BACKGROUND:Sotatercept is a novel drug therapy for pulmonary arterial hypertension (PAH) that significantly reduces clinical worsening and improves exercise capacity, functional class, and pulmonary haemodynamics. This study aims to use cardiovascular magnetic resonance (CMR) to monitor the cardiac response to sotatercept in patients with PAH. METHODS:Patients with PAH at intermediate-high or high mortality risk and already on background maximal triple PAH therapies, including parenteral prostacyclin analog for at least 3 months, were offered enrollment to a patient access program for sotatercept at the Royal Free Hospital National Pulmonary Hypertension Service. Baseline and follow-up CMR studies were performed at a median interval of 24 (interquartile range 6) weeks. RESULTS:Eighteen out of 23 patients enrolled in the sotatercept access program underwent baseline and follow-up CMR studies (3 patients paused or discontinued sotatercept prior to 12 weeks; 2 patients were unable to undergo CMR). All 18 patients were stratified as being of intermediate-high mortality risk. Significant improvements were observed in right ventricular (RV) size (RV end-diastolic volume -34±30 mL, p = 0.0023; RV end-systolic volume -27 ± 29 mL, p = 0.0023), RV mass (Z = -2.63, p = 0.016), RV function (RV ejection fraction 5 ± 8%, p = 0.034) and right atrial size (-6 ± 4 cm2, p = 0.0023). End-systolic interventricular septal curvature also significantly improved at follow-up (Z = 2.07, p = 0.046), suggesting improvement in RV afterload. Five (28%) patients also had a new-onset (1) or larger (4) pericardial effusion without haemodynamic compromise at follow-up, despite improvements in clinical, biochemical, and CMR metrics of PAH. The median increase in pericardial effusion volume was 69% (full range 33%-203%, Z = 2.0, p = 0.043). CONCLUSION:CMR tracks improvements in right heart chamber size, mass, and function along with metrics of RV afterload in patients with PAH receiving sotatercept. The improvements in RV size and function met or exceeded the clinically relevant minimally important differences for these CMR-derived metrics in patients with PAH. Routine interval surveillance with CMR in patients receiving sotatercept will also enable surveillance for the off-target finding of new-onset or worsening pericardial effusions.

Introduction The value of exercise cardiovascular magnetic resonance (CMR) has been shown in many clinical scenarios. We have developed a MR-compatible exercise apparatus and aim to validate it against the reference standard MR-conventional ergometer. Methods The novel device consisted of two half-pipes fixed to a wooden base, with participants wearing knee-length socks with a 0.5kg weight in each sock. Increased workload was achieved by increasing the rate of alternating leg flexion and extension in time with a bleep sound of increasing frequency. Twenty subjects (10 healthy volunteers, 10 patients with pulmonary hypertension) performed two CMR-augmented cardiopulmonary exercise tests (CMR-CPET) using the novel exercise apparatus and a conventional ergometer in a randomised order. Results Comparing peak metrics elicited on both exercise devices, there was a moderate correlation in peak oxygen consumption (VO2, r=0.86, P<0.001), cardiac output (CO, r=0.66, P=0.002), stroke volume (SV, r=0.75, P<0.001), peak heart rate (HR, r=0.65, P=0.002) and peak arteriovenous oxygen content gradient (△avO2, r=0.71, P<0.001). However, all metrics (except peak SV) were significantly lower from the novel device. Both devices were able to elicit statistically significant differences in VO2, HR and RVEF between patients and healthy subjects (P≤0.036). Conclusions We have created a simple, easy to use and affordable exercise apparatus for CMR environment. This may encourage greater dissemination of exercise CMR in clinical and research practice. Keywords: exercise CMR device, pulmonary hypertension, systemic sclerosis ### Competing Interest Statement Funding Dr D.S.K. is supported by a British Heart Foundation (BHF) Clinical Research Leave Fellowship (FS/CRLF/20/23004) and by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). Prof. M.F. is supported by a BHF Intermediate Fellowship (FS/18/21/33447). Declaration of interest There are no conflicts of interest in relation to the work in this manuscript. Non-conflicting relationships with industry are detailed below: D.S.K. reports consulting fees, speaker bureau fees and research funding from Johnson & Johnson. T.K. reports speaker bureau fees from Janssen and Inari. M.F. reports consulting income from Intellia, Novo Nordisk, Pfizer, Eidos, Prothena, Alnylam, Alexion, Janssen and Ionis. J.G.C. reports consulting fees from Acceleron, consulting and speaker bureau fees from Bayer, GSK and Johnson & Johnson, and research funding from Johnson & Johnson. R.V. reports support for attending meetings and travel from Janssen. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by UK National Health Service, Health Research Authority, Research Ethics Committee and the study conformed to the declaration of Helsinki (IRAS project ID 226101; REC reference 17/LO/1499, National Health Service Health Research Authority UK CRN 058274). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data are incorporated into the article and its online supplementary material. We do not have local ethical approval to make the study dataset publicly available. However, the study dataset will be made available to other researchers for purposes of reproducing the results or replicating the procedure upon reasonable request to the corresponding author, subject to institutional and ethical committee approvals.

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/m(2) and <= 1119 ms, respectively (P < 0.001). Patients with RVESVi <= 38 mL/m(2) and native T1 <= 1119 ms had significantly better outcomes than all other combinations (P < 0.001). Furthermore, patients with RVESVi > 38mL/m(2) and native T1 <= 1119 ms had significantly better survival than patients with RVESVi > 38mL/m(2) 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. [GRAPHICS]

Imatinib is a chemotherapeutic agent known to cause severe side effects when administrated systemically. Encapsulating imatinib in co-polymer poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) offers a targeted drug delivery. In this work, PLGA 50:50 and PLGA 75:25 NPs encapsulated imatinib using the electrohydrodynamic atomisation technique. All particles generated were spherical with a smooth surface with a size distribution of 455+115 nm (PLGA 50:50) and 363+147 nm (PLGA 75:25). Encapsulation of imatinib was shown to be higher than 75 % and was shown to increase the zeta potential of the loaded NPs. The release of imatinib showed an initial burst in the first 12 h, followed by different sustained releases with up to 70 %. Both types of imatinib-loaded NPs' effect on cell viability and their cellular uptake were also studied on A549 cells, and the antiproliferative effect was comparable to that of cells treated with free drugs. Finally, Rhodamine-B-loaded NPtreated cells demonstrated the cellular uptake of NPs.

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.

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.

ObjectivePulmonary hypertension (PH) is a serious complication of systemic sclerosis (SSc). In this study, we explored the prediction of short‐term risk for PH using serial pulmonary function tests (PFTs) and other disease features.MethodsSSc patients in whom disease onset occurred ≥10 years prior to data retrieval and for whom autoantibody specificity and PFT data were available were included in this study. Mixed‐effects modeling was used to describe changes in PFTs over time. Landmarking was utilized to include serial assessments and stratified Cox proportional hazards regression analysis with landmarks as strata was used to develop the PH prediction models.ResultsWe analyzed data from 1,247 SSc patients, 16.3% of whom were male and 35.8% of whom had diffuse cutaneous SSc. Anticentromere, antitopoisomerase, and anti–RNA polymerase antibodies were observed in 29.8%, 22.0%, and 11.4% of patients, respectively, and PH developed in 13.6% of patients. Over time, diffusing capacity for carbon monoxide (DLco) and carbon monoxide transfer coefficient (Kco) declined in all SSc patients (up to 1.5% per year) but demonstrated much greater annual decline (up to 4.5% and 4.8%, respectively) in the 5–7 years preceding PH diagnosis. Comparisons between multivariable models including either DLco, Kco, or forced vital capacity (FVC)/DLco ratio, demonstrated that both absolute values and change over the preceding year in those measurements were strongly associated with the risk of PH (hazard ratio [HR] 0.93 and 0.76 for Kco and its change; HR 0.90 and 0.96 for DLco and its change; and HR 1.08 and 2.01 for FVC/DLco ratio and its change; P < 0.001 for all). The Kco‐based model had the greatest discriminating ability (Harrell's C‐statistic 0.903).ConclusionOur findings strongly support the importance of PFT trends over time in identifying patients at risk of developing PH.

AbstractAimsCardiovascular 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 resultsA 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).ConclusionWe 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.

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/m(2)) (+0.7 l/min/m(2), P =0.003) and mixed venous oxygen saturation (SvO(2)) (+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 SvO(2) 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.

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

BACKGROUND:The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death.METHODS:A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research.RESULTS:Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning.CONCLUSIONS:With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.

Abstract Background Iron deficiency (ID) is more prevalent in systemic sclerosis (SSc) patients with pulmonary hypertension (PH) than those without and associated with worse prognosis. Few data are available about the relationship between serum iron parameters and pulmonary haemodynamics. Methods Right heart catheterisation (RHC) reports of SSc patients were retrospectively reviewed. Subjects were included in the study if they had serum iron studies done within 12 months of RHC and were either diagnosed as 1) pulmonary arteral hypertension (PAH, group 1 PH), defined as mean pulmonary artery pressure (mPAP)≥25 mmHg at rest with pulmonary artery wedge pressure ≤15 mmHg; or 2) no PH. Patients with gastrointestinal disorders that may cause low iron levels and glomerular filtration rate below 60 ml/min/1.73m2 were excluded. We recorded serum iron concentration (µmol/L), total iron-binding capacity (TIBC, µmol/L), transferrin saturation (TS, %), ferritin (µg/L), red cell distribution width (RDW, %), as well as mPAP (mmHg) and pulmonary vascular resistance (PVR, dynes/sec/cm-5). Univariable assocıatıons were assessed using Mann-Whitney test and Spearman's correlation as appropriate. Multiple regression of log-transformed mPAP and PVR and Cox regression were used to compare iron and RDW association with haemodynamics and survival. Results We included 122 subjects in the analysis, 84% were female and mean age at RHC was 57 years. The majority (73%) had limited cutaneous SSc and 34% carried anti-centromere antibodies, followed by 18% with anti-Scl70 and 8% with anti-U3RNP.At RHC, 53/122 (43%) of the patients were diagnosed with PAH. Among them we observed substantially lower levels of serum iron (8.7 vs. 12.1 µmol/L, p < 0.001), TS (15.3% vs. 22.5%, p < 0.001), ferritin (68.1 vs. 112.5 µg/L, p = 0.07), significantly higher RDW (16.4% vs. 14.8%, p < 0.001) and no difference in TIBC (57.4 vs. 54.3 µmol/L, p = 0.163), compared to subjects in whom PH was excluded. mPAP showed moderately strong negative correlation with iron concentration (Spearman's rho=-0.35, p < 0.001) and TS (Spearman's rho=-0.39, p < 0.001) and positive correlation with RDW (Spearman's rho=0.46, p < 0.001).PVR was significantly inversely correlated with iron concentration (Spearman's rho=-0.30, p = 0.001), TS (Spearman's rho=-0.37, p < 0.001 and ferritin (Spearman's rho=-0.22, p = 0.016), while it showed positive correlation with TIBC (Spearman's rho=0.28, p = 0.003) and RDW (Spearman's rho=0.37, p < 0.001).Compared to serum iron indices, RDW is a better predictor of mPAP and PVR. In addition, iron levels did not demonstrate any association with survival, while risk of death was significantly higher for patients with higher RDW (HR = 1.18, p = 0.002) and the association remained after adjusting for presence of PH (HR = 1.16, p = 0.013). Conclusion To our knowledge, this is the first study to demonstrate a significant relationship between ID state and haemodynamic measures of SSc-PAH. Our data also support RDW, as an indicator for functional iron deficiency, may serve as a biomarker for severity of pulmonary vasculopathy in SSc. Disclosures A. Sari None. S.I. Nihtyanova None. B.E. Schreiber None. G. Coghlan None. C.P. Denton None. V.H. Ong None.

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.

Sensitivity and versatility are characteristics that make a sensor device attractive for wide-spread applications in everyday life. Surface-enhanced Raman spectroscopy (SERS) is capable of providing the highest sensitivity, that of single-molecule detection, and excellent specificity due to its fingerprinting capability. However, conventional SERS substrates must be optimized to operate for a particular excitation wavelength. Here in this work, we achieve for the first time multiwavelength amplification with a hybrid plasmonic/photonic heterostructure integrating a gradient photonic crystal and an Ag nanotriangle array. We demonstrate the detection of ultrathin molecular layers showing a signal amplification for the typical laser wavelengths used in Raman spectroscopy detection. By combining photonics and plasmonics in a single silicon chip, we expand multiwavelength- and spatially-selective ultra-sensitive detection to a wide range of applications from biomedicine to safety.

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<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<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<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

Calcium pyrophosphate deposition (CPPD) disease is a crystal arthropathy primarily affecting peripheral joints, most commonly the wrist and the knees. However, CPPD in the cervical spine is a rare entity. This report describes a case of CPPD of the cervical spine which presents with symptoms of neck pain and brachalgia. A 62-year-old woman presented with left-sided upper limb and neck pain. MRI scanning revealed a low signal abnormality within the C6 and C7 vertebrae, and the possibility of lymphoma was raised. The patient was recalled for gadolinium-enhanced scans which showed perivertebral and marrow enhancement. Fine-needle aspirate histology initially suggested a spindle cell tumour or lymphoma. However, CT-guided biopsy showed positively birefringent crystals, confirming CPPD. CPPD of the spine is a rare differential of nerve impingement in the cervical spine when MRI scanning perivertebral signal enhancement. Furthermore, CPPD of the spine can mimic malignancy.

Background and Purpose Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH. Experimental Approach Twenty-one PAH patients stable on PDE5i therapy were recruited. Acute haemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14-day safety and efficacy evaluation. The primary endpoint in both steps was the maximum change in circulating atrial natriuretic peptide (ANP) concentration (Delta(max)), with secondary outcomes including pulmonary and systemic haemodynamics plus mechanistic biomarkers. Key Results Acute administration of racecadotril (100 mg) resulted in a 79% increase in the plasma ANP concentration and a 106% increase in plasma cGMP levels, with a concomitant 14% fall in pulmonary vascular resistance. Racecadotril (100 mg; t.i.d.) treatment for 14 days resulted in a 19% rise in plasma ANP concentration. Neither acute nor chronic administration of racecadotril resulted in a significant drop in mean arterial BP or any serious adverse effects. Conclusions and Implications This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger scale prospective trial.

Abstract Background The ESC/ERS 2015 guidelines presented a comprehensive risk assessment model with three risk categories based on different clinical and biomarkers data. Low, intermediate and high risk were defined with one-year mortality of <5%, 5–10% and >10%. Different groups suggested different methods of risk assessment based on this model. Purpose We applied three different methods to validate the ESC/ERS risk prediction model for one-year survival in SSc-PAH. Methods 309 patients with SSc-PAH have been diagnosed and managed in our institution from 2006 to 2017. We used three different risk assessment models that have been previously suggested. 1. Suggested by the Swedish group 1: Having a score of 1 (low risk), 2 (intermediate risk) or 3 (high risk) resulting from the average of the sum obtained after grading each of the variables (whichever available) from 1 to 3 according to ESC/ERS guidelines cut-offs for WHO-functional class (FC), 6-minute walking distance (6MWD), NT-Pro BNP, right atrial pressure (RAP) and cardiac index (CI). 2. Suggested by the French group 2: Having none, 1, 2, 3 or 4 of the following low-risk criteria of; FC, 6MWD, RAP and CI. 3. Instead of the invasive data, The French group also suggested the use of a non-invasive model including NT-Pro BNP. Patients were divided into different risk groups according to data obtained at baseline and at their 6-month follow-up. Survival analysis over a 5-year period was performed using Kaplan-Meier analysis. Results Overall median follow-up was 33.3 months. One year survival was significantly different between the risk groups (p<0.001) using either baseline or follow-up data. Applying the French group non-invasive model, almost two thirds of the population ended up in the higher risk group. Whilst applying the Swedish model, two thirds of the population ended up in the intermediate risk group. In all the models used, there were significantly less number of patients in the lower risk groups at onset with improvement of risk profile at follow up. An important advantage of the Swedish model, that it can be calculated even in the presence of missing data, a problem commonly encountered. The French models are easier to calculate but they cannot be applied when there is missing data. 5-year survival with different models Conclusion All models used were valuable in risk prediction of SSc-PAH both at onset and at follow up. However, each model has some caveats which should be considered. In all the methods used, the prevalence of high risk criteria is higher amongst the SSc-PAH population which indicates the higher risk profile at the time of diagnosis in comparison to other PAH populations, which could explain the poorer outcome.