Systemic Sclerosis-associated Pulmonary Hypertension Research Articles

Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis-Associated and Idiopathic Pulmonary Hypertension.

Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH. We analyzed single-cell RNA sequencing profiles of endothelial and perivascular mesenchymal populations from explanted lung tissue of patients with SSc-associated PH (n=16), idiopathic pulmonary arterial hypertension (n=3), and healthy controls (n=15). Findings were validated by immunofluorescence staining of explanted human lung tissue. Three disease-associated endothelial populations emerged. Two angiogenic endothelial cell (EC) subtypes markedly expanded in SSc-associated PH lungs: tip ECs expressing canonical tip markers PGF and APLN and phalanx ECs expressing genes associated with vascular development, endothelial barrier integrity, and Notch signaling. Gene regulatory network analysis suggested enrichment of Smad1 (SMAD family member 1) and PPAR-γ (peroxisome proliferator-activated receptor-γ) regulon activities in these 2 populations, respectively. Mapping of potential ligand-receptor interactions highlighted Notch, apelin-APJ (apelin receptor), and angiopoietin-Tie (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) signaling pathways between angiogenic ECs and perivascular cells. Transitional cells, expressing both endothelial and pericyte/smooth muscle cell markers, provided evidence for the presence of endothelial-to-mesenchymal transition. Transcriptional programs associated with arterial endothelial dysfunction implicated VEGF-A (vascular endothelial growth factor-A), TGF-β1 (transforming growth factor beta-1), angiotensin, and TNFSF12 (tumor necrosis factor ligand superfamily member 12)/TWEAK (TNF-related weak inducer of apoptosis) in the injury/remodeling phenotype of PH arterial ECs. These data provide high-resolution insights into the complexity and plasticity of the pulmonary endothelium in SSc-associated PH and idiopathic pulmonary arterial hypertension and provide direct molecular insights into soluble mediators and transcription factors driving PH vasculopathy.

Native myocardial T1 and right ventricular size by CMR predict outcome in systemic sclerosis-associated pulmonary hypertension.

Measures of right heart size and function are prognostic in systemic sclerosis-associated pulmonary hypertension (SSc-PH), but the importance of myocardial tissue characterisation remains unclear. We aimed to investigate the predictive potential and interaction of cardiovascular magnetic resonance (CMR) myocardial tissue characterisation and right heart size and function in SSc-PH. A retrospective, single-centre, observational study of 148 SSc-PH patients confirmed by right heart catheterization who underwent clinically-indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2023 was performed. Sixty-six (45%) patients died during follow-up (median 3.5 years, range 0.1-7.3). Patients who died were older (65 vs 60 years, p= 0.035) with more dilated (RVEDVi and RVESVi, p< 0.001), hypertrophied (RVMi, p= 0.013) and impaired (RVEF, p< 0.001) right ventricles, more dilated right atria (RAi, p= 0.043) and higher native myocardial T1 (p< 0.001).After adjustment for age, RVESVi (p = 0.0023) and native T1 (p = 0.0024) were independent predictors of all-cause mortality. Both RVESVi and native T1 remained independently predictive after adjusting for age and PH subtype (RVESVi p < 0.001, T1 p = 0.0056). Optimal prognostic thresholds for RVESVi and native T1 were ≤38 mL/m2 and ≤1119 ms, respectively (p < 0.001). Patients with RVESVi ≤ 38 mL/m2 and native T1 ≤ 1119 ms had significantly better outcomes than all other combinations (p < 0.001). Furthermore, patients with RVESVi > 38mL/m2 and native T1 ≤ 1119 ms had significantly better survival than patients with RVESVi > 38mL/m2 and native T1 > 1119ms (p = 0.017). We identified prognostically relevant CMR metrics and thresholds for patients with SSc-PH. Assessing myocardial tissue characterisation alongside RV function confers added value in SSc-PH and may represent an additional treatment target.

Kiosk 4R-FB-01 - Native Myocardial T1 and Right Ventricular Size by CMR Are Independently Prognostic in Systemic Sclerosis-associated Pulmonary Hypertension

Kiosk 4R-FB-01 - Native Myocardial T1 and Right Ventricular Size by CMR Are Independently Prognostic in Systemic Sclerosis-associated Pulmonary Hypertension

Proteomic biomarkers for survival in systemic sclerosis-associated pulmonary hypertension

Proteomic biomarkers for survival in systemic sclerosis-associated pulmonary hypertension

Proteomic biomarkers for survival in systemic sclerosis-associated pulmonary hypertension

BackgroundInterstitial lung disease (ILD) and pulmonary hypertension (PH) represent the major causes of mortality in systemic sclerosis (SSc). Patients with systemic sclerosis and combined PH and ILD (SSc-PH-ILD) generally have a poor prognosis. Predictors of survival and of potential benefit of treatment are lacking in patients with SSc-PH-ILD.ObjectiveTo identify specific plasma protein expression patterns associated with survival in patients with SSc-PH-ILD.Materials and methodsPost-hoc analysis of a prospective multicenter French study in patients with PH-ILD. An untargeted proteomic analysis using mass spectrometry was performed to identify plasma protein changes associated with long-term overall survival in patients with SSc-PH-ILD.ResultsThirty two patients were included in the analysis, of whom 13 died during follow-up (median survival: 76.5 months). At baseline, survivors had less severe hemodynamic impairment [pulmonary vascular resistance of 4.4 Wood Units (IQR 3–5.2) vs. 6.2 Wood Units (IQR 4.2–10.7)] and higher carbon monoxide diffusing capacity [median 39% (IQR 35–44%) vs. 25% (IQR 22–30.5%)], than the 13 patients who died. Seven proteins, associated with haemostasis and fibrosis, were differentially expressed according to patients’ survival. In the survivor group, two proteins were increased (ADAMTS13, SERPIND1) and five were decreased (PTGDS, OLFM1, C7, IGFBP7, FBN1) compared to the non-survivor groups.ConclusionThe prognosis of SSc-PH-ILD patients is poor. This proteomic approach found 7 plasma proteins (involved in haemostasis and fibrosis pathways) associated with survival. These potential biomarkers may be good candidates to prognostic enrichment.

Endothelial Biomarkers of Systemic Sclerosis-Associated Pulmonary Hypertension.

Despite efforts at early detection, patients with systemic sclerosis (SSc) pulmonary hypertension (PH) present with advanced disease. We sought to determine whether endothelial biomarkers (asymmetric dimethylarginine [ADMA], soluble endoglin [sEng], and pentraxin-3 [PTX-3]) can determine SSc-PH risk or differentiate between SSc-PH subgroups. ADMA, sEng, and PTX-3 were measured by enzyme-linked immunosorbent assay in four groups: 1) 18 healthy controls, 2) 74 patients with SSc-PH, 3) 44 patients at high risk for PH features, and 4) 10 patients with low risk for PH features. High-risk features included a diffusion capacity (DLco) less than 55% with a forced vital capacity (FVC) greater than 70%, an FVC/DLco ratio of >1.6, or a right ventricular systolic pressure on an echocardiogram greater than or equal to 40 mm Hg. ADMA, sEng, and PTX-3 were compared between these four groups as well as stratified based on the three SSc-PH clinical classification groups (pulmonary arterial hypertension [PAH], left-heart disease, and interstitial lung disease [ILD]). PTX-3 was significantly lower in subjects with SSc at low risk for PH (median 27.0 pg/ml [interquartile range (IQR) 19.0-47.3]; P < 0.003) than the other groups. The area under the receiver operating characteristic curve was 0.87 (95% confidence interval 0.76-0.98, P = 0.0002) to differentiate low risk from high risk for patients with PH. PTX-3 was significantly lower in SSc-PH from disease of the left side of the heart (57.5 pg/ml [IQR 39.8-79.0]; P < 0.01) compared to SSc-PH from either PAH (85.5 pg/ml [IQR 56.3-104.5]) or ILD (90.3 pg/ml [IQR 74.9-111.0]). Neither ADMA nor sEng differed between the four groups. PTX-3 is a promising biomarker of PH risk status in patients with SSc as well as a possible marker of precapillary PH, which should be validated in an external cohort.

Prognostic significance of pericardial effusion in systemic sclerosis-associated pulmonary hypertension: analysis from the PHAROS Registry.

Pulmonary hypertension (PH) is a leading cause of death in patients with SSc. The purpose of this study was to determine the prognostic significance of pericardial effusion in patients with SSc-PH. Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) is a prospective multicentre registry which enrolled patients with newly diagnosed SSc-PH from 2005 to 2016. The prognostic impact of pericardial effusion status, including those who ever or never had pericardial effusion, and those who had persistent or intermittent pericardial effusion, was analysed. Kaplan-Meier survival analyses, log-rank test, and multivariable Cox proportional hazards regression were performed. Of the 335 patients with SSc-PH diagnosed by right heart catheterization and documentation of pericardial effusion presence or absence on echocardiogram, 166 (50%) ever had pericardial effusion. Ever having pericardial effusion was not predictive of survival (log-rank test P = 0.49). Of the 245 SSc-PH patients who had at least two echocardiograms, 44% had a change in pericardial effusion status over an average of 4.3 years of follow up. Having a persistent pericardial effusion was an independent predictor of survival [adjusted hazard ratio (aHR)=2.34, 95% CI 1.20, 4.64, P = 0.002], while intermittent pericardial effusion was not a predictor of survival (aHR = 0.89, 95% CI 0.52, 1.56, P = 0.68), in a multivariable-adjusted analysis. Persistent pericardial effusion, but not ever having had pericardial effusion or intermittent pericardial effusion, was independently associated with poorer survival. Incorporating information from serial echocardiograms may help clinicians better prognosticate survival in their SSc-PH patients.

Nailfold capillaroscopy and candidate-biomarker levels in systemic sclerosis-associated pulmonary hypertension: A cross-sectional study.

Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension. A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances. No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis-pulmonary hypertension and systemic sclerosis-no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis-pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension. This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies.

A signal recognition particle-related joint model of LASSO regression, SVM-RFE and artificial neural network for the diagnosis of systemic sclerosis-associated pulmonary hypertension.

Background: Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is one of the most common causes of death in patients with systemic sclerosis (SSc). The complexity of SSc-PH and the heterogeneity of clinical features in SSc-PH patients contribute to the difficulty of diagnosis. Therefore, there is a pressing need to develop and optimize models for the diagnosis of SSc-PH. Signal recognition particle (SRP) deficiency has been found to promote the progression of multiple cancers, but the relationship between SRP and SSc-PH has not been explored. Methods: First, we obtained the GSE19617 and GSE33463 datasets from the Gene Expression Omnibus (GEO) database as the training set, GSE22356 as the test set, and the SRP-related gene set from the MSigDB database. Next, we identified differentially expressed SRP-related genes (DE-SRPGs) and performed unsupervised clustering and gene enrichment analyses. Then, we used least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) to identify SRP-related diagnostic genes (SRP-DGs). We constructed an SRP scoring system and a nomogram model based on the SRP-DGs and established an artificial neural network (ANN) for diagnosis. We used receiver operating characteristic (ROC) curves to identify the SRP-related signature in the training and test sets. Finally, we analyzed immune features, signaling pathways, and drugs associated with SRP and investigated SRP-DGs' functions using single gene batch correlation analysis-based GSEA. Results: We obtained 30 DE-SRPGs and found that they were enriched in functions and pathways such as "protein targeting to ER," "cytosolic ribosome," and "coronavirus disease-COVID-19". Subsequently, we identified seven SRP-DGs whose expression levels and diagnostic efficacy were validated in the test set. As one signature, the area under the ROC curve (AUC) values for seven SRP-DGs were 0.769 and 1.000 in the training and test sets, respectively. Predictions made using the nomogram model are likely beneficial for SSc-PH patients. The AUC values of the ANN were 0.999 and 0.860 in the training and test sets, respectively. Finally, we discovered that some immune cells and pathways, such as activated dendritic cells, complement activation, and heme metabolism, were significantly associated with SRP-DGs and identified ten drugs targeting SRP-DGs. Conclusion: We constructed a reliable SRP-related ANN model for the diagnosis of SSc-PH and investigated the possible role of SRP in the etiopathogenesis of SSc-PH by bioinformatics methods to provide a basis for precision and personalized medicine.

Improved Survival for Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension: The Johns Hopkins Registry.

Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of patients with SSc-PH and compare their characteristics and survival between the last two decades. Methods: Patients with SSc-PH prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients whose disease was diagnosed between 1999 and 2010, and cohort B included those whose disease was diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 patients with SSc-PH distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension group 1, 43 (9%) had group 2, and 151 (30%) had group 3 disease. Patients with group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis than those in cohort A (P < 0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for group 2 or 3 patients with SSc-PH, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of patients with SSc-PH between the last two decades. Transplant-free survival has improved significantly for those with group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with group 2 or 3 disease continue to have dismal prognosis.

Prevalence of aortic stenosis and TAVR outcomes in patients with systemic sclerosis-associated pulmonary hypertension.

There is little known about performing transcatheter aortic valve replacement (TAVR) in patients with group 1 pulmonary arterial hypertension (PAH) on advanced pulmonary vasodilator therapy. Retrospective cohort study among 90 patients with systemic sclerosis‐associated pulmonary arterial hypertension and systemic sclerosis‐associated pulmonary hypertension (SSc‐PAH/PH) evaluated at a tertiary PH center. The SSc‐PAH/PH cohort was stratified by the presence or absence of aortic stenosis (AS) to identify differences in baseline characteristics, hemodynamics, and long‐term outcomes. Of the 90 SSc‐PAH/PH patients, 13 patients were diagnosed with AS at PH diagnosis and another 6 patients developed AS during the study period. The period prevalence of AS was 21.1% (19/90, 95% confidence interval: 13.2%–30.1%) of which 94.7% was mild (18/19) at diagnosis with mean age at AS diagnosis of 66.3 + 2.2 years. Among AS patients, 31.6% (6/19) progressed to severe AS, five of which underwent TAVR (median age: 70 years) while on advanced PAH therapy. One of the five TAVR patients developed worsening pulmonary hypertension post‐TAVR. The 5‐year survival rate for all AS patients from diagnosis date was 37.2%. There was a high prevalence of AS in this cohort of SSc‐PAH/PH patients, with mean age of onset younger than patients with nonbicuspid aortic valve stenosis. This is the largest series of SSc‐PAH/PH patients on advanced pulmonary vasodilator therapy who underwent TAVR with acceptable early outcomes.

Increased risk of mortality in systemic sclerosis-associated pulmonary hypertension: a systemic review and meta-analysis

BackgroundPulmonary hypertension (PH) is a frequent complication of systemic sclerosis (SSc) and is currently one of the primary causes of death in patients with this disease. We conducted a systematic review and meta-analysis to assess the association between PH and mortality in patients with SSc to verify trends in mortality in patients with SSc-associated PH.MethodsWe searched the PubMed and Embase databases for published studies on SSc-associated PH from inception to May 2021. All cohort studies in which mortality and/or survival for SSc-associated PH were reported were included in the analysis. The outcome parameters were pooled and analyzed using a random-effects model via generic inverse-variance weighting in conventional and cumulative meta-analysis.ResultsThe literature search identified 1161 citations, and the full texts of 54 studies were examined. Sixteen articles, with a total of 7857 patients with SSc and 1140 patients with SSc-associated PH, were included in the meta-analysis. Patients with SSc-associated PH had a higher pooled risk of mortality than patients with SSc without PH (risk ratio = 3.12; 95% confidence interval: [2.44, 3.98]).ConclusionsThis meta-analysis revealed a higher mortality in patients with SSc-associated PH. PH was a significant predictor of death in patients with SSc. Thus, early diagnosis and treatment of PH are important in patients with SSc.

Clinical phenotypes, hemodynamic characteristics and prognosis of Chinese patients with systemic sclerosis-associated precapillary pulmonary hypertension: a retrospective study.

Systemic sclerosis (SSc) is associated with interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). This study aimed to explore the prevalence, clinical features, hemodynamic characteristics and prognosis of different severity of ILD in a cohort of patients with SSc-associated precapillary pulmonary hypertension (SSc-PH) and investigate the differences between SSc-PAH and idiopathic pulmonary arterial hypertension (IPAH) patients. SSc-PH patients and IPAH patients, admitted to Shanghai Pulmonary Hospital (August 1, 2008-January 31, 2020) and diagnosed by right-sided heart catheterization (RHC) or echocardiography, were retrospectively included. SSc-PH patients had a baseline chest high-resolution computed tomography (HRCT), and PH classification was based on the extent of ILD. Clinical, pulmonary function, hemodynamic characteristics and survival data were extracted. The study included 45 SSc-PH patients (60% had coexisting ILD and 77.8% were SSc-Group 1 PH/SSc-PAH [without ILD or with mild ILD], 22.2% were SSc-Group 3 PH/SSc-PH with severe ILD) and 52 IPAH patients. SSc-PH with ILD had lower arterial oxygen partial pressure (PaO2) than those without ILD. Hemodynamic characteristics and survival rates were comparable between SSc-PAH with mild ILD and those without ILD. SSc-Group 3 PH had lower pulmonary vascular resistance (PVR) and more severe restrictive ventilatory dysfunction than SSc-Group 1 PH, but the survival rate was equally poor. SSc-PAH had a poorer prognosis than IPAH patients despite the better hemodynamic characteristics. ILD was common in SSc-PH patients. Careful phenotyping of PH in SSc-PH patients is very important as it is imperative to recognize its impact on clinical course, treatment and survival. • ILD was common in Chinese SSc-PH patients. • SSc-PH patients with ILD had lower PaO2 than those without ILD. • Hemodynamic characteristics and survival rates were similar in SSc-PAH patients with mild ILD and those without ILD. • Patients in SSc-Group 3 PH had lower pulmonary vascular resistance (PVR) and more severe restrictive ventilatory dysfunction than those in SSc-Group 1 PH, but the survival rate was equally poor. SSc-PAH patients had a poorer prognosis than IPAH patients despite their better hemodynamic characteristics.

Pulmonary Hypertension in Collagen Vascular Disorders: Systemic Sclerosis: An Overview of Systemic Sclerosis-Associated Pulmonary Hypertension

Pulmonary Hypertension in Collagen Vascular Disorders: Systemic Sclerosis: An Overview of Systemic Sclerosis-Associated Pulmonary Hypertension

Screening for Pulmonary Hypertension in Systemic Sclerosis-A Primer for Cardio-Rheumatology Clinics.

Systemic sclerosis (SSc) is a rare disease, with unfavorable clinical course and prognosis, characterized by progressive multisystemic involvement. SSc associated pulmonary hypertension (SSc-PAH) and interstitial lung disease (ILD) are the most important factors for morbi-mortality in these patients, being responsible for more than 60% of total deaths. Though pulmonary arterial hypertension (PAH) is the dominant subtype seen in SSc, PH secondary to ILD, left-heart pathology, and pulmonary veno-occlusive disease (PVOD) are also possible occurrences. Initial evaluation of a SSc case is complex and should be performed with a multidisciplinary approach. Early detection of SSc-PAH is imperative, given the fact that new and effective medications are available and early treatment was shown to improve outcomes. Therefore, screening algorithms must be used adequately and in a cost-effective manner. Sensitivity and negative predictive value (NPV) are the most important performance measures in a screening test. Several algorithms were developed in the last decade (e.g., DETECT and ASIG) and demonstrated higher efficiency when compared to older algorithms. The present manuscript details the risk factors for SSc-PAH and includes a critical description of current detection algorithms, as a primer for clinicians working in the field of cardio-rheumatology.

Systemic Sclerosis-Associated Pulmonary Hypertension: Spectrum and Impact.

Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a catastrophic complication of one of the most common and devastating autoimmune diseases. Once diagnosed, it becomes the leading cause of mortality among this patient population. Screening modalities and risk assessments have been designed and validated by various organizations and societies in order to identify patients early in their disease course and promptly refer them to expert centers for a hemodynamic assessment and formal diagnosis. Moreover, several large multicenter clinical trials have now included patients with SSc-PAH to assess their response to therapy. Despite an improved understanding of the condition and significant advances in supportive and targeted therapy, outcomes have remained far from optimal. Therefore, rigorous phenotyping and search for novel therapies are desperately needed for this devastating condition.

P5262Subclinical myocardial abnormalities in systemic sclerosis-associated versus non-connective tissue disease pulmonary hypertension by CMR multiparametric mapping

Abstract Introduction Scleroderma (SSc)-associated pulmonary arterial hypertension (PAH) has the worst prognosis of all PAH subtypes despite having relatively more favourable haemodynamic and cardiac functional profiles. Myocardial abnormalities in SSc have been demonstrated by cardiovascular magnetic resonance (CMR) multiparametric tissue mapping. However, myocardial tissue characterisation studies across distinct PAH subtypes including SSc are limited. Purpose We compared indices of tissue characterisation by CMR multiparametric mapping between patients with SSc with and without PAH, non-connective tissue disease pulmonary hypertension (non-CTD PH) and healthy volunteers. Methods One-hundred and thirty-six patients underwent a CMR study over a 30-month period: 104 patients with systemic sclerosis, of whom 39 had SSc-PAH and 65 had no PH; 32 patients with idiopathic PAH, chronic thromboembolic PH or portopulmonary PH (non-CTD PH group). Patients underwent comprehensive CMR tissue characterisation including quantification of native myocardial T1 (MOLLI), myocardial T2 and ECV from automatically generated tissue maps along with conventional late gadolinium enhancement (LGE) imaging. Twenty age-matched controls underwent the same CMR study protocol. Patients were assessed for PH by right heart catheterisation. Results Native myocardial T1 and myocardial T2 and myocardial ECV are significantly elevated in SSc-PAH versus non-CTD PH (all p&lt;0.05, Figure 1) despite no differences in LV systolic function between these patient cohorts. Patients with SSc have similar degrees of elevated T1, T2 and ECV irrespective of the presence or absence of PAH, suggesting a diffuse myocardial process due to SSc itself. Both SSc sub-groups have significantly higher T1, T2 and ECV compared with controls (all p&lt;0.05). All patients with SSc were subdivided by the presence or absence of ventricular insertion point LGE. Even in the absence of LGE, T1, T2 and ECV were significantly higher in SSc patients versus controls (all p&lt;0.001). However, the presence of focal insertional LGE in SSc was not associated with different burdens of interstitial disease, as defined by median ECV. This highlights the unique role of multiparametric tissue maps in assessing diffuse myocardial involvement beyond the identification of focal LGE. Conclusion Subclinical abnormalities of the myocardium can be detected by CMR multiparametric tissue mapping in patients with SSc. The higher native myocardial T1 and T2 along with the elevated ECV in SSc-PAH are likely to be accounted for by SSc involvement itself. Abnormalities of the myocardial architecture could be a potential contributory reason for the poorer outcomes in SSc-PAH versus non-CTD PH despite the more favourable haemodynamics and right heart function observed in the former patient sub-group. Further work should be directed at determining the prognostic capacity of these metrics in SSc-PAH. Acknowledgement/Funding British Heart Foundation, Action Pharmaceuticals Ltd

KCNA5 gene variation is not associated with the pulmonary hypertension in systemic sclerosis patients

Background: The association between KCNA5 gene variation and systemic sclerosis-associated pulmonary hypertension (SSc-PAH) is unclear. The present meta-analysis was conducted to assess the association between KCNA5 gene variation and SSc-PAH. Methods: Electronic databases were searched for relevant studies on the relationship between KCNA5 gene variation and SSc-PAH. Odds ratio (OR) with 95% confidence interval (CI) was selected as the effect scale indicators using a random-effects model. Statistical analysis was performed using RevMan 5.3 software. Results: A total of 2 articles and 7,583 subjects were included. Among them, 298 were SSc-PAH patients. There was no significant difference found in the comparisons of C/C homozygotes (0.7% vs . 1.7%, OR=0.51, P=0.41), C/T heterozygotes (17.1% vs . 22.7%, OR=0.64, P=0.25) and C/C+C/T heterozygotes (17.8% vs . 24.4%, OR=0.59, P=0.25) between the two groups. Conclusions: The pooled analysis of available data indicates that KCNA5 rs10744676 is not confirmed as an SSc-PAH genetic susceptibility factor.

Aggressive combination therapy for treatment of systemic sclerosis-associated pulmonary hypertension.

Pulmonary arterial hypertension is an important complication of systemic sclerosis with high mortality but should be regarded as a treatable manifestation of the disease. Management draws on experience from other forms of pulmonary arterial hypertension and benefits from an increasing number of licenced therapies. Outcome is variable but recent clinical trials suggest that combination therapies used early in the disease may be associated with better outcomes. This is important because previous clinical trials using short-term gain in exercise capacity did not show significant benefit compared to that observed for idiopathic or heritable forms of pulmonary arterial hypertension. Thus, it is important to identify cases as early as possible and to manage cases that are in a high-risk group using early combination therapy. This review summarises the most recent analyses of clinical trial data, with a focus on those patients with SSc-associated pulmonary arterial hypertension and provides the evidence base that supports current treatment recommendations for aggressive pulmonary arterial hypertension occurring in systemic sclerosis, including the early use of combination pulmonary arterial hypertension-specific drugs in appropriate cases.

New insights into the recognition, classification and management of systemic sclerosis-associated pulmonary hypertension.

Pulmonary hypertension is a common complication of systemic sclerosis (SSc), and remains a leading cause of morbidity and mortality. We will review recent developments in the recognition, classification and treatment of pulmonary hypertension in SSc. Advances in screening for pulmonary arterial hypertension (PAH) and use of exercise haemodynamics may help to identify pulmonary vascular disease earlier in SSc. Recent studies have led to changes in recommendations for adjunct therapy and selection of pulmonary vasodilators for the treatment of SSc-associated PAH. Recent advances in the diagnosis, classification and management of pulmonary hypertension in SSc have continued to improve our understanding of this challenging disease. Ongoing investigation in the pathogenesis of this disease will afford the opportunity to develop targeted therapies to improve outcomes for SSc patients with pulmonary hypertension.