunt, dilated Right Atrium (RA), Right Ventricle (RV), severe Tricuspid Regurgitation (TR) (max PG 85 mmHg) and RV dysfunction. She was intubated and put on mechanical ventilator. CT chest showed right lower lobe bronchiectasis with infective changes. However repeated attempts to wean patient off Bipap support were unsuccessful. Subsequently cardiac catheterization and Balloon Occlusion of ASD revealed Qp/Qs ratio of 8:1 with step up in oxygen saturation of 19%. Mean pulmonary artery pressure was 35 mmHg. Later she underwent successful device closure for ASD with AMPLATZER septal occlude (36 mm) (AGA Medical Corp., Minneapolis, MN, USA). Her physical activity and symptoms were much improved. Follow up transthoracic echocardiography after 5 months revealed normal RV contractility and no PAH. While initially chest infection prevented ASD device closure, underlying bronchiectasis which got worsened by ASD shunt, prevented her from weaning off ventilator. ASD device closure thereby helped to reduce pulmonary blood flow and improvement in lung function enabling her to wean off ventilator support.

Incidence of Pulmonary Arterial Hypertension in Patients with Psoriasis: A Retrospective Cohort Study.

Inflammatory signaling may play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). To assess the incidence of PAH in patients with mild and severe psoriasis compared with their respective controls. From January 2004 to November 2012, we performed a retrospective cohort study of patients with psoriasis in the Kaiser Permanente Southern California Health Plan. Patients with an International Classification of Diseases, Ninth Revision Clinical Modification diagnostic code for psoriasis (696.1) or psoriatic arthritis (696.0) without a prior diagnosis of primary PAH (416.0) or secondary PAH (416.8) were eligible for inclusion. Patients who had never received a diagnosis of psoriasis were frequency-matched by age, sex, and race to form the control cohorts. Incidence of PAH in patients with psoriasis compared with matched controls. There were 10,115 patients with mild psoriasis, 3821 with severe psoriasis, and 69,360 matched controls. On multivariable analysis, there was a significantly increased risk of PAH developing in the severe psoriasis cohort vs their controls (hazard ratio = 1.46, 95% confidence interval = 1.09-1.94). The systemic inflammatory process underlying psoriasis may be a cause for an increased risk of PAH, but there are numerous secondary causes of PAH, some of which were not accounted for in our study. Further prospective, randomized controlled trials are necessary to establish psoriasis as a risk factor for PAH.

The role of genetics in pulmonary arterial hypertension.

Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH) is a rare disease characterized by proliferation and occlusion of small pulmonary arterioles, leading to progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, and right ventricular failure. Historically, it has been associated with a high mortality rate, although, over the last decade, treatment has improved survival. PAH includes idiopathic PAH (IPAH), heritable PAH (HPAH), and PAH associated with certain medical conditions. The aetiology of PAH is heterogeneous, and genetics play an important role in some cases. Mutations in BMPR2, encoding bone morphogenetic protein receptor 2, a member of the transforming growth factor-β superfamily of receptors, have been identified in 70% of cases of HPAH, and in 10-40% of cases of IPAH. Other genetic causes of PAH include mutations in the genes encoding activin receptor-like type 1, endoglin, SMAD9, caveolin 1, and potassium two-pore-domain channel subfamily K member 3. Mutations in the gene encoding T-box 4 have been identified in 10-30% of paediatric PAH patients, but rarely in adults with PAH. PAH in children is much more heterogeneous than in adults, and can be associated with several genetic syndromes, congenital heart disease, pulmonary disease, and vascular disease. In addition to rare mutations as a monogenic cause of HPAH, common variants in the gene encoding cerebellin 2 increase the risk of PAH by approximately two-fold. A PAH panel of genes is available for clinical testing, and should be considered for use in clinical management, especially for patients with a family history of PAH. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

HRCT diagnosis of combined pulmonary fibrosis and emphysema in a patient of chronic obstructive pulmonary disease with pulmonary hypertension and clinical or radiograph suspicion of pulmonary fibrosis

Combined pulmonary fibrosis and emphysema (CPFE) is a unique pulmonary condition characterized by simultaneous coexistence of both upper lobe emphysema and lower lobe fibrosis. Pulmonologists should be aware of the entity while evaluating patients with chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis. Airflow and lung volume are relatively preserved but oxygenation is disproportionately impaired in patients with CPFE. We describe a case of an 83-year-old male patient with past history of heavy smoking, in whom the search for the cause of pulmonary arterial hypertension and exercise-induced arterial oxygen desaturation disproportionate to be explained by COPD resulted in a diagnosis of CPFE. He complained of dyspnoea on exertion and non-productive cough. Physical examination revealed basal Velcro rales and clubbing. Chest radiography showed prominent vascular markings, preserved lung volume and subtle fibrosis of the bases. Definitive diagnosis was made on CT scan of the chest, which revealed upper lobe emphysema and lower lobe fibrosis and honeycombing. The patient was managed by long-term oxygen therapy, inhaled corticosteroid, long-acting bronchodilator and antimuscarinic agents, diuretic, pirfenidone (antifibrotic agent), proton pump inhibitor and N-acetyl cysteine (antioxidant). We emphasize the importance of the diagnosis of CPFE in early stages through CT in a case of COPD with clinical, laboratory and chest radiographic evidence of fibrosis and the fact that CPFE is associated with pulmonary hypertension, a poor prognostic indicator.

Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation.

Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and tricarboxylic acid (TCA) cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP+ ratios observed in shunt PASMCs. Consistent with these findings, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1, or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.

Progressive fatigue and central cyanosis due to severe pulmonary arterial hypertension as the initial manifestation of systemic lupus erythematosus in a boy: A case report

Severe pulmonary arterial hypertension of systemic lupus erythematosus (SLE) in pediatrics is rarely seen, especially in boys. Sometimes SLE may only present as progressive fatigue and central cyanosis that may be diagnosed initially as cardiovascular diseases, which makes harder the diagnosis of SLE. We present a 13-year-old boy with a month of progressive fatigue and central cyanosis, diagnosed only as severe idiopathic pulmonary arterial hypertension. The boy was finally diagnosed as severe pulmonary arterial hypertension of systemic lupus erythematosus. Due to different choices of therapy, underlying cause of pulmonary arterial hypertension should be diagnosed and searched thoroughly.

Novel signaling pathways in pulmonary arterial hypertension (2015 Grover Conference Series).

The proliferative endothelial and smooth muscle cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Mutations in bone morphogenetic protein type 2 receptor (BMPR2) have been identified as the most common genetic cause of PAH and females with BMPR2 mutations are 2.5 times as likely to develop heritable forms of PAH than males. Higher levels of estrogen have also been observed in males with PAH, implicating sex hormones in PAH pathogenesis. Recently, the estrogen metabolite 16α-OHE1 (hydroxyestrone) was implicated in the regulation of miR29, a microRNA involved in modulating energy metabolism. In females, decreased miR96 enhances serotonin's effect by upregulating the 5-hydroxytryptamine 1B (5HT1B) receptor. Because PAH is characterized as a quasi-malignant disease, likely due to BMPR2 loss of function, altered signaling pathways that sustain this cancer-like phenotype are being explored. Extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinases (MAPKs) play a critical role in proliferation and cell motility, and dysregulated MAPK signaling is observed in various experimental models of PAH. Wnt signaling pathways preserve pulmonary vascular homeostasis, and dysregulation of this pathway could contribute to limited vascular regeneration in response to injury. In this review, we take a closer look at sex, sex hormones, and the interplay between sex hormones and microRNA regulation. We also focus on MAPK and Wnt signaling pathways in the emergence of a proproliferative, antiapoptotic endothelial phenotype, which then orchestrates an angioproliferative process of vascular remodeling, with the hope of developing novel therapies that could reverse the phenotype.