Association Of Pulmonary Arterial Hypertension Research Articles

Characteristics of Patients With Pulmonary Arterial Hypertension in a Pulmonary Hypertension Association-Accredited Comprehensive Care Center: A Contrast in Features When Compared With US National Registry Data.

Background Since the initial description in the 1980s, our understanding of the diversity of pulmonary arterial hypertension (PAH) has continued to evolve. In this study, we report the characteristics of patients seen in an academic medical center for PAH from August 2020 through November 2021 and contrast those with nationally reported data from the United States Pulmonary Hypertension Scientific Registry (USPHSR). Study Design Investigators at the University of Utah Pulmonary Hypertension Program prospectively enrolled adult patients diagnosed with WHO Group 1 PAH, who were evaluated between August 2020 and November 2021 in a program-specific registry. Patient exposure and health histories were collected through structured interviews and questionnaires, along with clinical data and medication use. A total of 242 patients were enrolled in the University of Utah Pulmonary Hypertension Registry (UUPHR). Results Of the 242 enrolled patients, the most common etiology was associated PAH (APAH), accounting for 71.1% of the population. The second largest etiology was idiopathic PAH (IPAH) at 26.4%. The remaining patients were distributed between familial PAH (FPAH), pulmonary veno-occlusive disease (PVOD), and others. Of the total population classified as APAH, 39% of cases were noted as secondary to connective tissue disease (CTD) and 33% as toxin-induced. These represented 28% and 24% of the total population, respectively. Conclusions In this US-based accredited academic medical center, the etiology of PAH in our patient population contrasts with national registry data. In the UUPHR, APAH, specifically CTD-PAH and toxin-associated PAH, accounts for the majority of patients with PAH. This contrasts with IPAH, which nationally is the most reported cause of PAH. Differences in our population may reflect the regional variation of the referral site, but it is noteworthy for its contrast with historically reported phenotypes.

Platelet-leukocyte aggregate formation and inflammation in patients with pulmonary arterial hypertension and CTEPH

Pulmonary hypertension (PH) is defined by increased mean pulmonary artery pressure, and the clinical classification includes five etiologies, of which we investigated subgroup 1, pulmonary arterial hypertension (PAH) and subgroup 4, chronic thrombotic and/or embolic disease (CTEPH). Platelets participate in both innate and adaptive immune responses and could possibly contribute to the suggested systemic inflammation associated with PAH. In this study, we utilized flow cytometry to analyze platelet activation and platelet-monocyte (PMA) and granulocyte (PGA) aggregates in PAH and CTEPH patients and healthy control subjects. The plasma concentration of proinflammatory cytokines was measured by multiplex electrochemiluminescence. Our main finding is that circulating platelets are activated in the circulation and form aggregates with both monocytes and granulocytes in patients with idiopathic PAH (IPAH), associated PAH (APAH) and pulmonary hypertension due to CTEPH. There was a strong correlation between the platelet activation, assessed as P-selectin, and the number of aggregates formed. IL-6, IL-8, IL-10 and TNF-α were increased in all PH subgroups as compared to healthy controls, and PMAs were associated with circulating IL-6, IL-8 and IL-10, whereas PGAs were associated with IL-6. The increased concentrations of platelet-leukocyte aggregates found in PAH/CTEPH patients might thus contribute to the inflammatory state in PH.

Challenging Management of Pulmonary Regurgitation in an Adult Patient With Tetralogy of Fallot and Pulmonary Arterial Hypertension

Abstract Pulmonary regurgitation following correction of tetralogy of Fallot (ToF) is a common postoperative complication associated with progressive right ventricular (RV) enlargement and dysfunction, and is an important determinant of late morbidity and mortality. Usually, pulmonary regurgitation is well tolerated for many years following surgery, but it can lead to progressive exercise intolerance, heart failure, tachyarrhythmias, late sudden death requiring often re-intervention. The appropriate timing of such intervention can be a challenging topic given the risk of prosthetic valve degeneration, the increased risk of reoperation and the decision depends on assessment of right ventricle size and function. Pulmonary hypertension (PH) is not an usual finding in ToF patient and it can be caused by pulmonary agenesis, hypoplasia and/or thrombosis, residual ventricular septal defect, or a large prior systemic-to-pulmonary shunt. Association of pulmonary arterial hypertension in a patient with ToF and pulmonary regurgitation who needs valve correction involves higher surgical risks and the management must be taken in a multidisciplinary team.

Differential Diagnosis of Pulmonary Hypertension Using the Example of Collagenosis-associated PAH in the Context of Chronic Lung and Left Heart Disease

Pulmonary hypertension (PH) can be diagnosed in the context of connective tissue diseases (CTD) as well as in elderly patients with multiple comorbidities. A correct clinical differential diagnosis and classification is essential before adequate therapeutic decisions can be made. Differential diagnosis of PH in CTD comprises associated pulmonary arterial hypertension (APAH), group 2 or 3 PH (PH arising from left heart or chronic lung disease), chronic thromboembolic PH (PH) and group 5 (e. g. in the context of terminal renal insufficiency). This is also true of elderly patients in whom the decision has to be made if the increasing number of coincident diseases lead to PH or have to be interpreted as comorbidities. In this manuscript, the differential diagnosis of PH is elucidated, focusing on CTD, in the context of left heart disease and chronic lung disease. Furthermore, criteria are presented facilitating an objective approach in this context.

Pulmonary arterial hypertension associated with congenital heart disease: classification and pathophysiology

While the development of pulmonary arterial hypertension is not uncommon in adult congenital heart disease patients, other forms of pulmonary hypertension (PH) may also be present. A good understanding of PH classification is therefore vital for clinicians managing adult patients with congenital heart disease. This paper reviews both the general classification of PH and more detailed approaches to classifying pulmonary arterial hypertension in association with congenital heart disease.

ASSOCIATION OF METHAMPHETAMINE USE WITH PULMONARY HYPERTENSION: RESULTS FROM NATIONAL INPATIENT SAMPLE

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Meth-amphetamine use has significantly increased during the past 2 decades. Meth-amphetamines can have a number of toxic effects on cardiopulmonary system like acute lung injury, myocardial infarction and pulmonary hypertension. Using retrospective data, we sought to identify trends in meth-amphetamine associated pulmonary arterial hypertension (APAH) and compare the outcomes to idiopathic pulmonary arterial hypertension (iPAH) METHODS: We analyzed data from the National Inpatient Sample (NIS), Health Care and Utilization Project (HCUP) for the years 2010 to 2014. We identified discharges associated with Pulmonary Hypertension using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 416.0, 416.8 and 416.9. All possible known causes of secondary pulmonary hypertension were excluded using ICD-9-CM codes. Trend analysis was performed via linear-by-linear association test. Comparison of categorical variables was done via Chi-square test. All analysis was performed using sample weights to calculate nationwide estimates. RESULTS: A total of 731,053 discharges (age = 18 years) were identified, 65.1% of which were females. Among those, 2,208 (0.3%) patients had APAH and rest were identified as iPAH. Patients with APAH were younger (mean age 45.2 vs 67.8, p<0.001), most of them were Caucasians (66.9%) followed by Hispanics (16.9%), and were more likely to be females (52.4%, p<0.001). Patients with APAH were more likely to have Acquired immunodeficiency syndrome and liver disease (p <0.001). Overall, patients with APAH had fewer comorbidities as compared to iPAH patients (Figure). Trend analysis showed an increase in the number of APAH cases from 2010 to 2014 (70% increase, p <0.001). On comparing inpatient mortality and hospital length of stay (LOS), APAH and iPAH patients had similar inpatient mortality rates (4.6% vs 4.2% p=0.430), however APAH patients had slightly longer LOS (mean days 7.01 vs 6.39 p<0.001) CONCLUSIONS: Our study from a national inpatient sample shows a rising trend of APAH in recent years with these patients having slightly increased LOS. It also shows APAH to be more likely in the younger female population with fewer comorbidities. Future studies are needed to explore the mechanisms of disease and potential therapeutic options. CLINICAL IMPLICATIONS: Our study highlights one of the many toxic effects of meth-amphetamine use. DISCLOSURES: No relevant relationships by Hammad Ali, source=Web Response No relevant relationships by Sourbha Dani, source=Web Response No relevant relationships by Amit Dey, source=Web Response No relevant relationships by Devesh Rai, source=Web Response No relevant relationships by Muhammad Waqas Tahir, source=Web Response No relevant relationships by Abdul Wahab, source=Web Response

High geographic prevalence of pulmonary artery hypertension: associations with ethnicity, drug use, and altitude.

While estimates of pulmonary arterial hypertension incidence and prevalence commonly range from 1–3/million and 15–25/million, respectively, clinical experience at our institution suggested much higher rates. We sought to describe the disease burden of pulmonary arterial hypertension in the geographic area served by our Pulmonary Hypertension Clinic and compare it to the REVEAL registry. Our secondary objectives were to document pulmonary arterial hypertension prevalence in minorities underrepresented in REVEAL (Hispanics and Native Americans) and to address the association of pulmonary arterial hypertension with exposure to drugs and moderately increased residential altitude in this population. Retrospective review of pulmonary arterial hypertension clinic patients alive during 2016 identified 154 patients. Hispanic patients made up 35.7% of the cohort, a much greater percentage than REVEAL, p < .001 but smaller than the percentage of Hispanic patients (48.4%) in geographic area served by the clinic. Pulmonary arterial hypertension due to drug exposure was more common and idiopathic pulmonary arterial hypertension was less common than in REVEAL (p < .001). Overall, pulmonary arterial hypertension incidence was 14 cases per million, greater than the REVEAL registry, odds ratio 6.3 (95% CI: 4.2–9.5), (p < .001). Annual period prevalence of pulmonary arterial hypertension was 93 cases per million, also greater than the REVEAL, odds ratio = 7.5 (95% CI: 6.4–8.8) and remained greater when the clinic cohort was constrained to patients with hemodynamic severity comparable to REVEAL, odds ratio = 3.8 (95% CI: 3.0–4.6), (p < .001). There was a strong association between pulmonary arterial hypertension prevalence and residence at altitude > 4000 ft, odds ratio = 26.6 (95% CI: 8.5–83.5), p < .001; however, this was potentially confounded by pulmonary arterial hypertension treatment referral patterns. These findings document a much higher local pulmonary arterial hypertension incidence and prevalence than previously reported in REVEAL. While population ethnicity differed markedly from REVEAL, the disease burden was not driven by these differences. The possible association of moderately increased residential altitude with pulmonary arterial hypertension warrants further evaluation.

LESSONS LEARNED FROM TRIPLE COMBINATION THERAPY IN PULMONARY ARTERIAL HYPERTENSION

SESSION TITLE: Monday Fellow Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Current guidelines published by Chest in 2019 suggest that patients who present with low or intermediate risk pulmonary arterial hypertension (PAH) should be initiated on oral therapy with endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE-5i) or soluble guanylate cyclase stimulators (sGCs) (1). They suggest using triple combination therapy including subcutaneous or IV prostacyclin analogues in high-risk patients (1). The following is a series of three patients with PAH who dramatically improved on triple combination therapy. CASE PRESENTATION: A 49 year old male with Sjogrens disease and associated PAH (APAH) was found to have clinical improvement on an ERA, PDE-5i, and prostacyclin analogue combination. With the switch of the PDE-5i to a sGCs based on the Respite trial and switch of ERA choice within the class due to side effect (nasal congestion and lower extremity edema), the patient had near normalization of his echocardiogram and right heart catherization (RHC) findings as well as an increase in his 6 minute walk distance (6MWD) (2) (see Table 1, Patient 1). Similarly, a 75 year-old female with scleroderma APAH was treated with an ERA, PDE-5 inhibitor, and a prostacyclin analogue. Significant hemodynamic improvement was noted when ERA choice was changed within its class and sildenafil was changed to a SGCs (2) (See Table 1, Patient 2). Finally, a 44 year-old female with PAH secondary to HIV was noted to have improvement in 6MWD and decrease in mean pulmonary artery pressure and pulmonary vascular resistance with the addition of an ERA and PDE-5 inhibitor to IV epropostenol. Interestingly, when IV epropostenol was switched to subcutaneous (SC) trepostinil due to recurrent line infections, the patient’s hemodynamics worsened. When the patient developed angioedema to ambrisentan, she was switched to macitentan with subsequent improvement in 6MWD and hemodynamics (see Table 1, Patient 3). DISCUSSION: Classically, it is considered of limited efficacy to switch ERAs within the class and there is limited information in added benefit of switching PDE-5 inhibitors to Riociguat, a sGC stimulator. In each of these patient cases, changes were made in medication regimens due to progression of disease or medication side effects and patterns of clinical improvement were subsequently noted. This suggests that by using triple drug combination therapy, including parental prostacyclines, and switching medications within the ERA class and between nitric oxide pathway agents (PDE-5 inhibitors to sGC stimulators), physicians may further optimize a patient’s clinical status by hemodynamic parameters and 6MWD. CONCLUSIONS: Triple combination therapy may lead to dramatic clinical and hemodynamic improvement. Further studies need to be performed to determine if triple therapy might lead to better long-term survival. Reference #1: Klinger, J. R. (2019). Therapy for Pulmonary Arterial Hypertension in Adults. Chest Journal, 155(3), 565-586. doi:https://doi.org/10.1016/j.chest.2018.11.030 Reference #2: Hoeper, M. M., Corris, P. A., Klinger, J. R., Langleben, D., Naeije, R., Simonneau, G., & Benza, R. L. (2016). RESPITE: Riociguat in pulmonary arterial hypertension patients with an inadequate response to phosphodiesterase type 5 inhibitors. 4.3 Pulmonary Circulation and Pulmonary Vascular Diseases. https://doi.org/10.1183/13993003.congress-2016.oa263 DISCLOSURES: No relevant relationships by Sheeja Schuster, source=Web Response Consultant relationship with Actelion Please note: $5001 - $20000 Added 03/15/2019 by Roxana Sulica, source=Web Response, value=Consulting fee Consultant relationship with Bayer Please note: $5001 - $20000 Added 03/15/2019 by Roxana Sulica, source=Web Response, value=Consulting fee Consultant relationship with United Therapeutics Please note: $5001 - $20000 Added 03/15/2019 by Roxana Sulica, source=Web Response, value=Consulting fee research relationship with Reata Please note: $5001 - $20000 Added 03/15/2019 by Roxana Sulica, source=Web Response, value=insitution was paid for resear

Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance

Objective: To evaluate the long-term safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH) in real-world clinical practice.Methods: This is an observational surveillance of PAH patients receiving tadalafil in the contracted sites. A sub-group analysis was performed of 391 pediatric PAH patients (<18 years) who were included from 1,704 total patients in this surveillance. Safety was assessed from the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included change in World Health Organization (WHO) functional classification of PAH, cardiac catheterization (pulmonary arterial pressure: PAP), and echocardiography (tricuspid regurgitation pressure gradient: TRPG). Survival rate was also measured.Results: The mean patient age was 5.7 ± 5.34 years. Associated PAH (APAH) and idiopathic PAH (IPAH) accounted for 76.0% and 17.6%, respectively, of the PAH patients. Patients were followed for up to 2 years. Among 391 patients analyzed for safety, the overall incidence rate of ADRs was 16.6%. The common ADRs (≥ 1%) were headache (2.8%), hepatic function abnormal, platelet count decreased (1.3% each), and epistaxis, (1.0%). Eleven patients (2.8%) reported 16 SADRs. Three patients died secondary to SADRs. For the effectiveness analysis, the incidence of WHO functional class improvement at 3 months, 1 year, and 2 years after the initiation of tadalafil and last observation in pediatric patients were 16.5%, 19.7%, and 16.3%, respectively. Both PAP and TRPG showed a statistically significant reduction at last observation.Conclusion: This manuscript reveals the use of tadalafil in the real-world pediatric population with an acceptable safety profile in Japan.

Diagnosis, Treatment, and Clinical Management of Pulmonary Arterial Hypertension in the Contemporary Era

Pulmonary arterial hypertension (PAH) is characterized by severe remodeling of the distal pulmonary arteries, increased pulmonary vascular resistance, and right ventricular dysfunction that promotes heart failure. Once regarded as largely untreatable, evidence-based decision making now guides clinical management of PAH and improves outcomes. However, misconceptions regarding the approach to PAH in the modern era are common and associated with substandard clinical care. The clinical profile of PAH has changed substantially since its original description. Patients are older at diagnosis than previously reported; disease severity appears greater in men compared with women; and patients with PAH in association with connective tissue disease are identified as a particularly high-risk subgroup. Risk stratification scales for PAH are now available at point of care, which inform treatment goals, including a 6-minute walk distance of greater than 440 m, peak volume of oxygen consumption of greater than 15 mL/min/kg, right atrial area of less than 18 cm2, cardiac index of greater than 2.5 L/min/m2, and absent or low symptom burden with routine physical activity. At present, 14 therapies targeting 6 PAH-specific molecular intermediaries are used clinically. Recent landmark trial data have demonstrated the critical importance of initial combination therapy in treatment-naive patients. These findings underscore a global shift in PAH that couples early disease detection with aggressive pharmacotherapy. Indeed, recent longitudinal data from patients receiving combination therapy show that the 3-year survival rate in PAH may be as high as 84% compared with 48% from the original National Institutes of Health registry on idiopathic PAH (1980-1985). Despite these gains, incomplete clinical evaluation and misdiagnosis by referring clinicians is common and associated with inappropriate therapy. Compared with the original clinical experience, PAH has evolved into a contemporary and treatable disease characterized by improved survival and a high standard for defining therapeutic success. However, underawareness among clinicians regarding the importance of early and accurate PAH diagnosis persists and is a potentially reversible cause of adverse outcome in this disease.

Quality of life among pulmonary hypertension patients in Finland

BackgroundThe purpose of the study was to examine pulmonary hypertension (PH) patients’ quality of life (QOL) for the first time in Finland.MethodsThis was a non-interventional, cross-sectional study. The SF-36v2 questionnaire was sent to the PH patients who had been referred to or followed up on at the Helsinki University Central Hospital's pulmonary clinic for idiopathic pulmonary arterial hypertension, associated pulmonary arterial hypertension (APAH), or chronic thromboembolic PH (CTEPH). The patients were on pulmonary arterial hypertension (PAH) – specific drugs, were at least 18 years old, and had signed an informed consent.ResultsThere were 62 patients who fulfilled the inclusion criteria, and 53% of respondents rated their health as moderate. Similarly, 55% of respondents rated their health status approximately the same compared to their situation 1 year ago. QOL was impaired in all other subscales, except for the mental health and mental component score. A majority of patients suffered from PH symptoms, which worsened their QOL. The greatest impact on their QOL was associated with a high World Health Organization (WHO) functional class (FC), poor performance in a 6-min walking test (6MWT), symptoms, oxygen therapy, elevated pro-brain natriuretic peptide, pericardial effusion, APAH etiology, and being retired from work.ConclusionsThe respondents had a reduced QOL, compared to the general population, in all other subscales, except for mental health. APAH patients had the worst QOL. Good results in functional capacity measures (WHO FC, 6MWT) were associated with a better QOL. Patients’ QOL can be improved by reducing the symptoms of PAH.

Proinflammatory high-density lipoprotein results from oxidized lipid mediators in the pathogenesis of both idiopathic and associated types of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for high-density lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the "inflammatory indices" HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a "dysfunctional HDL phenotype," that is, proinflammatory HDL effects. In contrast to "normal HDL function," the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant "salutary effect" of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of IPAH and APAH for the determined plasma eicosanoid levels in the HDL fractions. Our study has further implicated the putative role of "oxidant stress" and inflammation in the pathobiology of PAH. Our data suggest the influences on the "dysfunctional HDL phenotype" of increased oxidized fatty acids, which are paradoxically proinflammatory. We speculate that therapies that target either the "inflammatory milieu" or the "dysfunctional HDL phenotype," such as apoA-I mimetic peptides, may be valuable avenues of further research in pulmonary vascular diseases.

New potential diagnostic biomarkers for pulmonary hypertension.

This study aimed to determine whether the vascular endothelial growth factor (VEGF) family members soluble VEGF receptor 1 (also called soluble fms-like tyrosine kinase 1 (sFlt-1)) and placental growth factor (PlGF) could be used as biomarkers for pulmonary hypertension (PH). Consecutive patients undergoing right heart catheterisation were enrolled (those with mean pulmonary arterial pressure ≥25 mmHg were classed as having PH; those with mean pulmonary arterial pressure <25 mmHg acted as non-PH controls). Plasma from the time of PH diagnosis was analysed for PlGF and sFlt-1 using enzyme immunoassays. In total, 247 patients with PH were enrolled: 62 with idiopathic pulmonary arterial hypertension (IPAH), 14 with associated pulmonary arterial hypertension (APAH), 21 with collagen vascular disease (CVD), 26 with pulmonary venous hypertension, 67 with lung disease-associated PH and 57 with chronic thromboembolic PH. The non-PH control group consisted of 40 patients. sFlt-1 plasma levels were significantly higher in patients with IPAH, APAH, CVD and lung disease-associated PH versus controls; PlGF levels were significantly higher in all PH groups versus controls. The combination of sFlt-1 and PlGF resulted in a sensitivity of 83.7% with specificity of 100% for pulmonary arterial hypertension. There was no association between sFlt-1 or PlGF and haemodynamic parameters, 6-min walking distance or survival. In summary, PlGF and sFlt-1 are promising diagnostic biomarkers for PH.

Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension

IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.

(944) - De Novo Development of Pulmonary Arterial Hypertension in Association With Pregnancy: A Retrospective Case Series

(944) - De Novo Development of Pulmonary Arterial Hypertension in Association With Pregnancy: A Retrospective Case Series

Molecular and clinical analysis of TRPC6 and AGTR1 genes in patients with pulmonary arterial hypertension.

BackgroundPulmonary arterial hypertension (PAH) is a rare and progressive vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. The aim of this study was to analyze 5′UTR region in canonical transient receptor potential isoform 6 (TRPC6) and 3′UTR region in Angiotensin II type I receptor (AGTR1) genes in patients with idiopathic and associated PAH. Correlation among mutations and clinical and functional parameters was further analyzed.MethodsAnalysis of TRPC6 and AGTR1 genes was performed by polymerase chain reaction (PCR) and direct sequencing. We used a non-parametric test to determine if significant differences were found between the groups studied and chi-square test to compare clinical and hemodynamic variables among genotypes.ResultsFifty five patients and fifty two controls were included in this study. We found statistically significant differences for c.1-361A > T (p = 0.0077), c.1-254C > G (p < 0.0001) and c.1-218C > T (p = 0.0021) in TRPC6 gene and c.1166A > C (p < 0.001) in AGTR1 gene, between patients and controls. Idiopathic PAH patients (IPAH) and controls presented significant differences for all 3 TRPC6 polymorphisms (p = 0.020), (p = 0.002) and (p = 0.008) respectively, and also showed differences for AGTR1 gene (p < 0.001). In associated PAH (APAH) patients we found statistical differences for c.1-254C > G (p < 0.001) and c.1-218C > T (p = 0.001) in TRPC6 gene and c.1166A > C (p = 0.001) in AGTR1 gene. Several clinical and hemodynamic parameters showed significant differences between carriers and non-carriers of these single nucleotide polymorphisms (SNPs). Nineteen patients were carriers of all 3 SNPs in TRPC6 gene and presented a more severe phenotype with differences in mean pulmonary arterial pressure (p = 0.016), systolic pulmonary arterial pressure (p = 0.040), cardiac index (p < 0.001) and 6 minute walking test (p = 0.049). 16 of these patients harbored the SNP in AGTR1 gene. These patients showed differences in age at diagnosis (p = 0.049), mean pulmonary arterial pressure (p = 0.033), cardiac index (p = 0.002) and 6 minute walking test (p = 0.039).ConclusionsPAH is a rare disease with pulmonary vascular remodeling caused in part by a heterogeneous constellation of genetic arrangements. This study seems to suggest that c.1-361A > T, c.1-254C > G and c.1-218C > T polymorphisms in TRPC6 gene and c.1166A > C polymorphism in AGTR1 could have a role in the development of this disease.

Building the case for novel clinical trials in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance caused by remodeling of distal pulmonary arterioles that occurs as a consequence of a complex interplay between molecular and genetic factors.1 The incidence of PAH is estimated at 7 to 10 individuals per million people,2 with a prevalence of ≤50 cases per million.3 The most recent World Health Organization clinical classification of pulmonary hypertension4 distinguishes group 1 pulmonary hypertension from pulmonary vascular disease related to lung disease, left atrial hypertension or venothromboemoblism by including PAH in association with anorexigen exposure, connective tissue disease, HIV, or portal hypertension, among other specific comorbidities. In turn, idiopathic PAH is diagnosed in patients without a hereditary or other identifiable cause of PAH. Because of the diversity of diseases implicated in the pathogenesis of PAH, an evolving goal among pulmonary hypertension care centers5 is pathophenotyping patients with pulmonary vascular disease to calibrate suitable therapy.6 Before PAH-specific drug treatment availability, diagnosing PAH functioned principally to inform (a dismal) patient prognosis as treatment was relegated primarily to the careful use of warfarin, digoxin, diuretics, and oxygen.7 The discovery of calcium channel blocker efficacy in this disease was a breakthrough, but this therapy was considered to be appropriate for only a minority of patients, which remains true today.8,9 However, subsequent seminal discoveries of key signaling pathways implicated in the pathogenesis of PAH in some patients exposed for the first time disease-specific treatment targets.10 In turn, results from conventional randomized clinical trials (RCTs) validated their translational relevance and introduced 4 novel drug classes to clinical practice that improve incrementally quality of life or longevity in patients with PAH.8,11–17 Even in the era of contemporary PAH therapies, however, progressive heart failure and diminished …

Connective tissue disease-associated pulmonary arterial hypertension in Chinese patients

We sought to investigate the characteristics, survival and risk factors for mortality in Chinese patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (APAH) in modern therapy era. 129 consecutive adult patients who visited one of three referral centres in China with a diagnosis of CTD-APAH confirmed by right heart catheterisation during the previous 5 years were enrolled. The end-point was all-cause death or data censoring. Systemic lupus erythematosus was the most common underlying CTD (49%) and systemic sclerosis just accounted for 6% in this cohort. The overall survival at 1 and 3 years was 92% and 80%, respectively. Pericardial effusion, a shorter 6-min walk distance, lower mixed venous oxygen saturation, higher pulmonary vascular resistance (PVR) and alkaline phosphatase (ALP), and lower total cholesterol levels were all associated with a higher risk of death among the study population. Higher PVR and ALP were independent predictors of mortality. In conclusion, unlike in western patients, systemic lupus erythematosus is the most common underlying disease in Chinese patients with CTD-APAH. The survival of Chinese patients with CTD-APAH in the modern treatment era is similar to that in western countries. Elevated PVR and ALP are independent risk factors for poor outcomes.

Pulmonary Arterial Hypertension and Systemic Sclerosis Relation: A Single Centre Experience

In systemic sclerosis (SSc), this single-centre study aimed to define the frequency and association of pulmonary arterial hypertension (PAH), occurring either alone in SSc-PAH or together with interstitial lung disease (ILD-PH). SSc cases between the years 1990-2011 were reviewed, retrospectively. Patients' clinical, laboratory findings, Modified Rodnan Skin Score and Medsger score, 6-minute walk distance (6MWD), carbon monoxide diffusion test (DLCO), echocardiography, thorax HRCT, and right heart catheterisation findings were recorded. One hundred and forty-one cases (F/M:124/17, diffuse cutaneous SSc (DcSSc)/limited cutaneous SSc (LcSSc): 84/57) were included in the study with the mean age of 52.70±15.17 years and disease duration of 107.07±99.44 months. PaO₂, FEV1 and FVC were lower in DcSSc (p<0.05) as compared to LcSSc, but DLCO and 6MWD did not differ significantly, between the two forms. Ground glass opacity (64.7%) and interlobular septal thickening (58.8%) were the most frequent findings on HRCT of such subjects. PAH was detected in 34 subjects (24.1%). Seven of them had SSc associated PAH (SSc-PAH) and 27 ILD-PH. Both frequencies were similar between DcSSc and LcSSc. Mean sPAP was higher in SSc-PAH. PAH was observed in approximately one fourth of patients; therefore advanced cardio-pulmonary investigation should be routinely performed in the SSc patients' management.

The Essential Role of Imaging in the Evaluation of Patients With Pulmonary Arterial Hypertension in Association With Congenital Heart Disease

Pulmonary arterial hypertension (PAH) is a hemodynamic and pathophysiologic condition defined as an increase in mean pulmonary artery pressure (MPAP) of ≥25 mm Hg at rest measured at right heart catheterization (RHC).12 Patients with PAH associated with congenital heart disease (PAH-CHD) are a growing population consisting of an anatomically and phenotypically heterogeneous group, where differences among specific cardiac defects, along with their varied clinical course and prognosis, influence treatment choices for the individual patient.