Systemic Sclerosis-associated Pulmonary Arterial Hypertension Research Articles

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again.

Systemic sclerosis (SSc) is a heterogeneous disease characterized by autoimmunity, vasculopathy, and fibrosis which affects the skin and internal organs. One key aspect of SSc vasculopathy is pulmonary arterial hypertension (SSc-PAH) which represents a leading cause of morbidity and mortality in patients with SSc. The pathogenesis of pulmonary hypertension is complex, with multiple vascular cell types, inflammation, and intracellular signaling pathways contributing to vascular pathology and remodeling. In this review, we focus on shared molecular features of pulmonary hypertension and those which make SSc-PAH a unique entity. We highlight advances in the understanding of the clinical and translational science pertinent to this disease. We first review clinical presentations and phenotypes, pathology, and novel biomarkers, and then highlight relevant animal models, key cellular and molecular pathways in pathogenesis, and explore emerging treatment strategies in SSc-PAH.

Aberrant Long-Chain Fatty Acid Metabolism Associated with Evolving Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n=22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared to metabolites assayed in matched SSc patients who did not develop PAH (n=22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 years) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to two years prior to clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including prior to clinical diagnosis and in mild disease.

Evaluation of the European Society of Cardiology Risk Assessment Score in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

Patients with pulmonary arterial hypertension (PAH) may be stratified as low, intermediate, or high risk of 1-year mortality. In 2022, the European Society of Cardiology (ESC) updated and simplified its risk stratification tool, based on three variables: World Health Organization functional class, serum N-terminal pro-brain type natriuretic peptide and six-minute walk distance, applied at follow-up visits, intended to guide therapy over time. We applied the 2022 ESC risk assessment tool at baseline and follow-up (within 2 years) to a multinational incident cohort of systemic sclerosis-associated PAH (SSc-PAH). Kaplan-Meier curves, Cox hazards regression, and accelerated failure time models were used to evaluate survival by risk score. At baseline (n = 260), the majority of SSc-PAH (72.2%) were graded as intermediate risk of death according to the 2022 tool. At follow-up, according to 2022 tool, half (55.5%) of the cohort were classified as low or intermediate-low risk. The 2022 risk model at follow-up was able to differentiate survival between risk strata. All three individual parameters (World Health Organization functional class, N-terminal pro-brain type natriuretic peptide, six-minute walk distance) were significantly associated with mortality at baseline and/or follow-up. The 2022 ESC risk assessment strategy applied at baseline and follow-up predicts survival in SSc-PAH. Treatment decisions for SSc-PAH should include risk assessments, aiming to achieve low-risk status according to the 2022 ESC guidelines.

Systemic sclerosis-associated pulmonary arterial hypertension is characterized by a distinct peripheral T helper cell profile.

Systemic sclerosis (SSc) is characterized by multiple clinical manifestations. Vasculopathy is a main disease hallmark and ranges in severity from an exacerbated Raynaud phenomenon to pulmonary arterial hypertension (PAH). The potential involvement of immune system in SSc associated vascular abnormalities is not clear. Here, we set out to study SSc-related immune parameters and determine whether and which peripheral T cell subsets associate with vascular severity in SSc patients. Peripheral blood and clinical data were collected from 30 SSc patients, 5 patients with idiopathic pulmonary arterial hypertension (IPAH) and 15 age and sex-matched healthy donors (HD). In this cross-sectional cohort SSc patients with PAH (n = 15) were matched for their age, sex and medication with SSc patients with no signs of PAH (n = 15). Lymphocyte subsets were quantified by multi-colour flow cytometry. SSc patients exhibited elevated percentages of T peripheral helper cells (Tph), CD4+GZMB+ T cells and decreased levels of Th1 cells compared with HD. Increased presence of both CD4+ and CD8+ exhausted-like (CD28-) T cells, characterized by raised cytokine and cytotoxic signature, was also observed in SSc compared with HD blood. Furthermore, IL-4 expressing CD4+CD8+ T cells were significantly increased in SSc peripheral blood. Interestingly, the presence of PAH in SSc was accompanied by a distinct T helper profile, characterized by raised percentages of Th17 and Tph cells. SSc patients with severe vasculopathy (presence of PAH) exhibited a distinct T cell profile, suggesting for a potential role of auto-immune inflammation in SSc vascular complications.

Longitudinal Risk Phenotyping in Incident Systemic Sclerosis-associated Pulmonary Arterial Hypertension (SSc-PAH): An Unsupervised Cluster Analysis of the PHAROS Registry

Background: Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is characterized by pulmonary arterial remodeling resulting in right ventricular failure and death if untreated. Despite therapeutic advances, there is survival variability within the SSc-PAH population. The aim of this study was to delineate high-risk subgroups of SSc-PAH using readily available clinical parameters. Methods: We analyzed data from the PHAROS database, a prospective observational registry of incident SSc-PAH patients. Latent class modeling was performed based on trends in 6MWD over time. We compared survival between the clusters regarding baseline clinical parameters and changes in these parameters over time. Results: We identified four unique groups within 103 patients meeting our inclusion criteria, based on trajectories of 6MWD. Patients in Cluster 4 exhibited a decline in 6MWD over time and had the worst prognosis with a median survival of 3 years. Patients in Cluster 3, with the lowest baseline 6MWD, were associated with lower median survival (5 years) when compared to Clusters 1 and 2 (> 9 and 7 years, respectively), despite an improvement in 6MWD over time. There were no meaningful changes in SF-36 and WHO functional class between the clusters, but BNP trended higher over time in the higher-risk clusters. Conclusion: We identified high-risk subsets of SSc-PAH characterized by significantly worse survival. Incident SSc-PAH patients with a decline in 6MWD over time or low baseline 6MWD had worse survival when compared to SSc-PAH patients who demonstrated relatively stable or mild reduction in 6MWD over time.

B-cells in pulmonary arterial hypertension: friend, foe or bystander?

There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B-cells in its pathogenesis and evaluate the relevance of B-cell-targeted therapies. Circulating B-cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B-cells) and chronic activation. B-cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular autoantigens through cognate B-cell receptors; 2) costimulatory signals provided by T follicular helper cells (interleukin (IL)-21), type 2 T helper cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B-cell activating factor pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilisation factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B-cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B-cells, immunoglobulin (Ig)G-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B-cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.

Kiosk 4R-FA-06 - Right Ventricular Contractile Reserve by Exercise CMR Is Prognostic in Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension (SSc-PAH) and a Low- or Intermediate-risk PAH Profile

Kiosk 4R-FA-06 - Right Ventricular Contractile Reserve by Exercise CMR Is Prognostic in Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension (SSc-PAH) and a Low- or Intermediate-risk PAH Profile

Autologous MPO Knock-out Hematopoietic Stem and Progenitor Cells for Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive condition for which there is no cure. Even with substantial pharmacologic advances in the modern treatment era, existing treatments provide only symptomatic relief and survival remains unacceptably poor. Patients who fail to respond to medications usually have the worst prognosis and patients with persistently elevated pulmonary pressure and right heart failure usually die within 5 years. PAH is a severe complication of Systemic sclerosis (SSc) affecting approximately 8%-12% of patients. SSc affects 13.5-44.3 per 100,000 individuals and is complex and diverse, with limited treatment options. SSc-associated PAH is the second largest group of patients with PAH. Once diagnosed, it becomes the leading cause of mortality among this patient population, with a 50% mortality rate within 3 years of PAH diagnosis. Inflammation and endothelial injury being the main components of the syndrome, investigation regarding the underlying mechanisms of this immune response may lead to the development of a new efficient therapy. There is extensive evidence for a pathogenic role for neutrophil myeloperoxidase (MPO) in PAH disease. PAH patients with higher levels of MPO have a poorer outcome. Studies in murine models of PAH demonstrate significant disease amelioration by elimination of neutrophil MPO by hematopoietic stem cell (HSC) transplantation with HSC lacking MPO from germline MPO gene knock-out. We developed a gene therapy approach to PAH in which autologous HSCs will undergo gene editing using CRISPR/Cas9 to achieve bi-allelic disruption of the MPO gene. These MPO-knock-out HSCs will then be autologous transplanted. That autologous transplantation of HSPC in which the MPO gene is disrupted is expected to prevent progression of PAH due to the essential role of neutrophil MPO activity on disease development. We identified a sgRNA that leads to high frequency disruption of MPO in primary human CD34+ hematopoietic stem and progenitor cells (HSPC), leading to efficient elimination of MPO protein in the resultant neutrophils. That sequence was assessed for genome-wide off-target and showed no detectable locus, validating it as a lead candidate for safe gene editing strategy. We validated in an in vitro neutrophil differentiation model the functional efficiency of the knock-out. MPO KO differentiated cells exhibit reduced neutrophil extracellular traps formation (NETosis) and absence of MPO protein. An optimized gene editing protocol for HSC was optimized and showed consistent allelic disruption over 80%. The edited cells retain hematopoietic potential and showed no skewing in the generated lineages in an in vitro colony forming assay. We developed a surrogate gene editing protocol for murine cells and optimized electroporation to achieve high allelic disruption of the murine MPO gene in lineage negative murine hematopoietic cells. The protocol will be tested in a hypoxia-induced PAH murine model. The presented work can represent a major improvement for PAH patient. The limited therapeutic options and severity of the disease urges to develop new approaches. The gene therapy protocol developed showed promising result in vitro and rely on clinical evidences for the implication of MPO in the disease. Results will be tested in a pre-clinical murine model

Independent Predictors of Mortality in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis.

The aim of this study is to determine the predictors of mortality in patients with systemic sclerosis-induced pulmonary arterial hypertension (SSc-PAH).This systematic review and meta-analysis were carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement guidelines.We searched the PubMed, EMBASE, and Web of Science databases from January 2010 to April 2023 using the following keywords: "systemic sclerosis," "pulmonary arterial hypertension," "death," and "predictors," along with medical subject headings (MeSH), to identify relevant studies. A total of eight studies with a total of 530 patients were included in the present systematic review and meta-analysis.The pooled one-year, three-year, and five-year survival was 90% (95% CI: 86-93%), 66% (95% CI: 59-72%), and 44% (95% CI: 23-65%), respectively. Factors associated with mortality inSSc-PAH included age (p-value: 0.02), male gender (p-value: 0.008), pericardial effusion (p-value: 0.003), cardiac index (p-value: 0.0001), six-minute walking distance (p-value: 0.04), pulmonary arterial pressure (PAP) (p-value: 0.01), andNew York Heart Association (NYHA) classification (p-value: 0.0002). The findings of this study have important clinical implications. Assessing and managing the identified predictors, such as age, gender, pericardial effusion, PAP, cardiac index, and NYHA class, could help identify individuals at higher risk of mortality and guide treatment strategies.

Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis

ObjectivesTo mine the serum proteome of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and to detect biomarkers that may assist in earlier and more effective diagnosis and treatment.MethodsPatients with...

Soluble markers of B cell activation suggest a role of B cells in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension.

IntroductionSoluble markers of B cell activation are interesting diagnostic and prognostic tools in autoimmune diseases. Data in systemic sclerosis (SSc) are scarce and few studies focused on their association with disease characteristics.Methods1. Serum levels of 14 B cell biomarkers (β2-microglobulin, rheumatoid factor (RF), immunoglobulins (Ig) G, IgA, IgM, BAFF, APRIL, soluble (s)TACI, sBCMA sCD21, sCD23, sCD25, sCD27, CXCL13) were measured in SSc patients and healthy controls (HC). 2. Associations between these biomarkers and SSc characteristics were assessed. 3. The pathophysiological relevance of identified associations was explored by studying protein production in B cell culture supernatant.ResultsIn a discovery panel of 80 SSc patients encompassing the broad spectrum of disease manifestations, we observed a higher frequency of RF positivity, and increased levels of β2-microglobulin, IgG and CXCL13 compared with HC. We found significant associations between several biomarkers and SSc characteristics related to disease phenotype, activity and severity. Especially, serum IgG levels were associated with pulmonary hypertension (PH); β2-microglobulin with Nt-pro-BNP and DLCO; and BAFF with peak tricuspid regurgitation velocity (TRV). In a validation cohort of limited cutaneous SSc patients without extensive ILD, we observed lower serum IgG levels, and higher β2-microglobulin, sBCMA, sCD23 and sCD27 levels in patients with pulmonary arterial hypertension (PAH). BAFF levels strongly correlated with Nt-pro-BNP levels, FVC/DLCO ratio and peak TRV in SSc-PAH patients. Cultured SSc B cells showed increased production of various angiogenic factors (angiogenin, angiopoietin-1, VEGFR-1, PDGF-AA, MMP-8, TIMP-1, L-selectin) and decreased production of angiopoietin-2 compared to HC.ConclusionSoluble markers of B cell activation could be relevant tools to assess organ involvements, activity and severity in SSc. Their associations with PAH could plead for a role of B cell activation in the pathogenesis of pulmonary microangiopathy. B cells may contribute to SSc vasculopathy through production of angiogenic mediators.

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.

Contribution of fatty acid oxidation to the pathogenesis of pulmonary hypertension.

Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.

Right Ventricle to Pulmonary Artery Coupling Predicts the Risk Stratification in Patients With Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

BackgroundPulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc). PAH has high mortality, and risk assessment is critical for proper management. Whether the right ventricle to pulmonary artery (RV-PA) coupling accurately assesses risk status and predicts prognosis in patients with SSc-associated PAH has not been investigated.MethodsBetween March 2010 and July 2018, 60 consecutive patients with SSc-associated PAH diagnosed by right heart catheterization were enrolled prospectively, and the mean follow-up period was 52.9 ± 27.0 months. The RV-PA coupling was assessed by the ratio of tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) which was obtained by transthoracic echocardiography. The simplified risk stratification strategy was applied to assess the risk level of participants, and the endpoint was a composite of all-cause death and clinical worsening.ResultsThe receiver operating characteristic (ROC) curve of the ability to determine high-risk patients identified the optimal cut-off value of the TAPSE/PASP ratio as 0.194 mm/mmHg, and the ratio appeared to be a reliable indicator in the stratification of patients with high risk (area under the curve = 0.878, ROC P-value = 0.003), which showed the highest positive likelihood ratio (LR) (5.4) and the lowest negative LR (0) among a series of echocardiographic parameters. The TAPSE/PASP ratio was an independent predictive factor (HR = 0.01, 95% CI: 0.00–0.77, P = 0.037) for the composite endpoint, and patients with a TAPSE/PASP ratio >0.194 had a better overall survival for both the composite endpoint (log-rank χ2 = 5.961, P = 0.015) and all-cause mortality (log-rank χ2 = 8.004, P = 0.005) compared to the patients with a TAPSE/PASP ≤ 0.194.ConclusionRV-PA coupling assessed by the TAPSE/PASP ratio provides added value as a straightforward and non-invasive approach for predicting risk stratification of patients with SSc-associated PAH. Meanwhile, a lower TAPSE/PASP ratio identified a subgroup with worse prognosis.

Impact of routine screening on detection, severity and outcome of pulmonary arterial hypertension in systemic sclerosis

Abstract Introduction It has been reported that up to 20% of systemic sclerosis (SSc) patients can be asymptomatic at the time of pulmonary arterial hypertension (PAH) diagnosis. The significant prevalence rate, lack of symptoms and high morbidity and mortality from SSc-PAH as well as the potential benefit from early intervention with the more widely available therapeutic options provide a strong rationale for active screening programs. The DETECT algorithm was developed in 2013 from a large prospective and multicentre study in SSc patients with higher risk of PAH. The objective of this study was to examine the impact of a screening program on the early detection of SSc-PAH. We looked at serial patients diagnosed with SSc associated PAH (SSC-PAH) in a large national pulmonary hypertension referral centre. Patients and methods All newly diagnosed adult patients with SSc-PAH prospectively enrolled in a large national pulmonary hypertension referral centre. The current study included newly diagnosed patients between January 2006 and January 2018. Results Three-hundred and five patients were diagnosed with SSc-PAH in our centre between 2006 and 2018. Of these, 164 patients were diagnosed before 2013 (January 2006 - December 2012) and 141 after 2013 (January 2013 - January 2018). Demographics were similar at presentation between the two groups. The non-invasive (WHO-FC, 6-MWD and NT-proBNP) and haemodynamic measurements (RAP, CI and SvO2) were used to calculate the ESC guidelines risk score. It was noted that higher proportion of patients in the post-2013 were in the higher risk categories than the pre 213 group (84.4% vs. 78%) but this was not found to be statistically significant (p value 0.356). There was no statistically significant difference in survival between the two groups (Post 2013 group, 1-, 3- year and 5-year survival was 87.9%, 60.4% and 52.1%, respectively and pre-2013 group 1-, 3- year and 5-year survival 89.6%, 65.2% and 49%, respectively) with a log rank p value of 0.869. Applying Cox regression analysis of proportional hazard and adjusting for ESC risk score at baseline, predicted survival was not found to be statistically different between the two groups. The ESC risk category at baseline was a highly significant predictor of survival as expected. Conclusion There remains a strong rationale for active screening for PAH in SSc patients which has a poor prognosis despite advances in therapeutic strategies. However, the current screening programme does not seem to have resulted in significantly earlier detection in this cohort. It would be important to analyse other patient populations in order to understand the impact of screening programmes. The current screening programs limitations may explain why we have not been able to detect more patients in the lower risk categories. Further development of these programs in order to overcome their shortfalls is direly needed. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Health ServiceRoyal Free NHS Trust Survival analysis

The expression profiling of microRNA in systemic sclerosis-associated pulmonary arterial hypertension.

BackgroundThe role of microRNAs (miRNAs) in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) remains to be fully elucidated. This study evaluated the expression profile of miRNAs in the lung tissue of patients with SSc-PAH.MethodsLung tissue samples were collected from 3 SSc-PAH patients and 4 healthy controls. A small RNA high throughput sequence approach was used for screening the differentially expressed miRNAs in the lung tissue samples. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate 4 highly significant differentially expressed miRNAs. Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for mRNAs were performed using the R package clusterProfiler software.ResultsA total of 82 upregulated miRNAs and 35 downregulated miRNAs were detected in the lung tissues of patients with SSc-PAH compared with healthy controls. GO enrichment analysis demonstrated that the upregulated target genes were closely involved in biological processes such as nervous system development, anatomical structure morphogenesis, system development, cellular macromolecule metabolic processes, and cellular processes. The downregulated target genes were involved in the plasma membrane bound cell projection morphogenesis and the regulation of macromolecule metabolic processes. The KEGG enrichment analysis showed that the upregulated genes were associated with important pathways involved in cancer biology, and the target genes of the downregulated miRNAs were involved in axon guidance. High throughput sequencing and qRT-PCR revealed that hsa-miR-205-5p and hsa-miR-539-3p were differentially expressed in SSc-PAH tissue. The target genes of hsa-miR-205-5p and hsa-miR-539-3p, IRF1and ADCYAP1, respectively, were verified using the high throughput dataset GSE48149.ConclusionsmiRNAs may play an important role in the pathogenesis of SSc-PAH, and hsa-miR-205-5p and hsa-miR-539-3p may be potential therapeutic targets in patients with SSc-PAH.

Systemic sclerosis-associated pulmonary arterial hypertension in children.

Systemic sclerosis (SSc) is a rare disease in childhood and is characterized by a combination of vasculopathy, inflammation, autoimmunity, and fibrogenesis with individually varying expression pattern. Pulmonary arterial hypertension (PAH) is a serious complication of SSc and affects approximately 10% of SSc patients. SSc-PAH is complex and difficult to diagnose, as symptoms are non-specific and may be complicated by other SSc-associated diseases such as interstitial lung disease or left heart disease. SSc-PAH patients can deteriorate rapidly, and disease progression can occur even in patients with mild PAH symptoms at diagnosis. Therefore, interdisciplinary care of SSc patients is essential, and treating physicians must be aware of the association between SSc and PAH. In order to detect PAH early, children with SSc should be regularly screened for PAH by pediatric cardiologists. If PAH is detected, a systematic diagnostic approach by trained PH specialists including careful phenotyping of PAH is required. Relevant interstitial lung disease and left heart disease should be ruled out in the differential diagnosis of SSc-PAH before starting any targeted therapy. Due to the progressive character of SSc-PAH known from adult studies, it appears appropriate to initiate targeted PAH-therapy in juvenile SSc-PAH early. Adapted from adult treatment algorithms, combination therapy regimens (addressing at least two pathophysiological pathways) are increasingly used for pediatric PAH patients, and there is growing evidence to support this approach also in SSc-PAH patients.

The assessment of left heart disease in patients with systemic sclerosis and pulmonary hypertension.

Systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) is of clinical significance owing to its poor outcome. One of the explanations for the outcome is the co-presence of left heart disease (LHD). The aim of this study is to assess LHD phenotype in patients with SSc and pulmonary hypertension (PH). This study included consecutive patients with SSc who underwent right heart catheterisation to diagnose PAH. Heart failure with preserved ejection fraction (HFpEF) was evaluated according to the recommendation of 6th WSPH and to the Framingham criteria. In total, 76 patients were enrolled in this study. Of them, 42 had PH (mPAP >20 mmHg) with a normal left ventricle ejection fraction (≥50%). Among the 42 patients, four and three patients were classified "HFpEF not excluded" and "HFpEF confirmed" whereas 10 had a clinical diagnosis of HFpEF according to 6th WSPH and Framingham criteria, respectively. These differences were due mainly to relatively low PAWP (<13 mmHg). By a combination of ROC curve and logistic regression analyses, left atrial dimension and left ventricular end-diastolic volume index assessed with echocardiography and cardiac MRI, respectively, had significantly higher predictive values for detecting the complication of HFpEF rather than PAWP. Morphological evaluation using echocardiography and cardiac MRI, compared with haemodynamic evaluation by PAWP, may better reflect the copresence of LHD phenotype in patients with SSc and PH. Our data would also indicate a limited elevation of PAWP in patients with SSc, PH and HFpEF.

Intravenous prostanoids in systemic sclerosis-associated pulmonary arterial hypertension: a single-centre experience.

The current study evaluates survival rates among SSc-associated pulmonary arterial hypertension (SSc-PAH) patients on i.v. prostanoids, and short-term impact of i.v. prostanoids on clinical and haemodynamic parameters. Baseline demographics, invasive and non-invasive data, European Society of Cardiology (ESC) score and REVEAL score of 81 SSc-PAH patients (median age 61 years, interquartile range 54-67 years, 84% females) were prospectively recorded, from November 2006 till November 2020, before initiation of i.v. prostanoids, and at first formal reassessment. Survival data were retrieved from National Health Service Spine and hospital databases. Significant improvements in clinical and haemodynamic parameters in response to i.v. prostanoid therapy were documented. Functional class (FC) (16.6% improved by 1FC, P =0.041), mean pulmonary arterial pressure (-6.5 mmHg, P =0.036), pulmonary vascular resistance (-2.6 WU, P =0.012), cardiac index (Q/m2) (+0.7 l/min/m2, P =0.003) and mixed venous oxygen saturation (SvO2) (+3%, P =0.036) improved. Estimated survival for CTD-PAH patients on i.v. prostanoids was 64%, 31% and 18%, at 1 year, 3 years and 5 years, respectively. Independent baseline predictors of mortality were older age (HR: 1.043, 95% CI: 1.011-1.075, P =0.007), higher N-terminal pro-brain natriuretic peptide levels (HR: 2.191, 95% CI: 1.131-4.243, P =0.020), and lower SvO2 levels (HR: 0.962, 95% CI: 0.926-0.998, P =0.039). High ESC risk or high and very high REVEAL score was associated with significantly worse survival compared with patients with lower risk scores, both at baseline and when reassessed after a median of 6.5 months. Survival among SSc-PAH patients on i.v. prostanoids remains poor, risk scoring at baseline and after 6.5 months of therapy improves prognostication.

Interventricular systolic asynchrony predicts prognosis in patients with systemic sclerosis-associated pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a serious complication of SSc with high mortality. Interventricular systolic asynchrony (IVSA) is observed in PAH patients, but the effect of IVSA and its association with long-term mortality and clinical events in SSc-associated PAH are unclear. This study aimed to investigate the impact of IVSA on the prognosis of SSc-associated PAH. Between March 2010 and July 2018, a total of 60 consecutive patients with SSc-associated PAH were enrolled. The end point was a composite of all-cause mortality and clinical worsening. Asynchrony was assessed by colour-coded tissue Doppler imaging (TDI) echocardiography. The myocardial sustained systole curves (Sm) of the basal portion of the right ventricular (RV) free wall and left ventricular (LV) lateral wall were obtained. IVSA was defined as the time difference from the onset of the QRS complex to the end of Sm between LV and RV. Patients with greater IVSA time differences presented with advanced pulmonary vascular resistance (PVR). The IVSA time difference was an independent predictive factor (Hazard Ratio (HR) = 1.018, 95% CI: 1.005, 1.031, P =0.005) for the composite end point and was significantly associated with PVR (r = 0.399, R2=0.092, P =0.002). Kaplan-Meier survival curves showed that patients with greater IVSA had worse prognoses (log-rank P =0.001). In conclusion, IVSA analysed by colour-coded TDI echocardiography provided added value as a noninvasive, easy-to-use approach for assessing the prognosis of patients with SSc-associated PAH. A significant IVSA time difference identifies the subgroup of patients at high risk of a poor prognosis.