Connective Tissue Disease-associated Pulmonary Arterial Hypertension Research Articles

Risk assessment models and survival in pulmonary arterial hypertension: a SPAHR analysis

BackgroundMulticomponent improvement (MCI) is a novel endpoint for predicting survival in patients with pulmonary arterial hypertension (PAH), included in the sotatercept clinical program. For the first time, we investigated the prognostic value of MCI, ESC/ERS 4-strata risk (4SR) assessment, and the non-invasive French risk stratification score (FRS), for predicting survival in PAH patients in Sweden. All risk prediction models are based on three parameters: WHO-FC (World Health Organization Functional Class), NT-proBNP, and 6MWD (6-minute walk distance). MethodsData from the Swedish PAH & CTEPH Registry (SPAHR) collected 2008-2021 were used for the analyses. The association of MCI achievement, 4SR, and FRS calculated at 6 months (6M), with transplant-free (TF) survival was investigated in the whole cohort, as well as categorized by age (<65 and ≥65 years). All risk prediction models are based on three parameters: WHO-FC (World Health Organization Function Class), NT-proBNP, and 6MWD (6-minute walk distance). Kaplan-Meier estimate/Log-Rank test and Cox proportional model were used for survival analyses. ResultsThe study included 411 patients (70% women) with a median [IQR] age of 66y.21 At 6M, the mean (SD) NT-proBNP decrease was 808 (603) and the mean 6MWD increase was 44 (11) meters. Median survival/follow-up time was 3.5y [1.7, 5.4]. After adjustment for sex and comorbidities, achievement of MCI independently predicted TF-survival; one MCI-criterion met (HR 0.65; CI 0.46-0.92, p=0.015); two MCI-criteria met (HR 0.45; CI 0.31-0.66, p<0.001); all three MCI-criteria met (HR 0.32; CI 0.21-0.52, p<0.001). Likewise, 4SR and FRS demonstrated a strong association with TF-survival with patients achieving lower risk scores exhibiting longer survival compared to those with higher risk scores. Patients ≥65Y more often had connective tissue disease-associated PAH, lower DLCO, more pronounced comorbidity burden, higher risk at baseline, less improvement during follow-up, and worse TF-survival then patients <65Y. ConclusionAll models were found to have prognostic relevance for TF-survival. Risk prediction was incremental with the number of low-risk criteria met, while improvements in only one of 6MWD, NT-proBNP, or FC showed a modest association with survival. The risk assessment tools predicted outcome in patients across both age categories.

Echocardiographic insights redefining risk in pulmonary arterial hypertension: a focus on right atrial volume index for enhanced stratification

Abstract Introduction In Pulmonary arterial hypertension (PAH), the right atrium plays a critical role, and its size, determined by echocardiography, is crucial for risk stratification. Despite this, current guidelines still prioritize right atrial area (RAA) over the right atrial volume index (RAVI). This approach is contrary to the recommendations of international echocardiography societies since 2016, which advocate for the use of RAVI for a more accurate assessment. Purpose Identify the RAVI value corresponding to the RAA, in PAH risk stratification used in the 2022 ESC guidelines. Methods We conducted a retrospective analysis of all consecutive patients of a single-center, since 2002. Patient's echocardiograms were revised for simultaneous assessment of RAA and right atrial volume index (RAVI). Over an average follow-up of 6.7 years (SD 5.9), we recorded a cohort of 82 patients diagnosed with PAH. From this group, we excluded 27 patients with congenital etiologies, 14 due to the insufficient quality of echocardiographic data, and one patient identified as an extreme statistical outlier. A Pearson's correlation analysis was used to access the correlation between RAA and RAVI for PAH diagnosis. Results A total of 40 patients were included with a mean age at diagnosis of 48.85 years (SD 17.82), predominantly female (77.5 %). The most prevalent etiologies were idiopathic (32.5%) and connective tissue disease-associated PAH (27.5%). Clinical presentations included right heart failure signs in 30% of patients, rapid symptom progression in 12.5%, syncope history in 15% and 77.5% in WHO-FC III-IV. Average 6-MWD and NT-proBNP levels were 392,1 m (SD 120,2) and 1636,18 ng/L (SD 2576,14), respectively. Average hemodynamics parameters were right atrial pressure 7,39 mmHg (SD 4,940); cardiac index 2,28 L/min/m2 (SD 2,06); stroke volume index 3,38 mL/m2 (SD 3,92) and mixed venous oxygen saturation 65,68% (SD 10,86). Average echocardiographic parameters were RAA 20,14 cm2 (SD 4,80); TAPSE/sPAP 0,34 mm/mmHg (SD 0,18) and RAVI 37,78 mL/m2 (SD 13,67), with 10% of pericardial effusion. Statistical analysis revealed a strong and significant correlation between RAA and RAVI (r=0.82, 95% CI: 0.69-0.90, p&amp;lt;0.001). The derived linear relationship is expressed as "y=2.8*X -18". Therefore, an RAA value of 18 cm² translates to a RAVI of 32 mL/m², while an RAA of 26 cm² corresponds to a RAVI of 55 mL/m². Conclusion Our study supports a revision in HAP risk assessment guidelines, suggesting a shift to a more comprehensive approach using right atrial volume index (RAVI) measurements. We propose categorizing risk as low for RAVI &amp;lt; 32 mL/m², intermediate for RAVI between 32 and 55 mL/m², and high for RAVI &amp;gt; 55 mL/m². This recommendation aligns with the standards of international societies and is grounded in best clinical practices, considering that indexing measurements of the right atrium to body size potentially offers greater accuracy than absolute values.

The role of anticoagulation on the long-term survival of patients with pulmonary arterial hypertension: A meta-analysis of 15 cohort studies

IntroductionAnticoagulation was once recommended for patients with pulmonary arterial hypertension (PAH). However, its survival benefit still remained controversial. We performed a meta-analysis to evaluate the effect of anticoagulation on the long-term survival of PAH patients. MethodsThe PubMed, EMBASE, Web of Science, and WanFang electronic database were searched for eligible studies. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated for effect estimate regarding anticoagulation on the survival of PAH patients. ResultsFifteen cohort studies involving 4266 PAH patients were included. Approximately 45.8 % patients received anticoagulation. The mean follow-up period ranged from 2.1 to 14 years. Anticoagulation had a tendency to, however, did not significantly reduce mortality of PAH patients (HR: 0.86, 95 % CI: 0.73–1.02). In subgroup analysis, anticoagulation decreased the mortality risk as analyzed from retrospective studies (HR: 0.80, 95 % CI: 0.65–0.98), but not prospective studies (HR: 0.95, 95 % CI: 0.70–1.29). For both idiopathic PAH (IPAH) and connective tissue disease associated PAH (CTD-PAH), anticoagulation therapy did not significantly improve the long-term survival rate (HR: 0.83, 95 % CI: 0.65–1.07, and HR: 1.05, 95 % CI: 0.77–1.42, respectively), and this result remained unchanged when pooling data from either retrospective or prospective studies. Further analysis showed that anticoagulation had no advantage in reducing mortality in patients with systemic sclerosis associated PAH, systemic erythematosus lupus related PAH (free of antiphospholipid syndrome), or CTD-PAH of non-specified etiology. ConclusionAnticoagulation may not reduce the long-term mortality of PAH patients, including those with IPAH and CTD-PAH. In the management of PAH, anticoagulants should be prescribed with caution before comprehensive risk to benefit evaluation. Larger and more vigorously designed controlled trials are warranted.

A Single Center Experience of Pulmonary Arterial Hypertension Management in Korea: A 25-Year Comparative Analysis Following the Introduction of Targeted Therapy.

The transformation of pulmonary arterial hypertension (PAH) treatment in Korea, ushered by targeted therapy's advent, prompted our analysis of baseline attributes, treatment trends, and survival shifts within our single-center registry. We examined 230 patients (72.6% female, mean age 40.6±17.4 years) diagnosed and/or treated between 1980 and 2021 in our PAH clinic. Given targeted therapy's introduction and active use since 2007, we compared diagnostic classification, demographics, and treatment patterns at that juncture. Survival analysis encompassed PAH types and the overall population. For historical survival comparison, 50 non-registry patients were retrospectively added, and age-sex matching enabled pooled analysis. Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) constituted the largest subset (43.0%), trailed by connective tissue disease-associated PAH (CTD-PAH, 29.6%) and idiopathic PAH (IPAH, 19.1%). Post-2007, CTD-PAH proportions surged, notably with an elevated initiation rate of targeted therapy (95.4%). Overall survival rates at 1, 5, and 10 years stood at 91.3%, 77.4%, and 65.8%, respectively, with CHD-PAH exhibiting superior survival to idiopathic or CTD-PAH. Age-sex matching analysis indicated survival disparities between those starting immediate targeted therapy vs. conservative treatment upon diagnosis, especially driven by IPAH. In the post-introduction of the targeted therapy era, patients with PAH promptly started treatment right away, and higher survival rates of patients who started initial PAH-targeted therapy were demonstrated. The transition towards early treatment initiation might have likely contributed to the elevated survival rates observed in Korea's PAH patient cohort.

Treatment of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review and meta-analysis

The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH.

Fragmented QRS complex could predict all-cause mortality in patients with connective tissue disease-associated pulmonary arterial hypertension.

To investigate the prognostic impact and pathophysiological characteristics of fragmented QRS complex (fQRS) on patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). This was a multicentre retrospective study recruiting 141 patients with CTD-PAH diagnosed by right heart catheterization (114 cases in the discovery cohort and 27 cases in the validation cohort). fQRS and ST-T change were detected on conventional 12-lead electrocardiogram (ECG). Patients were followed up every 3 months to update their status and the primary end point was all-cause death. Clinical information and ECG characteristics were compared between survival and death groups and Kaplan-Meier curve was used for survival analysis. There were significant differences in age, gender, 6-min walk distance, NT-proBNP, WHO class, presence of fQRS and presence of ST-T change in inferior leads between survival group and death group. Inferior fQRS and ST-T change were significantly associated with right ventricular (RV) dilatation and reduced RV ejection fraction (RVEF). Kaplan-Meier curve showed that all-cause mortality was higher in CTD-PAH with fQRS (p= 0.003) and inferior ST-T change (p= 0.012). Low- and intermediate-risk CTD-PAH with inferior ST-T change had higher all-cause mortality (p= 0.005). The prognostic value of fQRS and inferior ST-T change was validated in external validation cohort. The presence of inferior fQRS and ST-T change could predict poor prognosis in CTD-PAH. NCT05980728, https://clinicaltrials.gov.

Metabolomic Differences in Connective Tissue Disease-Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort.

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in patients with CTD-PAH versus patients with IPAH that might underlie these observed clinical differences. Adult participants with CTD-PAH (n=141) and IPAH (n=165) from the Pulmonary Vascular Disease Phenomics (PVDOMICS) study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad-based global metabolomic profiling of plasma samples. Participants were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD-PAH versus IPAH metabolomic profiles and to measure metabolite-phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 participants. Metabolomic profiles distinguished CTD-PAH from IPAH, with patients with CTD-PAH demonstrating aberrant lipid metabolism with lower circulating levels of sex steroid hormones and higher free fatty acids (FAs) and FA intermediates. Acylcholines were taken up by the right ventricular-pulmonary vascular (RV-PV) circulation, particularly in CTD-PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and RV measurements and with transplant-free survival. CTD-PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV-PV FA metabolism may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.

Initial Triple Combination Therapy Including Intravenous Prostaglandin I2 for the Treatment of Patients with Severe Pulmonary Arterial Hypertension.

Upfront combination therapy including intravenous prostaglandin I2 (PGI2-IV) is recognized as the most appropriate treatment for patients with severe pulmonary arterial hypertension (PAH). This retrospective study aimed to determine reasons why this therapy is not used for some patients with severe PAH and describe the hemodynamic and clinical prognoses of patients receiving initial combination treatment with (PGI2-IV+) or without (PGI2-IV-) PGI2-IV.Data for patients with severe PAH (World Health Organization Functional Class III/IV and mean pulmonary arterial pressure [mPAP] ≥ 40 mmHg) were extracted from the Japan Pulmonary Hypertension Registry. Overall, 73 patients were included (PGI2-IV + n = 17; PGI2-IV- n = 56). The PGI2-IV+ cohort was younger than the PGI2-IV- cohort (33.8 ± 10.6 versus 52.6 ± 18.2 years) and had higher mPAP (58.1 ± 12.9 versus 51.8 ± 9.0 mmHg), greater prevalence of idiopathic PAH (88% versus 32%), and less prevalence of connective tissue disease-associated PAH (0% versus 29%). Hemodynamic measures, including mPAP, showed improvement in both cohorts (post-treatment median [interquartile range] 38.5 [17.0-40.0] for the PGI2-IV + cohort and 33.0 [25.0-43.0] mmHg for the PGI2-IV - cohort). Deaths (8/56) and lung transplantation (1/56) occurred only in the PGI2-IV - cohort.These Japanese registry data indicate that older age, lower mPAP, and non-idiopathic PAH may influence clinicians against using upfront combination therapy including PGI2-IV for patients with severe PAH. Early combination therapy including PGI2-IV was associated with improved hemodynamics from baseline, but interpretation is limited by the small sample size.

Mortality and prognostic factors in connective tissue disease-associated pulmonary arterial hypertension patients complicated with right heart failure.

To identify predictive factors associated with mortality in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) patients who were complicated with right heart failure (RHF). In this single-center retrospective study, baseline demographics, clinical features, laboratory results, and hemodynamic assessments were collected. Kaplan-Meier analysis was applied to analyze all-cause mortality. Univariate and forward stepwise multivariate Cox proportional regression analyses were performed to identify independent predictors of mortality. A total of 51 right heart catheterization-confirmed CTD-PAH patients complicated with RHF were consecutively enrolled in this study from 2012 to 2022. Forty-eight (94%) enrolled patients were female and the mean age was 36.0 ± 11.8 years. Thirty-two (61.5%) were systemic lupus erythematosus-PAH and 33%/67% showed World Health Organization functional class III/IV, respectively. Twenty-five (49%) of those patients died and Kaplan-Meier analysis showed the overall 1-, 3-, and 5-week survival rates from the time of hospitalization as 86.28%, 60.78%, and 56.86%, respectively. RHF in CTD-PAH patients mainly resulted from progression of PAH (n=19) and infection (n=5), which also contributed to the leading causes of death. Statistical analysis between survivors and non-survivors showed that death from RHF was associated with higher levels of urea (9.66 vs 6.34 mmol/L, P=0.002), lactate (cLac: 2.65 vs 1.9 mmol/L, P=0.006), total bilirubin (23.1 vs 16.9 μmol/L, P=0.018) and direct bilirubin (10.5 vs 6.5 μmol/L, P=0.004), but with lower levels of hematocrit (33.7 vs 39, P=0.004), cNa+ (131 vs 136 mmol/L, P=0.003). Univariate and forward stepwise multivariate Cox proportional regression analyses indicated that the level of cLac (hazards ratio:1.297; 95% CI: 1.076-1.564; P=0.006) was an independent risk factor for mortality. The short-term prognosis of CTD-PAH complicated with RHF was very poor, and hyperlactic acidemia (cLac > 2.85 mmoL/L) was an independent predicting factor for mortality of CTD-PAH patients complicated with RHF.

Cross-cultural validation of the Chinese version of the EmPHasis-10 questionnaire in connective tissue disease patients with pulmonary arterial hypertension and its relationship with risk stratification

BackgroundsThe EmPHasis-10 questionnaire is a disease-specific quality of life (QoL) measurement in patients with pulmonary hypertension. We report the results of cross-cultural validation of the Chinese version of the EmPHasis-10 and its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH).MethodsThe Emphasis-10 was administered to 75 CTD-PAH patients along with the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The diagnosis of PAH was confirmed by right heart catheterization. Demographic and clinical data were obtained. Multivariable logistic regression was conducted based on the low risk profile assessed by a 4-strata risk assessment model (COMPERA 2.0) at follow-up.ResultsDate from 75 patients with CTD-PAH were analysed. The EmPHasis-10 demonstrated satisfactory reliability (Cronbach α = 0.95) and convergent validity showed by the significant relationship with WHO Functional Class (P = 0.003), SF-36 (P < 0.001) and EQ-5D (P = 0.002). EmPHasis-10 was significantly associated with achieving the low risk profile at 12 months of follow-up (Odds ratio: 0.928, P = 0.029) after adjusting for WHO Functional Class.ConclusionEmPHasis-10 has acceptable reliability and validity in CTD-PAH patients and may serve as an additional parameter in risk stratification.

Immunosuppressive therapy in patients with connective tissue disease-associated pulmonary arterial hypertension: A systematic review.

It is currently accepted that inflammation plays an important role in the pathogenesis of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). However, the efficacy of immunosuppressive therapy remains anecdotal. The objective of this systematic review was to evaluate the efficacy of immunosuppressive therapy in patients with CTD-PAH and to further assess whether response differs between CTD subtypes and clinical features. We systematically searched studies reporting the treatment response of immunosuppressants and biological agents in CTD-PAH from PUBMED, EMBASE, the Cochrane Library, and Scopus. Studies had to report treatment regime and response criteria. The risk of bias was assessed using the Newcastle-Ottawa scale. Seven independent cohorts, 1 trial, and 1 case-series encompassing 439 patients with CTD-PAH were included. Patients were divided into 2 groups according to the therapeutic regimen. There were 146 patients in the immunosuppressants group with better heart function at baseline and 52.1% (76/146) of them were responders. There were 236 patients treated with immunosuppressants combined with PAH-specific therapy who showed more severity at baseline and 41.1% (97/236) of them were responders. Among different CTD subtypes, patients with systemic lupus erythematosus-associated PAH (SLE-PAH) showed a better response to immunosuppressants (response rate 48.1%). What is more, 1 randomized controlled trial showed the potential therapeutic value of rituximab (n=57) in CTD-PAH patients. Current studies support the use of immunosuppressive therapy in CTD-PAH, especially in SLE-PAH. Further studies on biological agents and the therapeutic effect of different immunosuppressants are still needed.

Incidence and outcomes of pulmonary hypertension in the Ireland

IntroductionPulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature, which is characterised by premature morbidity and mortality. The aim of this study is to define the characteristics of...

Text Mining-Based Drug Discovery for Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: The current medical treatments for connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) do not show favorable efficiency for all patients, and identification of novel drugs is desired. Methods: Text mining was performed to obtain CTD- and PAH-related gene sets, and the intersection of the two gene sets was analyzed for functional enrichment through DAVID. The protein–protein interaction network of the overlapping genes and the significant gene modules were determined using STRING. The enriched candidate genes were further analyzed by Drug Gene Interaction database to identify drugs with potential therapeutic effects on CTD-PAH. Results: Based on text mining analysis, 179 genes related to CTD and PAH were identified. Through enrichment analysis of the genes, 20 genes representing six pathways were obtained. To further narrow the scope of potential existing drugs, we selected targeted drugs with a Query Score ≥5 and Interaction Score ≥1. Finally, 13 drugs targeting the six genes were selected as candidate drugs, which were divided into four drug–gene interaction types, and 12 of them had initial drug indications approved by the FDA. The potential gene targets of the drugs on this list are IL-6 (one drug) and IL-1β (two drugs), MMP9 (one drug), VEGFA (three drugs), TGFB1 (one drug), and EGFR (five drugs). These drugs might be used to treat CTD-PAH. Conclusion: We identified 13 drugs targeting six genes that may have potential therapeutic effects on CTD-PAH.

Effect of Levosimendan on Acute Decompensated Right Heart Failure in Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

AimsAcute decompensated right heart failure (RHF) in chronic precapillary pulmonary hypertension is often typified by a swiftly progressive syndrome involving systemic congestion. This results from the impairment of the right ventricular filling and/or a reduction in the flow output of the right ventricle, which has been linked to a dismal prognosis of short duration. Despite this, there are limited therapeutic data regarding these acute incidents. This study examined the effect of levosimendan on acute decompensated RHF in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH).MethodsThis retrospective study included 87 patients with confirmed CTD-PAH complicated acute decompensated RHF between November 2015 and April 2021. We collected biological, clinical, and demographic data, as well as therapy data, from patients with acute decompensated RHF who required levosimendan treatment in the cardiac care unit (CCU) for CTD-PAH. The patients were divided into two groups according to the levosimendan treatment. Patient information between the two groups was systematically compared in hospital and at follow-up.ResultsOxygen saturation of mixed venose blood (SvO2), estimated glomerular filtration rate (eGFR), 24-h urine output, and tricuspid annular plane systolic excursion (TAPSE) were found to be considerably elevated in the levosimendan cohort compared with the control cohort. Patients in the levosimendan cohort exhibited considerably reduced levels of C-reactive protein (CRP), white blood cell (WBC), troponin I, creatinine, NT-proBNP, and RV diameter compared with those in the control cohort. A higher survival rate was observed in the levosimendan cohort.ConclusionsLevosimendan treatment could effectively improve acute decompensated RHF and systemic hemodynamics in CTD-PAH patients, with positive effects on survival in hospital and can, therefore, be considered as an alternative treatment option for improving clinical short-term outcomes.

External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry.

IntroductionContemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators.MethodsWe evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan–Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches.ResultsAt baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk.ConclusionsThe four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.

CLINICAL CHARACTERISTICS OF PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION AND TREATMENT PATTERNS: A REAL-WORLD ANALYSIS FROM SPHERE (SELEXIPAG: THE USERS DRUG REGISTRY)

CLINICAL CHARACTERISTICS OF PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION AND TREATMENT PATTERNS: A REAL-WORLD ANALYSIS FROM SPHERE (SELEXIPAG: THE USERS DRUG REGISTRY)

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

BackgroundInflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling.MethodsWe conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg−1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels.ResultsWe recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88).ConclusionAdverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Soluble Receptor for Advanced Glycation End Products (sRAGE) Is a Sensitive Biomarker in Human Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis, better monitoring, and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury, and is associated with inflammation, cell proliferation and migration in PAH. For the adult cohort, we recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH) and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3332 ± 321.6 pg/mL) versus controls (1766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II+III PAH versus controls (p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults, but were similar in PH (n = 10) and non-PH controls (n = 10). Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.

Quality of life in ambulatory pulmonary arterial hypertension in connective tissue diseases and its relationship with risk stratification.

The Pulmonary Arterial Hypertension Symptoms and Impact Questionnaire (PAH-SYMPACT) is a PAH-specific patient-reported outcome scale assessing patients’ quality of life from four aspects: cardiopulmonary symptoms, cardiovascular symptoms, physical impacts and cognitive/emotional impacts. This study aimed to validate the Chinese version of PAH-SYMPACT and explore its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). In addition, 75 patients with CTD-PAH confirmed by right heart catheterization were invited to complete questionnaires including PAH-SYMPACT, the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The demographic, clinical, laboratory and treatment data were collected. The endpoint was treatment goal achievement status in 6–12 months after completing the questionnaires, defined as an integrated outcome. Participants’ mean age was 36.4 ± 11.9 years and the mean pulmonary arterial pressure was 38.9 ± 13.67 mmHg. The reliability of the PAH-SYMPACT domains ranged from 0.83 to 0.88. Results of factor analysis basically conformed the original PAH-SYMPACT. The treatment goal achievement (TGA) status in 6–12 months was significantly associated with physical impacts scores (odds ratio: 0.180, 95% confidence interval: 0.036–0.908, P=0.038). The Chinese version of PAH-SYMPACT is a reliable measurement to evaluate quality of life in CTD-PAH patients and is also a potential predictor of patient’s condition change in routine clinical practice.

Early risk prediction in idiopathic versus connective tissue disease-associated pulmonary arterial hypertension: call for a refined assessment.

Despite systematic screening and improved treatment strategies, the prognosis remains worse in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) compared to patients with idiopathic/hereditary pulmonary arterial hypertension (IPAH). We aimed to investigate differences in clinical characteristics, outcome and performance of the European Society of Cardiology (ESC)/ European Respiratory Society (ERS) risk stratification tool in these patient groups. This retrospective analysis included incident patients with CTD-PAH (n=197, of which 64 had interstitial lung disease, ILD) or IPAH (n=305) enrolled in the Swedish PAH Register (SPAHR) 2008–2019. Patients were classified as low, intermediate or high risk at baseline, according to the “SPAHR-equation”. One-year survival, stratified by type of PAH, was investigated by Cox proportional regression. At baseline, CTD-PAH patients had lower diffusing capacity for carbon monoxide and lower haemoglobin but, at the same time, lower N-terminal prohormone-brain natriuretic peptide, longer 6 min walk distance, better haemodynamics and more often a low-risk profile. No difference in age, World Health Organisation functional class (WHO-FC) or renal function between groups was found. One-year survival rates were 75, 82 and 83% in patients with CTD-PAH with ILD, CTD-PAH without ILD and IPAH, respectively. The 1-year mortality rates for low-, intermediate- and high-risk groups in the whole cohort were 0, 18 and 34% (p<0.001), respectively. Corresponding percentages for CTD-PAH with ILD, CTD-PAH without ILD and IPAH patients were: 0, 26, 67% (p=0.008); 0, 19, 39% (p=0.004); and 0, 16, 29% (p=0.001), respectively. The ESC/ERS risk assessment tool accurately identified low-risk patients but underestimated the 1-year mortality rate of CTD-PAH and IPAH patients assessed as having intermediate risk at diagnosis.