Prognostic utility of exercise cardiovascular magnetic resonance in patients with systemic sclerosis-associated pulmonary arterial hypertension.

AIMS: Systemic sclerosis complicated by pulmonary arterial hypertension (SSc-PAH) is a rare condition with poor prognosis. The majority of patients are categorized as intermediate risk of mortality. Cardiovascular magnetic resonance (CMR) is well placed to reproducibly assess right heart size and function, but most patients with SSc-PAH have less overtly abnormal right ventricles than other forms of PAH. The aim of this study was to assess if exercise CMR measures of cardiac size and function could better predict outcome in patients with intermediate risk SSc-PAH compared with resting CMR. METHODS AND RESULTS: Fifty patients with SSc-PAH categorized as intermediate risk underwent CMR-augmented cardiopulmonary exercise testing. Most patients had normal CMR-defined resting measures of right ventricular (RV) size and function. Nine (18%) patients died during a median follow-up period of 2.1 years (range 0.1-4.6). Peak exercise RV indexed end-systolic volume (ESVi) was the only CMR metric to predict prognosis on stepwise Cox regression analysis, with an optimal threshold < 39 mL/m2 to predict favourable outcome. Intermediate-low risk patients with peak RVESVi < 39 mL/m2 had significantly better survival than all other combinations of intermediate-low/-high risk status and peak RVESVi< or ≥39 mL/m2. In our cohort, ventilatory efficiency and resting oxygen consumption (VO2) were predictive of mortality, but not peak VO2, peak cardiac output, or peak tissue oxygen extraction. CONCLUSION: Exercise CMR assessment of RV size and function may help identify SSc-PAH patients with poorer prognosis amongst intermediate risk cohorts, even when resting CMR appears reassuring, and could offer added value to clinical PH risk stratification.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (P < 0.001), hypertrophied (P = 0.013) and impaired (P < 0.001) right ventricles, more dilated right atria (P = 0.043) and higher native myocardial T1 (P < 0.001).After adjustment for age, indexed right ventricular end-systolic volume (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). CONCLUSION: We identified prognostically relevant CMR metrics and thresholds for patients with SSc-PH. Assessing myocardial tissue characterisation alongside right ventricular function confers added value in SSc-PH and may represent an additional treatment target.

Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10-7) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10-4). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.

Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: a COMPERA analysis.

OBJECTIVES: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. METHODS: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. RESULTS: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively). CONCLUSIONS: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.

Performance of DETECT Pulmonary Arterial Hypertension Algorithm According to the Hemodynamic Definition of Pulmonary Arterial Hypertension in the 2022 European Society of Cardiology and the European Respiratory Society Guidelines.

OBJECTIVE: The evidence-based DETECT pulmonary arterial hypertension (PAH) algorithm is frequently used in patients with systemic sclerosis (SSc) to help clinicians screen for PAH by using noninvasive data to recommend patient referral to echocardiography and, if applicable, for a diagnostic right-sided heart catheterization. However, the hemodynamic definition of PAH was recently updated in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines. The performance of DETECT PAH in identifying patients with a high risk of PAH according to this new definition was assessed. METHODS: In this post hoc analysis of DETECT, which comprised 466 patients with SSc, the performance of the DETECT PAH algorithm in identifying patients with a high risk of PAH as defined in the 2022 ESC/ERS guidelines (mean pulmonary arterial pressure [mPAP] >20 mm Hg, pulmonary capillary wedge pressure [PCWP] ≤15 mm Hg, and pulmonary vascular resistance >2 Wood units) was assessed using summary statistics and was descriptively compared to the known performance of DETECT PAH as defined in 2014, when it was developed (mPAP ≥25 mm Hg and PCWP ≤15 mm Hg). RESULTS: The sensitivity of DETECT PAH in identifying patients with a high risk of PAH according to the 2022 ESC/ERS definition was lower (88.2%) compared to the 2014 definition (95.8%). Specificity improved from 47.8% to 50.8%. CONCLUSION: The performance of the DETECT algorithm to screen for PAH in patients with SSc is maintained when PAH is defined according to the 2022 ESC/ERS hemodynamic definition, indicating that DETECT remains applicable to screen for PAH in patients with SSc.

Pulmonary hypertension - the latest updates for physicians.

Pulmonary hypertension (PH) is common, with an estimated prevalence of approximately 1% that increases with age. Prompt and accurate diagnosis is key to institute timely and appropriate therapy to improve symptoms and prognosis. The international guidelines for the diagnosis and management of PH have recently been updated, with a lowering of the haemodynamic threshold for diagnosis to a mean pulmonary artery pressure >20 mmHg. New diagnostic algorithms and revised indications for screening in at-risk groups have been developed to facilitate early referral to specialist PH centres. This includes fast-track referral pathways for patients who are either clinically high-risk or are at-risk for pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). This review summarises key changes in the PH guidelines for general physicians who are, most often, the first healthcare professionals to encounter these patients and consequently have a key role as referrers into specialist PH services.

Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study.

BACKGROUND AND AIMS: Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. METHODS: A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21-24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21-24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group. RESULTS: Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21-24 mmHg) or PVR (>2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68.2% of patients with a mPAP 21-24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21-24 mmHg, survival curves only diverged after 5 years. CONCLUSIONS: This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines.

Early selexipag initiation and long-term outcomes: insights from randomised controlled trials in pulmonary arterial hypertension.

Further understanding of when to initiate therapies in pulmonary arterial hypertension (PAH) is important to improve long-term outcomes. Post hoc analyses of GRIPHON (NCT01106014) and exploratory analyses of TRITON (NCT02558231) suggested benefit of early selexipag initiation on long-term outcomes, despite no additional benefit versus initial double combination on haemodynamic and functional parameters in TRITON. Post hoc analyses investigated the effect of early selexipag initiation on disease progression and survival in a large, pooled PAH cohort. Data from newly diagnosed (≤6 months) PAH patients from GRIPHON and TRITON were pooled. Patients on active therapy with selexipag (pooled selexipag group) were compared with those on control therapy with placebo (pooled control group). Disease progression end-points were defined as per the individual studies. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) +7 days and time to all-cause death up to end of study were estimated using Cox regression models. The pooled dataset comprised 649 patients, with 44% on double background therapy. Selexipag reduced the risk of disease progression by 52% versus control (HR: 0.48; 95% CI: 0.35-0.66). HR for risk of all-cause death was 0.70 (95% CI: 0.46-1.10) for the pooled selexipag versus control group. Sensitivity analyses accounting for the impact of PAH background therapy showed consistent results, confirming the appropriateness of data pooling. These post hoc, pooled analyses build on previous insights, further supporting selexipag use within 6 months of diagnosis, including as part of triple therapy, to delay disease progression.

Distinct cardiovascular phenotypes are associated with prognosis in systemic sclerosis: a cardiovascular magnetic resonance study.

AIMS: Cardiovascular involvement in systemic sclerosis (SSc) is heterogeneous and ill-defined. This study aimed to: (i) discover cardiac phenotypes in SSc by cardiovascular magnetic resonance (CMR); (ii) provide a CMR-based algorithm for phenotypic classification; and (iii) examine for associations between phenotypes and mortality. METHODS AND RESULTS: A retrospective, single-centre, observational study of 260 SSc patients who underwent clinically indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2019 was performed. Agglomerative hierarchical clustering using only CMR variables revealed five clusters of SSc patients with shared CMR characteristics: dilated right hearts with right ventricular failure (RVF); biventricular failure dilatation and dysfunction (BVF); and normal function with average cavity (NF-AC), normal function with small cavity (NF-SC), and normal function with large cavity (NF-LC) sizes. Phenotypes did not co-segregate with clinical or antibody classifications. A CMR-based decision tree for phenotype classification was created. Sixty-three (24%) patients died during a median follow-up period of 3.4 years. After adjustment for age and presence of pulmonary hypertension (PH), independent CMR predictors of all-cause mortality were native T1 (P < 0.001) and right ventricular ejection fraction (RVEF) (P = 0.0032). NF-SC and NF-AC groups had more favourable prognoses (P≤0.036) than the other three groups which had no differences in prognoses between them (P > 0.14). Hazard ratios (HR) were statistically significant for RVF (HR = 8.9, P < 0.001), BVF (HR = 5.2, P = 0.006), and NF-LC (HR = 4.9, P = 0.002) groups. The NF-LC group remained significantly predictive of mortality after adjusting for RVEF, native T1, and PH diagnosis (P = 0.0046). CONCLUSION: We identified five CMR-defined cardiac SSc phenotypes that did not co-segregate with clinical data and had distinct outcomes, offering opportunities for a more precision-medicine based management approach.

Effects of late, repetitive remote ischaemic conditioning on myocardial strain in patients with acute myocardial infarction.

Late, repetitive or chronic remote ischaemic conditioning (CRIC) is a potential cardioprotective strategy against adverse remodelling following ST-segment elevation myocardial infarction (STEMI). In the randomised Daily Remote Ischaemic Conditioning Following Acute Myocardial Infarction (DREAM) trial, CRIC following primary percutaneous coronary intervention (P-PCI) did not improve global left ventricular (LV) systolic function. A post-hoc analysis was performed to determine whether CRIC improved regional strain. All 73 patients completing the original trial were studied (38 receiving 4 weeks' daily CRIC, 35 controls receiving sham conditioning). Patients underwent cardiovascular magnetic resonance at baseline (5-7 days post-STEMI) and after 4 months, with assessment of LV systolic function, infarct size and strain (longitudinal/circumferential, in infarct-related and remote territories). At both timepoints, there were no significant between-group differences in global indices (LV ejection fraction, infarct size, longitudinal/circumferential strain). However, regional analysis revealed a significant improvement in longitudinal strain in the infarcted segments of the CRIC group (from - 16.2 ± 5.2 at baseline to - 18.7 ± 6.3 at follow up, p = 0.0006) but not in corresponding segments of the control group (from - 15.5 ± 4.0 to - 15.2 ± 4.7, p = 0.81; for change: - 2.5 ± 3.6 versus + 0.3 ± 5.6, respectively, p = 0.027). In remote territories, there was a lower increment in subendocardial circumferential strain in the CRIC group than in controls (- 1.2 ± 4.4 versus - 2.5 ± 4.0, p = 0.038). In summary, CRIC following P-PCI for STEMI is associated with improved longitudinal strain in infarct-related segments, and an attenuated increase in circumferential strain in remote segments. Further work is needed to establish whether these changes may translate into a reduced incidence of adverse remodelling and clinical events. Clinical Trial Registration: http://clinicaltrials.gov/show/NCT01664611 .

Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension.

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

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

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

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Survival among SSc-PAH patients on i.v. prostanoids remains poor, risk scoring at baseline and after 6.5 months of therapy improves prognostication.

Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension.

INTRODUCTION: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag. METHODS: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019. RESULTS: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively. CONCLUSIONS: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.

Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy.

Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.

Reduced exercise capacity in patients with systemic sclerosis is associated with lower peak tissue oxygen extraction: a cardiovascular magnetic resonance-augmented cardiopulmonary exercise study.

BACKGROUND: Exercise intolerance in systemic sclerosis (SSc) is typically attributed to cardiopulmonary limitations. However, problems with skeletal muscle oxygen extraction have not been fully investigated. This study used cardiovascular magnetic resonance (CMR)-augmented cardiopulmonary exercise testing (CMR-CPET) to simultaneously measure oxygen consumption and cardiac output. This allowed calculation of arteriovenous oxygen content gradient, a recognized marker of oxygen extraction. We performed CMR-CPET in 4 groups: systemic sclerosis (SSc); systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH); non-connective tissue disease pulmonary hypertension (NC-PAH); and healthy controls. METHODS: We performed CMR-CPET in 60 subjects (15 in each group) using a supine ergometer following a ramped exercise protocol until exhaustion. Values for oxygen consumption, cardiac output and oxygen content gradient, as well as ventricular volumes, were obtained at rest and peak-exercise for all subjects. In addition, T1 and T2 maps were acquired at rest, and the most recent clinical measures (hemoglobin, lung function, 6-min walk, cardiac and catheterization) were collected. RESULTS: All patient groups had reduced peak oxygen consumption compared to healthy controls (p < 0.022). The SSc and SSc-PAH groups had reduced peak oxygen content gradient compared to healthy controls (p < 0.03). Conversely, the SSc-PAH and NC-PH patients had reduced peak cardiac output compared to healthy controls and SSc patients (p < 0.006). Higher hemoglobin was associated with higher peak oxygen content gradient (p = 0.025) and higher myocardial T1 was associated with lower peak stroke volume (p = 0.011). CONCLUSIONS: Reduced peak oxygen consumption in SSc patients is predominantly driven by reduced oxygen content gradient and in SSc-PAH patients this was amplified by reduced peak cardiac output. Trial registration The study is registered with ClinicalTrials.gov Protocol Registration and Results System (ClinicalTrials.gov ID: 100358).

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

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

Pulmonary thrombosis in Covid-19: before, during and after hospital admission.

Disordered coagulation, endothelial dysfunction, dehydration and immobility contribute to a substantially elevated risk of deep venous thrombosis, pulmonary embolism (PE) and systemic thrombosis in coronavirus disease 2019 (Covid-19). We evaluated the prevalence of pulmonary thrombosis and reported RV (right ventricular) dilatation/dysfunction associated with Covid-19 in a tertiary referral Covid-19 centre. Of 370 patients, positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 39 patients (mean age 62.3 ± 15 years, 56% male) underwent computed tomography pulmonary angiography (CTPA), due to increasing oxygen requirements or refractory hypoxia, not improving on oxygen, very elevated D-dimer or tachycardia disproportionate to clinical condition. Thrombosis in the pulmonary vasculature was found in 18 (46.2%) patients. However, pulmonary thrombosis did not predict survival (46.2% survivors vs 41.7% non-survivors, p = 0.796), but RV dilatation was less frequent among survivors (11.5% survivors vs 58.3% non-survivors, p = 0.002). Over the following month, we observed four Covid-19 patients, who were admitted with high and intermediate-high risk PE, and we treated them with UACTD (ultrasound-assisted catheter-directed thrombolysis), and four further patients, who were admitted with PE up to 4 weeks after recovery from Covid-19. Finally, we observed a case of RV dysfunction and pre-capillary pulmonary hypertension, associated with Covid-19 extensive lung disease. We demonstrated that pulmonary thrombosis is common in association with Covid-19. Also, the thrombotic risk in the pulmonary vasculature is present before and during hospital admission, and continues at least up to four weeks after discharge, and we present UACTD for high and intermediate-high risk PE management in Covid-19 patients.

EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study.

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively "(I/D/H)PAH"), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=-0.546), incremental shuttle walk distance (r=-0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0-16, 17-33 and 34-50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity.

Whole-Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome.

Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk.Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis.Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study.Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776; P = 0.012).Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.