Detection Of Pulmonary Arterial Hypertension Research Articles

Comparison of CT-Determined Pulmonary Artery Diameter among Smokers and Non-smokers: A Cross-sectional Study

Introduction: Tobacco smoking is a common addiction in our society. The toxic chemical compounds present in tobacco smoke cause epithelial damage and inflammation of the airways. Chronic smoking results in the thickening of the pulmonary arterial wall and vasoconstriction, leading to the development of pulmonary arterial hypertension. Hence, measurement of pulmonary artery diameter using Contrast Enhanced Computed Tomography (CECT) may be helpful in the early detection of pulmonary arterial hypertension. Aim: To compare the diameters of the Main Pulmonary Artery (MPA), Right Pulmonary Artery (RPA), and Left Pulmonary Artery (LPA) using CECT thorax in smokers and non-smokers. Materials and Methods: A cross-sectional study was conducted from April 2021 to March 2022 in the department of radiodiagnosis, KS Hegde Hospital, Karnataka, India, consisting of 100 patients referred for CECT thorax in the age group of 18-85 years. They were divided into two groups: smokers and non-smokers, with 50 patients in each group. They were further categorised into three age groups: < 50 years, 50-60 years, and >60 years. The widest diameters of the MPA were measured at the level of bifurcation of the artery and perpendicular to the long axis of the artery. At this level, RPA and LPA diameters were measured at the widest portion on 1.25 mm axial images of the arterial phase. Variation in the pulmonary artery diameter was compared between smokers and non-smokers with respect to age and analysed by unpaired t-test and Pearson correlation. Results: Diameters of MPA, RPA, and LPA were statistically significant (p<0.05) in smokers compared to non-smokers. In smokers, MPA and RPA diameters correlated with age, which was statistically significant (p<0.05). No significant correlation (p>0.05) was shown between age and MPA, RPA, and LPA diameter in non-smokers. The mean MPA diameter showed a significant difference (p<0.05) in all three age groups. Conclusion: The diameter of the pulmonary artery is statistically significant in smokers compared to non-smokers. Hence, assessment of pulmonary artery diameters among smokers using CECT thorax will help to diagnose Pulmonary Hypertension (PH) at an early stage.

The Early Detection of Pulmonary Hypertension.

Up to 1% of the world population and 10% of all persons over age 65 suffer from pulmonary hypertension (PH). The latency from the first symptom to the diagnosis is more than one year on average, and more than three years in 20% of patients. 40% seek help from more than four different physicians until their condition is finally diagnosed. This review is based on publications retrieved by a selective literature search on pulmonary hypertension. The most common causes of pulmonary hypertension are left heart diseases and lung diseases. Its cardinal symptom is exertional dyspnea that worsens as the disease progresses. Additional symptoms of right heart failure are seen in advanced stages. Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, difficult to diagnose, and of particular clinical relevance because specific treatments are available. For this reason, strategies for the early detection of PAH and CTEPH have been developed. The clinical suspicion of PH arises in a patient who has nonspecific symptoms, electrocardiographic changes, and an abnormal (NT-pro-)BNP concentration. Once the suspicion of PH has been confirmed by echocardiography and, if necessary, differential-diagnostic evaluation with a cardiopulmonary stress test, and after the exclusion of a primary left heart disease or lung disease, the patient should be referred to a PH center for further diagnostic assessment, classification, and treatment. If both the (NT-pro-)BNP and the ECG are normal, PH is unlikely. Knowledge of the characteristic clinical manifestations and test results of PH is needed so that patients can be properly selected for referral to specialists and experts in PH.

Timely PAH Identification in Adults With Repaired Congenital Heart Disease? The ACHD-QuERI Registry Insights

BackgroundThe Quality Enhancement Research Initiative (QuERI) in adults with congenital heart disease (ACHD) was developed to improve detection of pulmonary arterial hypertension (PAH) after repair of systemic-to-pulmonary arterial shunt lesions. ObjectivesThis study sought to standardize use of accepted criteria for PAH diagnosis and evaluate utility in at-risk patients with ACHD. MethodsPatients ≥18 years of age with ACHD repaired ≥1 year before enrollment and with additional risk factors for developing PAH were eligible. History, physical examination, electrocardiogram, transthoracic echocardiogram, World Health Organization functional class, and 6-minute walk distance were evaluated at baseline and yearly for 3 years. Pop-up reminders of patient-specific evidence-based recommendations for PAH detection appeared during data entry. ResultsAmong 217 eligible patients, mean age (enrollment) was 44.0 ± 15.9 years, 72.3% were women, and 82.0% were World Health Organization functional class I. Electrocardiogram was performed in >80% and TTE in >70% of patients annually; capture of required transthoracic echocardiography (TTE) measures and alignment between study- and core-center interpretation improved over time, with more frequent assessment of pulmonary arterial flow acceleration time and documentation of right ventricular outflow tract Doppler notching. Approximately 40% of patients had ≥2 high-risk features for PAH on TTE, but only 7% (6/82) underwent right heart catheterization (RHC). Using current definitions, 2 patients were confirmed by RHC to have a diagnosis of PAH (maximum follow-up 3 years). ConclusionsA structured protocol may improve screening for patients with repaired ACHD at risk of developing PAH. RHC may be underutilized in patients with ACHD with TTE findings suggestive of PAH. (Adult Congenital Heart Disease Registry [QuERI]; NCT01659411)

Irregularities of Coagulation in Hypertension.

This review article summarizes the role of coagulation in the pathogenesis of hypertension. It specifically focuses on significant factors and markers associated with coagulation, including D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, β-thromboglobulin, and Stuart-Prower factor. D-dimer levels were elevated in hypertensive individuals compared to healthy controls, and the levels increased with the severity of hypertension. These findings indicate that increased coagulation activity of fibrin plays a role in the development of thromboembolic complications in hypertensive patients. Additionally, both fibrinogen levels and D-dimer levels displayed a positive correlation with the duration of hypertension, suggesting that these biomarkers were positively associated with the length of time an individual had been hypertensive. Increased systolic and diastolic blood pressures have been linked to higher levels of prothrombin time and activated partial thromboplastin time in individuals with hypertension as well as those with normal blood pressure. Also, the presence of P-selectin, produced by activated platelets and endothelial cells during angiotensin II stimulation, played a role in the development of cardiac inflammation and fibrosis associated with hypertension. Moreover, the change in systolic blood pressure was associated with baseline soluble urokinase plasminogen activator receptor (suPAR) in hypertensive participants, and the change in suPAR levels was associated with the development of hypertension. Moreover, it was observed a decrease in thrombomodulin expression in the placenta of preeclamptic patients, suggesting its potential involvement in placental dysfunction, possibly driven by an imbalance in angiogenic factors. Tissue factors and autophagy might have significant implications in the pathogenesis of chronic thromboembolic pulmonary hypertension, particularly in the context of vascular remodelling. Likewise, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) might be a promising biomarker for the early detection of pulmonary arterial hypertension and the von Willebrand factor is a candidate prognostic biomarker. The arterial β-thromboglobulin levels were significantly lower than venous levels. This article concludes that D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, and β-thromboglobulin are important factors involved in the pathogenesis of hypertension.

2023 Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) Joint Consensus on Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.

729 BIOMARKERS FOR EARLY DIAGNOSIS OF CARDIAC INVOLVEMENT IN SYSTEMIC SCLEROSIS

Abstract Introduction Systemic Sclerosis (SSc) is an autoimmune disease characterized by microvascular damage, immune system dysregulation and fibrosis of skin and internal organs. It is reported that asymptomatic involvement of the heart was found in 70% of SSc patients. The role of biomarkers in the early detection of fibrosis and vascular damage in SSc is not yet completely defined. Serum levels of sST2, Galectin 3, ANP, IL6 are a potential marker of cardiac involvement. In patients with chronic heart failure elevated levels of galectin-3 (>17.8 ng/ml) are a marker of worse prognosis. Moreover, a previous study reported a possible role of galectin-3 as an independent predictor of all-cause and cardiovascular mortality in SSc. Material and Methods We enrolled 62 SSc patients (53 females, median age 52 years) who fulfilled inclusion criteria. 35 patients had limited cutaneous SSc and 27 diffuse cutaneous SSc. 30 Healthy Controls (HC) were also enrolled [20 females; median age 50 years]. All SSc patients had normal echocardiographic and cardiac MRI findings. Results In SSc patients, the median Galectin value was 16.7 ng/ml, significantly higher than HC median (10,7 ng/Ml). sST2 and IL-6 median value was 30 ng/mL and 12,3 pg/mL respectively, which resulted significantly higher than the median value of HC patient (21,55 ng/mL and 4,5 pg/mL respectively). Therefore, there was a significant difference in biomarkers levels in the SSc group compared with controls. Conclusion These data suggest that these biomarkers can help identify a subgroup of SSc patients, with normal echocardiographic and RMN findings, who are at risk of developing heart involvement. In fact, all patients are scheduled for yearly echocardiographic re-evaluation as ESC guidelines recommend for earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc).

Detection of pulmonary arterial hypertension associated with congenital heart disease based on time–frequency domain and deep learning features

The heart sounds reflect the health of the heart. Its recording is the phonocardiogram (PCG). Pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) is a serious heart disease and is often associated with severe disability and death. The disease is not well characterized onset. The most patients are severe when they have been diagnosed and miss the best time to treat them. The objective of this study was to develop a computer aided diagnosis, which based on single cycle with multiple features, for detecting pulmonary arterial hypertension associated with congenital heart disease. It is a non-invasive and simple method which may be hopeful at early diagnosis of CHD-PAH. The original heart sounds were pre- processed first, in which a double-threshold adaptive segmentation method was used to segment the signal into each cardiac cycle first. Then the time–frequency domain features and wavelet packet energy features of cardiac cycle and S2 component are extracted. And convolutional neural network (CNN) is used to extract the depth features of cardiac cycle. The above features were combined into a fused feature vector. Normal, CHD and CHD-PAH were classified using XGBoost as the classifier. Finally, the majority voting algorithm is used to obtain the best classification result for multiple results corresponding to multiple cardiac cycles of the same person. Using this new method, a classification accuracy of 88.61% was achieved.

Scientific substantiation of the concept of pharmacoeconomic analysis of technologies for early diagnosis and pharmacotherapy of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery) for no apparent reason.
 Because symptoms are nonspecific and physical signs may be subtle, the disease is often diagnosed at late stages. Over the past few decades, significant progress has been made in the field of pulmonary arterial hypertension. Technological progress allows to diagnose the disease in the early stages, as well as to better assess the severity of the disease.
 Today, screening studies are becoming increasingly important to establish a clinical diagnosis and minimize lost opportunities without timely diagnosis, especially in patients with idiopathic PAH.
 Therefore, the issue of early diagnosis of patients with suspected PAH and confirmation of the diagnosis is a very important and urgent issue today.
 The objective of the paper: to study the methods of implementation of technologies for early diagnosis and pharmacotherapy of pulmonary arterial hypertension and conceptual presentation of the results of their implementation.
 The work used available scientific sources of information on the results of the implementation of diagnostic screening for early detection of PAH and pharmacotherapy in the world. The analysis of input data was carried out using systematic, documentary, informational and graphical research methods.
 The result of the analysis of information materials showed that over the past two decades, significant progress has been made in the treatment of PAH and more than doubled the survival rate of patients.
 It has been found that diagnostic screening is a relatively unique medical technology in relation to other medical interventions and can be defined as the systematic use of diagnostic technologies in individuals at risk to detect the disease before the onset of symptoms.
 The study proposes a systematic concept of economic evaluation of the diagnostic screening program for PAH to determine its optimal design.
 At the same time, this concept embodies the complex effect of the introduction of technologies for early diagnosis and pharmacotherapy of PAH, which is expressed in the positive dynamics of clinical indicators, reduced mortality and improved quality of life.
 It should be noted that a number of new tools and approaches for diagnostic screening give hope that advances in the diagnosis of PAH will also affect the effectiveness of medical care.

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

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

Retinal vessel changes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is classically considered an isolated small vessel vasculopathy of the lungs with peripheral pulmonary vascular obliteration. Systemic manifestations of PAH are increasingly acknowledged, but data remain limited. We hypothesized that retinal vascular changes occur in PAH. PAH subjects underwent retinal fluorescein angiography (FA) and routine disease severity measures were collected from the medical record. FA studies were analyzed using VESsel GENerational Analysis (VESGEN), a noninvasive, user‐interactive computer software that assigns branching generation to large and small vessels. FAs from controls (n = 8) and PAH subjects (n = 9) were compared. The tortuosity of retinal arteries was higher in PAH subjects compared to unmatched controls (1.17, 95% confidence interval: [1.14, 1.20] in PAH vs. 1.13, 95% CI: [1.12, 1.14] in controls, p = 0.01). Venous tortuosity was higher and more variable in PAH (1.17, 95% CI: [1.14, 1.20]) compared to controls (1.13, 95% CI: [1.12, 1.15]), p = 0.02. PAH subjects without connective tissue disease had the highest degree of retinal tortuosity relative to controls (arterial, p = 0.01; venous, p = 0.03). Younger PAH subjects had greater retinal arterial tortuosity, which attenuated with age and was not observed in controls. Retinal vascular parameters correlated with some clinical measures of disease in PAH subjects. In conclusion, PAH subjects exhibit higher retinal vascular tortuosity. Retinal vascular changes may track with pulmonary vascular disease progression. Use of FA and VESGEN may facilitate early, noninvasive detection of PAH.

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

In systemic sclerosis, the TAPSE/sPAP ratio can be used in addition to the DETECT algorithm for pulmonary arterial hypertension diagnosis.

Early detection of pulmonary arterial hypertension (PAH) is crucial for improving patient outcomes. The aim of this study was to compare the positive predictive value (PPV) of the echocardiography-derived tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio with that of the DETECT algorithm for PAH screening in a cohort of SSc patients. Fifty-one SSc patients were screened for PAH using the DETECT algorithm and echocardiography. Echocardiography was recommended by the DETECT algorithm step 1 in 34 patients (66.7%). Right heart catheterization (RHC) was recommended by the DETECT algorithm step 2 in 16 patients (31.4%). PAH was confirmed by RHC in 5 patients. The DETECT algorithm PPV was 31.3%. The TAPSE/sPAP ratio was higher in SSc patients not referred for RHC than in SSc patients referred for RHC according to the DETECT algorithm step 2 [0.83 (0.35-1.40) mm/mmHg vs 0.74 (0.12-1.09) mm/mmHg, P < 0.05]. Using a cut-off of 0.60 mm/mmHg, 8 (15.7%) SSc patients had a TAPSE/sPAP ratio of ≤0.60 mm/mmHg. PAH was confirmed by RHC in 5 patients. The PPV of TAPSE/sPAP was 62.5%. In multiple regression analysis, TAPSE/sPAP was associated with age [β coefficient = -0.348 (95% CI: -0.011, -0.003); P < 0.01], DETECT algorithm step 1 [β coefficient = 1.023 (95% CI: 0.006, 0.024); P < 0.01] and DETECT algorithm step 2 (β coefficient = -1.758 [95% CI: -0.059, -0.021]; P < 0.0001). In SSc patients with a DETECT algorithm step 2 total score of >35, the TAPSE/sPAP ratio can be used to further select patients requiring RHC to confirm PAH diagnosis.

Diagnostic test accuracy of artificial intelligence analysis of cross-sectional imaging in pulmonary hypertension: a systematic literature review.

To undertake the first systematic review examining the performance of artificial intelligence (AI) applied to cross-sectional imaging for the diagnosis of acquired pulmonary arterial hypertension (PAH). Searches of Medline, Embase and Web of Science were undertaken on 1 July 2020. Original publications studying AI applied to cross-sectional imaging for the diagnosis of acquired PAH in adults were identified through two-staged double-blinded review. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies and Checklist for Artificial Intelligence in Medicine frameworks. Narrative synthesis was undertaken following Synthesis Without Meta-Analysis guidelines. This review received no funding and was registered in the International Prospective Register of Systematic Reviews (ID:CRD42020196295). Searches returned 476 citations. Three retrospective observational studies, published between 2016 and 2020, were selected for data-extraction. Two methods applied to cardiac-MRI demonstrated high diagnostic accuracy, with the best model achieving AUC=0.90 (95% CI: 0.85-0.93), 89% sensitivity and 81% specificity. Stronger results were achieved using cardiac-MRI for classification of idiopathic PAH, achieving AUC=0.97 (95% CI: 0.89-1.0), 96% sensitivity and 87% specificity. One study reporting CT-based AI demonstrated lower accuracy, with 64.6% sensitivity and 97.0% specificity. Automated methods for identifying PAH on cardiac-MRI are emerging with high diagnostic accuracy. AI applied to cross-sectional imaging may provide non-invasive support to reduce diagnostic delay in PAH. This would be helped by stronger solutions in other modalities. There is a significant shortage of research in this important area. Early detection of PAH would be supported by further research advances on the promising emerging technologies identified.

Uptake and Patient Perspectives on Additional Testing for Novel Disease-Associated Genes: Lessons from a PAH Cohort.

Background: Pulmonary arterial hypertension (PAH) has an identifiable genetic cause in 5% of all PAH cases. Due to health benefits conferred by the early detection of PAH and the recent identification of additional PAH-associated genes, we decided to offer (extended) genetic testing to all incident and prevalent idiopathic PAH (iPAH) and pulmonary veno-occlusive disease (PVOD) patients in our clinic. Here, we report the lessons learned from (re-)contacting iPAH/PVOD patients concerning the uptake and analysis of identified PAH-associated genes and patient perspectives of the approach. Methods: Between January 2018 and April 2020, all iPAH/PVOD patients who were not previously genetically tested (contact group) and those who tested negative on prior analysis of BMPR2 and SMAD9 variants (re-contact group) were (re-)contacted for (additional) genetic testing. Results: With our approach, 58% of patients (84 out of 165) opted for genetic counselling, and a pathogenic variant was found in 12% of cases (n = 10) (re-contact group, 11%, and contact group, 13%). Eighty-six percent of participants of the survey study appreciated being (re-)contacted for genetic testing. Mild psychosocial impacts were observed. Conclusions: Our report shows the importance of (re-)contact and interest of patients (as indicated by the uptake, mild psychosocial impact and appreciation) in PAH.

Low-Dose Dobutamine Stress Echocardiography for the Early Detection of Pulmonary Arterial Hypertension in Selected Patients with Systemic Sclerosis Whose Resting Echocardiography Is Non-Diagnostic for Pulmonary Hypertension.

Background: Dobutamine stress echocardiography (DSE) has limited application in systemic sclerosis (SSc). We examined DSE usefulness in revealing pulmonary arterial hypertension (PAH) in selected SSc patients whose resting echocardiography for pulmonary hypertension (PH) was non-diagnostic. Methods: Forty SSc patients underwent right heart catheterization (RHC) and, simultaneously, low-dose DSE (incremental doses up to 20 μg/kg/min). Inclusion criteria were: preserved left and right ventricular (RV) function (tricuspid annulus plane systolic excursion [TAPSE] ≥ 16 mm and tissue Doppler imaging-derived systolic velocity of tricuspid annulus [RVS’] > 10 cm/s), normal pulmonary function tests, and baseline maximal tricuspid regurgitation (TR) velocity of 2.7–3.2 m/s. Results: Of 36 patients who completed DSE, resting RHC diagnosed PAH in 12 patients (33.3%). At 20 μg/kg/min, patients with PAH had higher TR velocity, higher pulmonary arterial pressure measured by RHC, and lower RV inotropic response compared with patients without PAH. A cut-off value of maximal TR velocity >3.1 m/s had a sensitivity of 80%, a specificity of 84.2%, and an accuracy of 82.4% for the detection of PAH. Conclusions: Low-dose DSE has a satisfactory diagnostic accuracy for the early detection of PAH in highly selected SSc patients whose baseline echocardiographic measurements for PH lie in the gray zone.

Association of Lymphangiogenic Factors With Pulmonary Arterial Hypertension in Systemic Sclerosis.

Pulmonary arterial hypertension (PAH) is a major complication in systemic sclerosis (SSc), a disease marked by vascular and lymphatic vessel abnormalities. This study was undertaken to assess the role of the lymphangiogenic factors vascular endothelial growth factor C (VEGF-C) and angiopoietin 2 (Ang-2) and the soluble forms of their respective cognate receptors, soluble VEGF receptor 3 (sVEGFR-3) and soluble TIE-2, in patients with SSc, and to evaluate their predictive ability as markers for PAH development in SSc. In this cohort study, we used multiplex bead assays to assess serum levels of lymphangiogenic factors in 2 well-characterized SSc cohorts: an unselected identification cohort of SSc patients from Oslo University Hospital (n = 371), and a PAH-enriched validation cohort of SSc patients from Zurich University Hospital and Oslo University Hospital (n = 149). As controls for the identification and validation cohorts, we obtained serum samples from 100 healthy individuals and 68 healthy individuals, respectively. Patients in whom SSc-related PAH was identified by right-sided heart catheterization (RHC) in both cohorts were studied in prediction analyses. PAH was defined according to the European Society of Cardiology/European Respiratory Society 2015 guidelines for the diagnosis and treatment of PAH. Associations of serum levels of lymphangiogenic factors with the risk of PAH development were assessed in logistic regression and Cox regression analyses. Associations in Cox regression analyses were expressed as the hazard ratio (HR) with 95% confidence interval (95% CI). In the identification cohort, SSc patients had lower mean serum levels of VEGF-C and higher mean serum levels of Ang-2 compared to healthy controls (for VEGF-C, mean ± SD 2.1 ± 0.5 ng/ml in patients versus 2.5 ± 0.4 ng/ml in controls; for Ang-2, mean ± SD 6.1 ± 7.6 ng/ml in patients versus 2.8 ± 1.8 ng/ml in controls; each P < 0.001); these same trends were observed in SSc patients with PAH compared to those without PAH. The association of serum VEGF-C levels with SSc-PAH was confirmed in the PAH-enriched RHC validation cohort. For prediction analyses, we assembled all 251 cases of SSc-PAH identified by RHC from the identification and validation cohorts. In multivariable Cox regression analyses adjusted for age and sex, the mean serum levels of VEGF-C and sVEGFR-3 were predictive of PAH development in patients with SSc (for VEGF-C, HR 0.53 [95% CI 0.29-0.97], P = 0.04; for sVEGFR-3, HR 1.21 [95% CI 1.01-1.45], P = 0.042). These findings support the notion that lymphangiogenesis is deregulated during PAH development in SSc, and indicate that VEGF-C could be a promising marker for early PAH detection in patients with SSc.

Screening for the early detection of pulmonary arterial hypertension in patients with systemic sclerosis: A systematic review and meta-analysis of long-term outcomes

BackgroundSystemic sclerosis (scleroderma, SSc) is a chronic multisystem autoimmune disease characterised by fibrosis of the skin and internal organs and vasculopathy. One of the major contributors to mortality in patients with SSc is pulmonary arterial hypertension (PAH). International recommendations advise annual screening for the early detection of PAH in asymptomatic patients with SSc. ObjectivesTo evaluate by systematic review current measures employed for screening for PAH. To summarise by meta-analysis the current evidence for long-term outcomes of screening for PAH in SSc. MethodsManuscripts published until 12th March 2019 were identified through searching Medline, Embase and Cochrane Central Register of Controlled Trials and Database of Systematic Reviews. Eligible studies included abstracts or full reports investigating patients with SSc undergoing screening by any protocol to detect PAH. Risk of bias was assessed with reference to the QUADAS-2 tool. ResultsThe review resulted in 580 unique citations with 15 manuscripts included for final systematic review of screening methods, and six for meta-analysis. The systematic review demonstrated that there are varying protocols for screening for PAH. Screened populations were reported to have better risk stratification parameters at PAH diagnosis. Meta-analysis showed improved survival in patients with SSc-PAH diagnosed as a result of screening. There were trends towards having better risk stratification parameters at PAH diagnosis in those screened, although not all of these were statistically significant. LimitationsThere are no randomised controlled trials of screening for PAH in patients with SSc and the evidence presented in this review is derived from publications of registry data, cross-sectional and cohort studies. ConclusionsThis review demonstrates long-term benefit through the systematic screening of patients with SSc of varying disease duration for the early detection of PAH. Screened cohorts had improved survival, and were more likely to have better prognostic factors at the time of diagnosis with PAH.

Long-Term Outcomes in Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta-Analyses of Randomized, Controlled Trials and Observational Registries.

ObjectiveData on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)–associated PAH are limited. In this study, we performed meta‐analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD‐PAH.MethodsThe PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD‐PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long‐term risks of clinical morbidity and mortality or 6‐minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random‐effects models were used to pool the data.ResultsEleven RCTs (total of 4,329 patients; 1,267 with CTD‐PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD‐PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD‐PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD‐PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD‐PAH patients treated primarily after 2010 was higher than that in CTD‐PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years).ConclusionModern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD‐PAH when compared to the PAH population overall. Risk of death is higher in CTD‐PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up‐front intensive treatment are warranted.

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation.

BackgroundHeritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population.MethodsAsymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline.Results55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up.ConclusionsAsymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH.

Identifying early pulmonary arterial hypertension biomarkers in systemic sclerosis: machine learning on proteomics from the DETECT cohort

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.