Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus.

Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular condition in this group, present in up to 50% of people with Down syndrome and contributing to poor outcomes. Additional factors contributing to cardiovascular outcomes include pulmonary hypertension; coexistent pulmonary, endocrine, and metabolic diseases; and risk factors for atherosclerotic disease. Moreover, disparities in the cardiovascular care of people with Down syndrome compared with the general population, which vary across different geographies and health care systems, further contribute to cardiovascular mortality; this issue is often overlooked by the wider medical community. This review focuses on the diagnosis, prevalence, and management of cardiovascular disease encountered in people with Down syndrome and summarizes available evidence in 10 key areas relating to Down syndrome and cardiac disease, from prenatal diagnosis to disparities in care in areas of differing resource availability. All specialists and nonspecialist clinicians providing care for people with Down syndrome should be aware of best clinical practice in all aspects of care of this distinct population.

Improving Prognostication in Pulmonary Hypertension Using AI-quantified Fibrosis and Radiologic Severity Scoring at Baseline CT.

Background There is clinical need to better quantify lung disease severity in pulmonary hypertension (PH), particularly in idiopathic pulmonary arterial hypertension (IPAH) and PH associated with lung disease (PH-LD). Purpose To quantify fibrosis on CT pulmonary angiograms using an artificial intelligence (AI) model and to assess whether this approach can be used in combination with radiologic scoring to predict survival. Materials and Methods This retrospective multicenter study included adult patients with IPAH or PH-LD who underwent incidental CT imaging between February 2007 and January 2019. Patients were divided into training and test cohorts based on the institution of imaging. The test cohort included imaging examinations performed in 37 external hospitals. Fibrosis was quantified using an established AI model and radiologically scored by radiologists. Multivariable Cox regression adjusted for age, sex, World Health Organization functional class, pulmonary vascular resistance, and diffusing capacity of the lungs for carbon monoxide was performed. The performance of predictive models with or without AI-quantified fibrosis was assessed using the concordance index (C index). Results The training and test cohorts included 275 (median age, 68 years [IQR, 60-75 years]; 128 women) and 246 (median age, 65 years [IQR, 51-72 years]; 142 women) patients, respectively. Multivariable analysis showed that AI-quantified percentage of fibrosis was associated with an increased risk of patient mortality in the training cohort (hazard ratio, 1.01 [95% CI: 1.00, 1.02]; P = .04). This finding was validated in the external test cohort (C index, 0.76). The model combining AI-quantified fibrosis and radiologic scoring showed improved performance for predicting patient mortality compared with a model including radiologic scoring alone (C index, 0.67 vs 0.61; P < .001). Conclusion Percentage of lung fibrosis quantified on CT pulmonary angiograms by an AI model was associated with increased risk of mortality and showed improved performance for predicting patient survival when used in combination with radiologic severity scoring compared with radiologic scoring alone. © RSNA, 2024 Supplemental material is available for this article.

Systematic pulmonary embolism follow-up increases diagnostic rates of chronic thromboembolic pulmonary hypertension and identifies less severe disease: results from the ASPIRE Registry.

BACKGROUND: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS: Of 1956 patients attending the Sheffield PE clinic 3 months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2 years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS: In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.

Establishing minimally important differences for cardiac MRI end-points in pulmonary arterial hypertension.

BACKGROUND: Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives". METHODS: Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements. RESULTS: 254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening. CONCLUSIONS: This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.

Plain language summaryPulmonary arterial hypertension (PAH) is a disease of the vessels of the lung that causes their narrowing and stiffening. As a result, the heart pumping blood into these diseased lung vessels has to work harder and eventually gets worn out. PAH can affect patients' ability to function in daily activities and impact their quality of life. It also reduces their life expectancy dramatically. Patients are, therefore, often monitored and undergo several investigations to adapt treatment according to their situation. These investigations include a survey of how a patient feels (the emPHasis-10 questionnaire), functions (walking test) and how well the heart is coping with the disease (MRI of the heart). Until now, it is unclear how changes on MRI of the heart reflect changes in how a patient feels and functions. Our study identified patients that had the emPHasis-10 questionnaire, walking test and MRI of the heart at both the time of PAH diagnosis and one year later. This allowed us to compare how the changes in the different tests relate to each other. And because previous research identified thresholds for important changes in the emPHasis-10 questionnaire and the walking tests, we were able to use these tests as a benchmark for changes in the MRI of the heart. Our study identified thresholds for change on heart MRI that might indicate whether a patient has improved or worsened. This finding might have implications for how patients are monitored in clinical practice and future research on PAH treatments.

Surgery and Anesthesia in Patients with Pulmonary Hypertension.

Pulmonary hypertension is characterized by right ventricular impairment and a reduced ability to compensate for hemodynamic insults. Consequently, surgery can be challenging but is increasingly considered in view of available specific therapies and improved longer term survival. Optimal management requires a multidisciplinary patient-centered approach involving surgeons, anesthetists, pulmonary hypertension clinicians, and intensivists. The optimal pathway involves risk:benefit assessment for the proposed operation, optimization of pulmonary hypertension and any comorbidities, the appropriate anesthetic approach for the specific procedure and patient, and careful monitoring and management in the postoperative period. Where patients are carefully selected and meticulously managed, good outcomes can be achieved.

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.

Assessment of Right Ventricular Function-a State of the Art.

PURPOSE OF REVIEW: The right ventricle (RV) has a complex geometry and physiology which is distinct from the left. RV dysfunction and failure can be the aftermath of volume- and/or pressure-loading conditions, as well as myocardial and pericardial diseases. RECENT FINDINGS: Echocardiography, magnetic resonance imaging and right heart catheterisation can assess RV function by using several qualitative and quantitative parameters. In pulmonary hypertension (PH) in particular, RV function can be impaired and is related to survival. An accurate assessment of RV function is crucial for the early diagnosis and management of these patients. This review focuses on the different modalities and indices used for the evaluation of RV function with an emphasis on PH.

Cardiac magnetic resonance identifies raised left ventricular filling pressure: prognostic implications.

AIMS: Non-invasive imaging is routinely used to estimate left ventricular (LV) filling pressure (LVFP) in heart failure (HF). Cardiovascular magnetic resonance (CMR) is emerging as an important imaging tool for sub-phenotyping HF. However, currently, LVFP cannot be estimated from CMR. This study sought to investigate (i) if CMR can estimate LVFP in patients with suspected HF and (ii) if CMR-modelled LVFP has prognostic power. METHODS AND RESULTS: Suspected HF patients underwent right heart catheterization (RHC), CMR and transthoracic echocardiography (TTE) (validation cohort only) within 24 h of each other. Right heart catheterization measured pulmonary capillary wedge pressure (PCWP) was used as a reference for LVFP. At follow-up, death was considered as the primary endpoint. We enrolled 835 patients (mean age: 65 ± 13 years, 40% male). In the derivation cohort (n = 708, 85%), two CMR metrics were associated with RHC PCWP:LV mass and left atrial volume. When applied to the validation cohort (n = 127, 15%), the correlation coefficient between RHC PCWP and CMR-modelled PCWP was 0.55 (95% confidence interval: 0.41-0.66, P < 0.0001). Cardiovascular magnetic resonance-modelled PCWP was superior to TTE in classifying patients as normal or raised filling pressures (76 vs. 25%). Cardiovascular magnetic resonance-modelled PCWP was associated with an increased risk of death (hazard ratio: 1.77, P < 0.001). At Kaplan-Meier analysis, CMR-modelled PCWP was comparable to RHC PCWP (≥15 mmHg) to predict survival at 7-year follow-up (35 vs. 37%, χ2 = 0.41, P = 0.52). CONCLUSION: A physiological CMR model can estimate LVFP in patients with suspected HF. In addition, CMR-modelled LVFP has a prognostic role.

The Left Atrial Area Derived Cardiovascular Magnetic Resonance Left Ventricular Filling Pressure Equation Shows Superiority over Integrated Echocardiography.

Background and objectives: Evaluating left ventricular filling pressure (LVFP) plays a crucial role in diagnosing and managing heart failure (HF). While traditional assessment methods involve multi-parametric transthoracic echocardiography (TTE) or right heart catheterisation (RHC), cardiovascular magnetic resonance (CMR) has emerged as a valuable diagnostic tool in HF. This study aimed to assess a simple CMR-derived model to estimate pulmonary capillary wedge pressure (PCWP) in a cohort of patients with suspected or proven heart failure and to investigate its performance in risk-stratifying patients. Materials and methods: A total of 835 patients with breathlessness were evaluated using RHC and CMR and split into derivation (85%) and validation cohorts (15%). Uni-variate and multi-variate linear regression analyses were used to derive a model for PCWP estimation using CMR. The model's performance was evaluated by comparing CMR-derived PCWP with PCWP obtained from RHC. Results: A CMR-derived PCWP incorporating left ventricular mass and the left atrial area (LAA) demonstrated good diagnostic accuracy. The model correctly reclassified 66% of participants whose TTE was 'indeterminate' or 'incorrect' in identifying raised filling pressures. On survival analysis, the CMR-derived PCWP model was predictive for mortality (HR 1.15, 95% CI 1.04-1.28, p = 0.005), which was not the case for PCWP obtained using RHC or TTE. Conclusions: The simplified CMR-derived PCWP model provides an accurate and practical tool for estimating PCWP in patients with suspected or proven heart failure. Its predictive value for mortality suggests the ability to play a valuable adjunctive role in echocardiography, especially in cases with unclear echocardiographic assessment.

Quantitative CT Evaluation of Small Pulmonary Vessels Has Functional and Prognostic Value in Pulmonary Hypertension.

Background The in vivo relationship between peel pulmonary vessels, small pulmonary vessels, and pulmonary hypertension (PH) is not fully understood. Purpose To quantitatively assess peel pulmonary vessel volumes (PPVVs) and small pulmonary vessel volumes (SPVVs) as estimated from CT pulmonary angiography (CTPA) in different subtypes of PH compared with controls, their relationship to pulmonary function and right heart catheter metrics, and their prognostic value. Materials and Methods In this retrospective single-center study performed from January 2008 to February 2018, quantitative CTPA analysis of total SPVV (TSPVV) (0.4- to 2-mm vessel diameter) and PPVV (within 15, 30, and 45 mm from the lung surface) was performed. Results A total of 1823 patients (mean age, 69 years ± 13 [SD]; 1192 women [65%]) were retrospectively analyzed; 1593 patients with PH (mean pulmonary arterial pressure [mPAP], 43 mmHg ± 13 [SD]) were compared with 230 patient controls (mPAP, 19 mm Hg ± 3). The mean vessel volumes in pulmonary peels at 15-, 30-, and 45-mm depths were higher in pulmonary arterial hypertension (PAH) and PH secondary to lung disease compared with chronic thromboembolic PH (45-mm peel, mean difference: 6.4 mL [95% CI: 1, 11] [P < .001] vs 6.8 mL [95% CI: 1, 12] [P = .01]). Mean small vessel volumes at a diameter of less than 2 mm were lower in PAH and PH associated with left heart disease compared with controls (1.6-mm vessels, mean difference: -4.3 mL [95% CI: -8, -0.1] [P = .03] vs -6.8 mL [95% CI: -11, -2] [P < .001]). In patients with PH, the most significant positive correlation was noted with forced vital capacity percentage predicted (r = 0.30-0.40 [all P < .001] for TSPVVs and r = 0.21-0.25 [all P < .001] for PPVVs). Conclusion The volume of pulmonary small vessels is reduced in pulmonary arterial hypertension and pulmonary hypertension (PH) associated with left heart disease, with similar volume of peel vessels compared with controls. For chronic thromboembolic PH, the volume of peel vessels is reduced. In PH, small pulmonary vessel volume is associated with pulmonary function tests. Clinical trial registration no. NCT02565030 Published under a CC BY 4.0 license Online supplemental material is available for this article.

Validation of Artificial Intelligence Cardiac MRI Measurements: Relationship to Heart Catheterization and Mortality Prediction.

Background Cardiac MRI measurements have diagnostic and prognostic value in the evaluation of cardiopulmonary disease. Artificial intelligence approaches to automate cardiac MRI segmentation are emerging but require clinical testing. Purpose To develop and evaluate a deep learning tool for quantitative evaluation of cardiac MRI functional studies and assess its use for prognosis in patients suspected of having pulmonary hypertension. Materials and Methods A retrospective multicenter and multivendor data set was used to develop a deep learning-based cardiac MRI contouring model using a cohort of patients suspected of having cardiopulmonary disease from multiple pathologic causes. Correlation with same-day right heart catheterization (RHC) and scan-rescan repeatability was assessed in prospectively recruited participants. Prognostic impact was assessed using Cox proportional hazard regression analysis of 3487 patients from the ASPIRE (Assessing the Severity of Pulmonary Hypertension In a Pulmonary Hypertension Referral Centre) registry, including a subset of 920 patients with pulmonary arterial hypertension. The generalizability of the automatic assessment was evaluated in 40 multivendor studies from 32 centers. Results The training data set included 539 patients (mean age, 54 years ± 20 [SD]; 315 women). Automatic cardiac MRI measurements were better correlated with RHC parameters than were manual measurements, including left ventricular stroke volume (r = 0.72 vs 0.68; P = .03). Interstudy repeatability of cardiac MRI measurements was high for all automatic measurements (intraclass correlation coefficient range, 0.79-0.99) and similarly repeatable to manual measurements (all paired t test P > .05). Automated right ventricle and left ventricle cardiac MRI measurements were associated with mortality in patients suspected of having pulmonary hypertension. Conclusion An automatic cardiac MRI measurement approach was developed and tested in a large cohort of patients, including a broad spectrum of right ventricular and left ventricular conditions, with internal and external testing. Fully automatic cardiac MRI assessment correlated strongly with invasive hemodynamics, had prognostic value, were highly repeatable, and showed excellent generalizability. Clinical trial registration no. NCT03841344 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Ambale-Venkatesh and Lima in this issue. An earlier incorrect version appeared online. This article was corrected on June 27, 2022.

Training and clinical testing of artificial intelligence derived right atrial cardiovascular magnetic resonance measurements.

BACKGROUND: Right atrial (RA) area predicts mortality in patients with pulmonary hypertension, and is recommended by the European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. The advent of deep learning may allow more reliable measurement of RA areas to improve clinical assessments. The aim of this study was to automate cardiovascular magnetic resonance (CMR) RA area measurements and evaluate the clinical utility by assessing repeatability, correlation with invasive haemodynamics and prognostic value. METHODS: A deep learning RA area CMR contouring model was trained in a multicentre cohort of 365 patients with pulmonary hypertension, left ventricular pathology and healthy subjects. Inter-study repeatability (intraclass correlation coefficient (ICC)) and agreement of contours (DICE similarity coefficient (DSC)) were assessed in a prospective cohort (n = 36). Clinical testing and mortality prediction was performed in n = 400 patients that were not used in the training nor prospective cohort, and the correlation of automatic and manual RA measurements with invasive haemodynamics assessed in n = 212/400. Radiologist quality control (QC) was performed in the ASPIRE registry, n = 3795 patients. The primary QC observer evaluated all the segmentations and recorded them as satisfactory, suboptimal or failure. A second QC observer analysed a random subcohort to assess QC agreement (n = 1018). RESULTS: All deep learning RA measurements showed higher interstudy repeatability (ICC 0.91 to 0.95) compared to manual RA measurements (1st observer ICC 0.82 to 0.88, 2nd observer ICC 0.88 to 0.91). DSC showed high agreement comparing automatic artificial intelligence and manual CMR readers. Maximal RA area mean and standard deviation (SD) DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 is 92.4 ± 3.5 cm2, 91.2 ± 4.5 cm2 and 93.2 ± 3.2 cm2, respectively. Minimal RA area mean and SD DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 was 89.8 ± 3.9 cm2, 87.0 ± 5.8 cm2 and 91.8 ± 4.8 cm2. Automatic RA area measurements all showed moderate correlation with invasive parameters (r = 0.45 to 0.66), manual (r = 0.36 to 0.57). Maximal RA area could accurately predict elevated mean RA pressure low and high-risk thresholds (area under the receiver operating characteristic curve artificial intelligence = 0.82/0.87 vs manual = 0.78/0.83), and predicted mortality similar to manual measurements, both p < 0.01. In the QC evaluation, artificial intelligence segmentations were suboptimal at 108/3795 and a low failure rate of 16/3795. In a subcohort (n = 1018), agreement by two QC observers was excellent, kappa 0.84. CONCLUSION: Automatic artificial intelligence CMR derived RA size and function are accurate, have excellent repeatability, moderate associations with invasive haemodynamics and predict mortality.

Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study.

End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test-retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen's d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log10NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen's d 0.81), whereas the effect size for the 6 min walk test (Cohen's d 0.22) and log10NT-proBNP (Cohen's d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials.Trial registration number NCT03841344.

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.

Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension.

RATIONALE: Accumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, although it remains unknown if distinct immune phenotypes exist. OBJECTIVE: Identify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles. METHODS AND RESULTS: In a prospective observational study of group 1 PAH patients evaluated at Stanford University (discovery cohort; n=281) and University of Sheffield (validation cohort; n=104) between 2008 and 2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks-cluster 1 (n=58; TRAIL [tumor necrosis factor-related apoptosis-inducing ligand], CCL5 [C-C motif chemokine ligand 5], CCL7, CCL4, MIF [macrophage migration inhibitory factor]), cluster 3 (n=77; IL [interleukin]-12, IL-17, IL-10, IL-7, VEGF [vascular endothelial growth factor]), and cluster 4 (n=37; IL-8, IL-4, PDGF-ß [platelet-derived growth factor beta], IL-6, CCL11). Demographics, PAH clinical subtypes, comorbidities, and medications were similar across clusters. Noninvasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%; 95% CI, 35.4%-64.1%) and favorable for cluster 3 (82.4%; 95% CI, 72.0%-94.3%; across-cluster P<0.001). Findings were replicated in the validation cohort, where machine learning classified 4 immune clusters with comparable proteomic, clinical, and prognostic features. CONCLUSIONS: Blood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity.

Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement.

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.

Identification of Cardiac Magnetic Resonance Imaging Thresholds for Risk Stratification in Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a life-shortening condition. The European Society of Cardiology and European Respiratory Society and the REVEAL (North American Registry to Evaluate Early and Long-Term PAH Disease Management) risk score calculator (REVEAL 2.0) identify thresholds to predict 1-year mortality.Objectives: This study evaluates whether cardiac magnetic resonance imaging (MRI) thresholds can be identified and used to aid risk stratification and facilitate decision-making.Methods: Consecutive patients with PAH (n = 438) undergoing cardiac MRI were identified from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Center) MRI database. Thresholds were identified from a discovery cohort and evaluated in a test cohort.Measurements and Main Results: A percentage-predicted right ventricular end-systolic volume index threshold of 227% or a left ventricular end-diastolic volume index of 58 ml/m2 identified patients at low (<5%) and high (>10%) risk of 1-year mortality. These metrics respectively identified 63% and 34% of patients as low risk. Right ventricular ejection fraction >54%, 37-54%, and <37% identified 21%, 43%, and 36% of patients at low, intermediate, and high risk, respectively, of 1-year mortality. At follow-up cardiac MRI, patients who improved to or were maintained in a low-risk group had a 1-year mortality <5%. Percentage-predicted right ventricular end-systolic volume index independently predicted outcome and, when used in conjunction with the REVEAL 2.0 risk score calculator or a modified French Pulmonary Hypertension Registry approach, improved risk stratification for 1-year mortality.Conclusions: Cardiac MRI can be used to risk stratify patients with PAH using a threshold approach. Percentage-predicted right ventricular end-systolic volume index can identify a high percentage of patients at low-risk of 1-year mortality and, when used in conjunction with current risk stratification approaches, can improve risk stratification. This study supports further evaluation of cardiac MRI in risk stratification in PAH.

Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

Respiratory follow-up of patients with COVID-19 pneumonia.

The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.

Mild parenchymal lung disease and/or low diffusion capacity impacts survival and treatment response in patients diagnosed with idiopathic pulmonary arterial hypertension.

There are limited published data defining survival and treatment response in patients with mild lung disease and/or reduced gas transfer who fulfil diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH).Patients diagnosed with IPAH between 2001 and 2019 were identified in the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) registry. Using prespecified criteria based on computed tomography (CT) imaging and spirometry, patients with a diagnosis of IPAH and no lung disease were termed IPAHno-LD (n=303), and those with minor/mild emphysema or fibrosis were described as IPAHmild-LD (n=190).Survival was significantly better in IPAHno-LD than in IPAHmild-LD (1- and 5-year survival 95% and 70% versus 78% and 22%, respectively; p<0.0001). In the combined group of IPAHno-LD and IPAHmild-LD, independent predictors of higher mortality were increasing age, lower diffusing capacity of the lung for carbon monoxide (D LCO), lower exercise capacity and a diagnosis of IPAHmild-LD (all p<0.05). Exercise capacity and quality of life improved (both p<0.0001) following treatment in patients with IPAHno-LD, but not IPAHmild-LD A proportion of patients with IPAHno-LD had a D LCO <45%; these patients had poorer survival than patients with D LCO ≥45%, although they demonstrated improved exercise capacity following treatment.The presence of even mild parenchymal lung disease in patients who would be classified as IPAH according to current recommendations has a significant adverse effect on outcomes. This phenotype can be identified using lung function testing and clinical CT reports. Patients with IPAH, no lung disease and severely reduced D LCO may represent a further distinct phenotype. These data suggest that randomised controlled trials of targeted therapies in patients with these phenotypes are required.