Factor In Pulmonary Arterial Hypertension Research Articles

Risk stratification refinements with inclusion of haemodynamic variables at follow-up in patients with pulmonary arterial hypertension.

Haemodynamic variables are prognostic factors in pulmonary arterial hypertension (PAH). However, right heart catheterization (RHC) is not systematically recommended to assess the risk-status during follow-up. This study aimed to assess the added value of haemodynamic variables in prevalent patients to predict the risk of death or lung transplantation according to their risk status assessed by the non-invasive 4 strata model as recommended by the European guidelines. We evaluated incident patients with PAH enrolled in the French PAH Registry between 2009 and 2020 who had a first follow-up RHC. Cox regression identified, in each follow-up risk status, haemodynamic variables significantly associated with transplant-free survival (TFS). Optimal thresholds were determined by time-dependent Receiver-Operating Characteristics. Several multivariable Cox regression models were performed to identify the haemodynamic variables improving the non-invasive risk stratification model. We analysed 1240 incident patients reassessed within a year by RHC. None of haemodynamic variable were significantly associated with TFS among low-risk (n=386) or high-risk (n=71) patients. Among patients at intermediate (-low, n=483, -high, n=300) risk at first follow-up, multivariable models including either stroke volume index (SVi) or mixed venous oxygen saturation (SvO2) were the best. The prognostic performance of refined 6 strata risk stratification model including the non-invasive 4 strata model and SVi>37 mL·m-2 and/or SvO2>65% for patients at intermediate-risk (Area Under the Curve 0.81, c-index 0.74), was better than that of 4 strata model (0.79, p=0.009; c-index 0.72). Cardiopulmonary haemodynamics may improve risk stratification at follow-up in patients at intermediate-risk.

Risk Factors for Pulmonary Arterial Hypertension in Patients With Systemic Lupus Erythematosus: A Systematic Review and Expert Consensus.

This study aimed to identify risk factors associated with the development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE). We conducted a systematic literature review of studies focusing on adult patients classified as having SLE-related PAH by searching the electronic databases Embase, Medline, Medline in-progress, Wanfang, China National Knowledge Infrastructure, Ichushi Web, Kmbase, and KoreaMed. Based on the findings, we conducted a Delphi survey to build expert consensus on issues related to screening for PAH in patients with SLE and on the importance and feasibility of measuring the identified factors in clinical practice. We included 21 eligible studies for data synthesis. Sixteen factors were associated with an increased risk of SLE-PAH: pericardial effusion, serositis, longer duration of SLE, arthritis, acute and subacute cutaneous lupus, scleroderma pattern on nailfold capillaroscopy, diffusion capacity of carbon monoxide in the lungs (DLCO) <70% predicted, interstitial lung disease, thrombocytopenia, and seven serological factors. Six factors were associated with a decreased risk of SLE-PAH: malar/acute rash, hematologic disorder, renal disorder, higher Systemic Lupus Erythematosus Disease Activity Index score, and two serological factors. Among these, there were six risk factors on which the panelists reached strong or general consensus (peak tricuspid regurgitation velocity on echocardiography >2.8 m/s, pericardial effusion, DLCO <70% predicted, scleroderma pattern on nailfold capillaroscopy, brain natriuretic peptide >50 ng/l, and N-terminal pro-brain natriuretic peptide >300 ng/l). The Delphi panel confirmed the need for a screening tool to identify patients with SLE at high risk of developing PAH and provided consensus on the importance and/or practicality of measuring the identified factors. The risk factors we identified could be used in a screening algorithm to identify patients with SLE with a high risk of developing PAH to facilitate early diagnosis, which could improve prognosis and management of these patients.

CT-derived lung vessel morphology correlates with prognostic markers in precapillary pulmonary hypertension

While computed tomography pulmonary angiography (CTPA) is an integral part of the work-up in patients with suspected pulmonary hypertension (PH), there is no established CTPA-derived prognostic marker. We aimed to assess whether quantitative readouts of lung vessel morphology correlate with established prognostic indicators in PH. We applied a fully-automatic in-house developed algorithm for segmentation of arteries and veins to determine lung vessel morphology in patients with precapillary PH who underwent right heart catheterization and CTPA between May 2016 and May 2019. Primary endpoint of this retrospective study was the calculation of receiver operating characteristics for identifying low and high mortality risk according to the 3-strata risk assessment model presented in the current guidelines. We analyzed 73 patients, median age 65years (interquartile range (IQR): 54-76), female/male ratio 35/38, median mean pulmonary arterial pressure 37mm Hg (IQR: 30-46), and found significant correlations with important prognostic factors in pulmonary arterial hypertension. N-terminal pro-brain natriuretic peptide, cardiac index, mixed venous oxygen saturation, and 6-minute walking distance were correlated with the ratio of the number of arteries over veins with vessel diameters of 6-10mm (Spearman correlation coefficients ρ=0.64, p<0.001; ρ=-0.60, p<0.001; ρ=-0.47, p=0.005; ρ=-0.45, p=0.001, respectively). This ratio predicted a low- and high-risk score with an area under the curve of 0.73 (95% confidence interval (CI): 0.56-0.90) and 0.86 (95% CI: 0.74-0.97), respectively. The ratio of the number of arteries over veins with diameters between 6 and 10mm is significantly correlated with prognostic markers in pulmonary hypertension and predicts low and high mortality risk.

Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions invitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice invivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.

Polychlorinated Biphenyls and Pulmonary Hypertension.

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that were banned because of their potential carcinogenicity. Population studies have shown that PCBs are associated with lung toxicity and hypertension. The objective of this study was to evaluate whether higher exposure to PCB congeners is associated with the risk of pulmonary hypertension. Serum levels of PCBs in 284 subjects with combined risk factors for pulmonary arterial hypertension (PAH) were compared to 4210 subjects with no risk for PAH using the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. The major findings from this study include significantly higher PCB levels in PAH subjects compared to non-PAH subjects; for example, the geometric mean (GM) of PCB74 was 15.91 (ng/g) (14.45–17.53) vs. 11.48 (ng/g) (10.84–12.16), respectively. Serum levels of PCB congeners showed an increasing trend in the age group 20–59 years as PCB180 GM was 19.45 (ng/g) in PAH vs. 12.75 (ng/g) in the control. A higher body burden of PCB153 followed by PCB138, PCB180, and PCB118 was observed. Estimated age, race, BMI, and gender-adjusted ORs for PCB congener levels in subjects with the combined risk factors for PAH compared to controls was significant; for example, PCB99 (OR: 1.5 (CI: 1.49–1.50). In summary, these findings indicate that exposure, as well as body burden estimated based on lipid adjustment of PCBs, were higher in people with risk factors for PAH, and PCB congeners accumulated with age. These findings should be interpreted with caution because of the use of cross-sectional self-reported data and a small sample size of subjects with combined risk factors for pulmonary arterial hypertension. Nonetheless, our finding emphasizes a need for a comprehensive environmental molecular epidemiologic study to determine the potential role of environmental exposures to PCBs in the development of pulmonary arterial hypertension.

Hispanic Ethnicity and Social Determinants of Health: Harnessing Data from The Pulmonary Hypertension Association Registry

Pulmonary arterial hypertension (PAH) is a chronic, progressive, and debilitating disease associated with increased cardiopulmonary morbidity and mortality. Current knowledge is derived from registries and landmark clinical trials, although concern exists that minorities are underrepresented in these datasets, and it remains unknown if there are intrinsic differences in minorities and disadvantaged groups. The Pulmonary Hypertension Association Registry offers a unique opportunity for the understanding of the unique social background of minorities in the United States because it routinely collects information related to socioeconomic factors such as annual income and health care insurance. Furthermore, representation of Hispanic patients may be slightly higher than in other US-based registries. In this review, we discuss the interplay between biologic, socioeconomic, and racial or ethnic factors in PAH, with special emphasis on the Hispanic population. We describe the unique socioeconomic profile of Hispanic individuals and propose next steps to improve representation and fight inequality for Hispanic patients with PAH.

Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension.

Rationale: NT-proBNP (N-terminal pro-brain natriuretic peptide), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH. Objectives: Identify prognostic proteins in PAH that complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan version 4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable, or drug-induced PAH from the UK National Cohort of PAH (n = 357) and the French EFORT (Evaluation of Prognostic Factors and Therapeutic Targets in PAH) study (n = 79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute-walk distance and NT-proBNP entered least absolute shrinkage and selection operator modeling, and the best combination in a single score was evaluated against clinical targets in EFORT. Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-minute-walk distance in the UK cohort. A weighted combination score of six proteins was validated at baseline (5-yr mortality; area under the curve [AUC], 0.73; 95% confidence interval [CI], 0.63-0.85) and follow-up in EFORT (AUC, 0.84; 95% CI, 0.75-0.94; P = 9.96 × 10-6). The protein score risk stratified patients independent of established clinical targets and risk equations. The addition of the six-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC 0.762 (0.702-0.821) to 0.818 (0.767-0.869) by receiver operating characteristic analysis (P = 0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response.

Abstract 10231: Parp1-Pkm2 Axis Mediates Right Ventricular Failure Associated with Pulmonary Arterial Hypertension

Introduction: Right ventricular (RV) function is the poor prognosis factor in pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative DNA damage, and glycolysis are key triggering pathways that induce cardiomyocytes (CM) dysfunction. Oxidative DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and inflammation through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite PARP1/PKM2 axis is involved in many pathologies, their role in RV failure (RVF) remains unclear. We hypothesized that sustained PARP1 activation induces nuclear PKM2 localization, cardiac inflammation, and myocytes apoptosis resulting in transition from compensated (cRV) to decompensated RV (dRV). Methods and Results: We found that PARP1/PKM2 expression/activity (IF, WB) is upregulated in dRV patients (died of RVF, n=11) compared to cRV patients (CI&gt;2.2, n=12) and control donors (n=19). Similar findings were seen in two rat models of RVF (monocrotaline, PA banding). In vitro , we confirmed that oxidative DNA damage (ET-1+H 2 O 2 ) as well as inflammatory stress (ET-1+LPS) induced nuclear expression of PARP1/PKM2 (IF, WB) leading to inflammation (NF-κB nuclear translocation) and CM death (TUNEL). These effects were prevented by treatment with PARP1 inhibitor (ABT-888, Olaparib) or enforced cytosolic retention of PKM2 (TEPP-46, DASA-58). Cardiomyocytes isolated from neonatal Parp1 deficient mice were resistant to myocyte dysfunction (PKM2 nuclear upregulation, NF-κB nuclear translocation, TUNEL) induced by oxidative DNA damage (ET-1+H 2 O 2 ). In vivo , Olaparib (10mg/kg) as well as TEPP-46 (25mg/kg) prevented RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) induced by PAB in rats (n=8~12 per group). Moreover, we confirmed that global Parp1 loss-of-function confers protection against PAB induced-RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis, n=10 per group). (All p&lt;0.05) Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical signal pathway RV decompensation. Targeting PARP1/PKM2 axis may represent a promising avenue for tackling maladaptive RV remodeling and pulmonary circulation, simultaneously.

Liver fibrosis index as a novel prognostic factor in patients with pulmonary arterial hypertension.

Liver dysfunction is an important determinant of the prognosis of left heart failure patients. However, few studies have reported on cardiohepatic interactions in right heart failure patients, a condition that is an important prognostic factor in pulmonary arterial hypertension (PAH). This study aimed to evaluate the existence and extent of hepatic fibrosis and its contribution as a prognostic factor in PAH. This prospective study enrolled 60 consecutive patients with PAH in the International University of Health and Welfare Mita Hospital from June 2016 to December 2017. After the application of the exclusion criteria, 35 patients were assessed for hepatic fibrosis, using real-time tissue elastography, and for clinical deterioration. Sixteen healthy controls were also assessed for comparison. The liver fibrosis index (LFI) was significantly higher in PAH patients than in healthy controls (1.214 ± 0.047 vs. 0.911 ± 0.059, P < 0.001), suggesting that PAH patients exhibited mild liver fibrosis. However, patients with deterioration (vs. no deterioration) had significantly higher LFI values (1.507 ± 0.078 vs. 1.080 ± 0.034, P < 0.001), independent from other established liver function parameters. A receiver operating characteristic curve analysis identified that an LFI ≥ 1.275 indicated a significant probability of clinical deterioration (hazard ratio: 8.4 (95% CI 1.5-45.4, P = 0.012), independent from other known PAH prognostic factors. PAH patients may exhibit subclinical liver fibrosis associated with chronic right heart failure. The LFI can serve as both a non-invasive evaluation of liver fibrosis and a predictive marker for the deterioration of PAH patients.

Role of Krüppel-like factors in pulmonary arterial hypertension.

Pulmonary arterial hypertension is a rare but deadly disease with a complex pathogenesis. Recent evidence demonstrates that Krüppel-like factors, a diverse family of transcription factors, are involved in several key disease processes such as the phenotypic transition of endothelial cells and smooth muscle cells. Importantly, manipulation of certain Krüppel-like factors enables protection or attenuation against pulmonary arterial hypertension in both animal models and preliminary human studies. In this review, we discuss how Krüppel-like factors, in particular Krüppel-like factors 2, 4 and 5 contribute to the pathological phenomena seen in pulmonary arterial hypertension and how associated signaling and microRNA pathways may be suitable targets for new therapies.

Risk factors of pulmonary arterial hypertension in patients with systemic lupus erythematosus.

Pulmonary arterial hypertension symptoms in systemic lupus erythematosus patients are non-specific and early diagnosis and intervention are challenging. It remains essential to explore risk factors for pulmonary arterial hypertension in systemic lupus erythematosus patients to identify high risk patients and allow intensive monitoring. From January 2010 to December 2018, 84 patients with systemic lupus erythematosus and pulmonary arterial hypertension and 160 patients with systemic lupus erythematosus but without pulmonary arterial hypertension were enrolled. Clinical manifestations and laboratory test results were compared between the two groups to identify predictors of pulmonary arterial hypertension. Candidate pulmonary arterial hypertension risk factors were further compared among systemic lupus erythematosus-pulmonary arterial hypertension patients with different characteristics. Among collected patient characteristics, Raynaud's phenomenon (OR 2.32, 95% CI: 1.17-4.61), digital vasculitis (OR 4.12, 95% CI: 1.48-11.49), pericardial effusion, pulmonary interstitial lesions, positive anti-u1 ribonucleoprotein antibodies, and positive anticardiolipin antibodies immunoglobulin G were associated with significantly higher risk of pulmonary arterial hypertension in systemic lupus erythematosus patients. Among these candidate risk factors, positive anti-u1 ribonucleoprotein antibody was independently associated with severe pulmonary arterial hypertension and more active disease. Digital vasculitis was independently associated with systemic lupus erythematosus alleviation, while pericardial effusion was associated with systemic lupus erythematosus deterioration. Pericardial effusion was associated with longer pulmonary arterial hypertension duration. The significant association between studied clinical and laboratory indicators and risk of pulmonary arterial hypertension, pulmonary arterial hypertension and systemic lupus erythematosus characteristics suggested that these factors can be used to identify patients at higher risk of pulmonary arterial hypertension and adverse outcomes. Close monitoring may be indicated in patients with these risk factors, especially with more than one risk factor.

Roles of growth factors on vascular remodeling in pulmonary hypertension

Pulmonary hypertension (PH) is defined as mean pulmonary arterial pressure at rest ≥25 mmHg. Pulmonary arterial hypertension (PAH) is classified as group 1 of PH and is a progressive and fatal disease of the pulmonary artery. The pathogenesis is sustained pulmonary vasoconstriction and pulmonary vascular remodeling, which cause progressive elevations in pulmonary vascular resistance and pulmonary arterial pressure. Elevated pulmonary arterial pressure leads to right heart failure and finally death. The pulmonary vascular remodeling is triggered by an increase in cytosolic Ca2+ concentration ([Ca2+]cyt). [Ca2+]cyt is regulated by the stimulation of vasoconstrictors and growth factors though their receptors and ion channels on the plasma membrane. It has been reported that the epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are involved in the development of PAH. Upon binding of these growth factors with their specific receptor tyrosine kinases, their receptors activate cytosolic Ca2+ signaling and signal transduction cascades to induce cell proliferation, differentiation, and migration. Expressions of some growth factors and their receptors upregulate in PAH patients, which contributes to the formation of vascular remodeling and plexiform lesions in PAH. We have recently found that enhanced Ca2+-sensing receptor (CaSR) function is involved the development of PAH and CaSR expression is upregulated by PDGF in pulmonary arterial smooth muscle cells (PASMCs) from idiopathic PAH patients. This review will be discussed the physiological and pathological roles of growth factors in PAH.

Abstract 15826: SCUBE1 Controls BMPR2-relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a morbid vascular disease where mutations of bone morphogenetic protein receptor 2 (BMPR2) control pulmonary endothelial pathophenotypes. Transcriptomic screening from endothelial cells (ECs) derived from hereditary BMPR2-driven disease offers an opportunity to identify novel effectors in PAH pathogenesis. Methods: Public RNA-sequencing data were analyzed from inducible pluripotent stem (iPS) cell-derived endothelial cells with and without BMPR2 mutations. Candidate genes were assessed in cultured pulmonary arterial ECs (PAECs) and in rodent and human PAH. Correlations were assessed of human plasma expression with clinical disease indices. Results: Signal Peptide CUB-EGF-Domain Containing Protein 1 (SCUBE1), a putative binding partner to BMPR2, was differentially expressed in ECs carrying BMPR2 mutations. SCUBE1 was enriched in PAECs, dependent on hypoxia inducible factor-1α, and downregulated by PAH triggers, including BMPR2 knockdown, hypoxia, and IL-1β exposure. In vitro analyses defined SCUBE1 as a pathogenic effector activating BMPR2-associated SMAD1/5/9, thus regulating endothelial angiogenic potential, proliferation, and apoptosis. SCUBE1 was decreased specifically in plasma and lungs in rodents and patients with PAH but not in those with pulmonary hypertension due to left heart disease, or in the patients of other acute and chronic cardiopulmonary pathologies, including pneumonia, acute lung injury, chronic obstructive pulmonary disease, ischemic heart disease, and cardiomyopathy. An optimal plasma SCUBE1 cut point of 5.02 ng/mL was defined to diagnose PAH from control cohort with a sensitivity of 0.65 and a specificity of 0.82. In PAH patients, plasma SCUBE1 levels negatively correlated with pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular dysfunction. Conclusions: Guided by iPSC-EC sequencing, SCUBE1 was identified as a downregulated secreted factor in PAH, controlling endothelial pathophenotypes and correlated with disease indices. Clinically, SCUBE1 is a sensitive and specific PAH diagnostic marker. It may also serve as a therapeutic target given its inherent links to controlling PAH predisposition and severity.

β-arrestin1 inhibits hypoxic injury-induced autophagy in human pulmonary artery endothelial cells via the Akt/mTOR signaling pathway.

Autophagy has been greatly implicated in injured endothelial cells during pulmonary arterial hypertension (PAH). β-arrestin1, a multifunctional cytoplasmic protein, has attracted considerable attention as an essential protective factor in PAH. However, its role in autophagy of injured pulmonary arterial endothelial cells (PAECs) remains to be determined. Here, we investigated the potential effects of β-arrestin1 on autophagy and apoptosis in human PAECs (hPAECs) under hypoxic stress. Hypoxic stimuli increases autophagy and decreases the level of β-arrestin1 in hPAECs. Furthermore, pathologic changes, namely increased proliferation, migration, and apoptosis resistance, are observed after hypoxia exposure. These are reversed after β-arrestin1 overexpression (β-arrestin1-OV) or treatment with 3-MA, an autophagy inhibitor. Finally, β-arrestin1 suppresses the increase in autophagy and apoptosis resistance of hypoxic hPAECs. Mechanistically, β-arrestin1 upregulates the activity of the Akt/mTOR signaling pathway and downregulates the expression of BNIP3 and Nix after hypoxic stress. Collectively, we have demonstrated, for the first time, that β-arrestin1 reduces excessive autophagy and apoptosis resistance by activating the Akt/mTOR axis in hypoxic hPAECs. This knowledge suggests a promising therapeutic target for PAH.

Growth factors in pulmonary arterial hypertension: Focus on preserving right ventricular function

Pulmonary arterial hypertension (PAH) is a rare and progressive disease, characterized by increased vascular resistance leading to right ventricle (RV) failure. The extent of right ventricular dysfunction crucially influences disease prognosis; however, currently no therapies have specific cardioprotective effects. Besides discussing the pathophysiology of right ventricular adaptation in PAH, this review focuses on the roles of growth factors (GFs) in disease pathomechanism. We also summarize the involvement of GFs in the preservation of cardiomyocyte function, to evaluate their potential as cardioprotective biomarkers and novel therapeutic targets in PAH.

Relationship between compliance and pulmonary vascular resistance in pulmonary arterial hypertension.

BackgroundPulmonary arterial compliance (PAC) was previously shown to be an important prognostic factor in pulmonary arterial hypertension (PAH), in addition to the conventional pulmonary vascular resistance (PVR). The product of PAC and PVR, the arterial time (RC) constant, expresses the logarithmic relationship between the hemodynamic parameters. The objective of the study was to test RC constant stability in PAH patients followed beyond 12 months after diagnosis, and to report possible RC variations in different etiologies.MethodsFourteen PAH patients followed between 2008 and 2019 were included. Type 1 PAH was defined as a mean pulmonary artery pressure (PAP) ≥25 mmHg at rest and PVR ≥3 Wood units (WU). All patients who fulfilled WHO group I PAH criteria and had undergone two right heart catheterizations at least 1 year apart were included. The recorded hemodynamic data for each patient were used to compute PVR and PAC.ResultsPAH etiologies included scleroderma (n=2), liver cirrhosis (n=1), hereditary hemorrhagic telangiectasia (HHT) (n=1), mixed connective tissue disease (MCTD) (n=3), and idiopathic (n=7). The RC constant remained stable for all 14 patients over a follow-up period of 3.9±2 years. Patients with MCTD displayed more favorable hemodynamics, evidenced by higher RC (12.54 vs. 10.01, P<0.01) and PAC values (2.59 vs. 1.62, P=0.02), when compared with non-MCTD PAH patients. For the entire cohort the mean PAP measured 51±14 mmHg at baseline, and 46±13 mmHg at follow-up, respectively.ConclusionsThe relationship between PAC and PVR remains stable in follow-up periods averaging 4 years, making compliance an important disease marker past the early stages. Patients with MCTD displayed more advantageous hemodynamic profiles when compared with patients with other PAH etiologies.

Drug- and toxin-induced pulmonary arterial hypertension: Current state of the literature

Drug- and toxin-induced pulmonary arterial hypertension (PAH) is an increasingly important sub-group of group 1 pulmonary hypertension (PH). In the last 60 years, we have seen the rise and fall of numerous prescription and illicit agents that have caused severe and deadly outbreaks of PAH. Currently, drugs and toxins are classified into “possible” and “definite” risk factors for PAH. While the exact mechanisms and pathogenesis of drug- and toxin-induced PAH are currently unknown, novel clinical and basic science studies are beginning to unravel the biologic factors and genetic underpinnings responsible for disease development. The clinical management of affected patients can be challenging as it is often difficult to identify patients early and demonstrate causality between drugs and PAH. Given the recent trends in drug utilization and development, it is highly likely that we will continue to identify new agents capable of causing pulmonary vascular disease. We must keep a high index of suspicion in order to identify patients and new compounds deemed definite or likely risk factors for PAH. Practicing pharmacovigilance, raising awareness, and working in tandem with PH patient associations and drug regulatory agencies may ultimately be our most effective strategy in preventing the next deadly outbreak of drug- and toxin-induced PAH.

Sex hormone exposure and reproductive factors in pulmonary arterial hypertension: a case-control study.

Pulmonary arterial hypertension (PAH) is a sexually dimorphic disease that for unknown reasons affects women more than men. The role of estrogens, both endogenous and exogenous, and reproductive factors in this female susceptibility is still poorly understood. It has been strongly suggested that sex hormones may influence the development and progression of the disease. We sought to determine whether sex hormone exposures and reproductive factors associate with PAH patients compared to control subjects, using a questionnaire and interview to obtain information regarding these potential risk factors. We conducted a single-center unmatched case–control study. Six hundred and thirty-four women and men with PAH, as well as 27 subjects with BMPR2 mutations but no PAH and 132 healthy population controls were enrolled from the Vanderbilt Pulmonary Hypertension Research Cohort and researchmatch.org. Questionnaires and nurse-led interviews were conducted to obtain information regarding sex hormone exposures and reproductive factors. Additional history was obtained on enrolled patients including disease severity variables and comorbidities. Responses to the questionnaires were analyzed to describe these exposures in this population as well as assess the association between disease severity variables and sex hormone exposures. Reproductive and endogenous factors that determine lifelong estrogen exposure were similar between PAH cases and controls. Patients with associated PAH were significantly more likely to be postmenopausal compared to controls. There were similar rates of “ever-use” and duration of use of oral contraceptive pills and hormone replacement therapy in patients when compared to controls. Disease severity variables were not significantly affected by any exposure after adjusting for PAH sub-group. In contrast to our hypothesis, that a greater exposure to exogenous sources of female sex hormones associates with PAH case status, we found similar rates of endogenous and exogenous sex hormone exposure between PAH patients and unmatched controls.

ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure: A Possible Novel Therapeutic Target.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling. Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure. We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTSΔSM22). Hypoxia-induced PH was attenuated in ADAMTSΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTSΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8ΔαMHC). ADAMTS8ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models. These results indicate that ADAMTS8 is a novel therapeutic target in PAH.

Characteristics and risk factors for pulmonary arterial hypertension associated with primary Sjögren's syndrome: 15 new cases from a single center.

This study aimed to retrospectively describe 15 new primary Sjögren's syndrome-pulmonary arterial hypertension (pSS-PAH) cases confirmed by right heart catheterization (RHC). Demographic and clinical characteristics were analyzed and risk factors for PAH in pSS were explored. We retrospectively described 15 new pSS-PAH cases confirmed by RHC referred to our institution between January 2013 and March 2018. We present PAH and pSS characteristics, hemodynamic evaluations, medical management, and outcomes. A matched case control study was carried out to determine the risk factors of PAH in pSS compared with pSS-non-PAH patients. All patients were female with a mean age at PAH diagnosis of 52.9±14.6years. The delay between the first symptom and PAH diagnosis was 18.7±19.7months. The most common primary manifestation at PAH onset was exertional dyspnea (13/15). At diagnosis of PAH, PAH was severe with a mean pulmonary artery pressure of 48.8±13.7mmHg (range, 27-72mmHg) and a mean cardiac index of 2.3±0.6L/min/m2 (range, 1.47-3.41L/min/m2 ). Compared with the pSS-PAH without pericardial effusion, pSS-PAH with pericardial effusion had larger right arterial (53 [45-56.75] vs 38 [35.5-46.5], P=.018) and right ventricular sizes (47 [42.75-51.25] vs 36 [32.5-41], P=.007). Compared with the pSS non-PAH group, we identified 2 risk factors for PAH in pSS: pericardial effusion (odds ratio [OR] [95% CI], 14.29 [1.14-166.67], P=.039) and liver involvement (OR [95% CI], 14.71 [1.14-166.67], P=.035). For pSS patients, PAH can be the first manifestation. We believe that systemic evaluation, especially in patients with pericardial effusion and liver involvement, is important to identify high-risk patients for PAH, improving their prognosis.