Robin Condliffe

Background: Right heart catheterization is the gold standard for diagnosing heart failure with preserved ejection fraction but is invasive and not readily accessible. The left atrioventricular coupling index (LACI), defined as the ratio of left atrial minimal volume to left ventricular end‐diastolic volume, has been proposed as a surrogate of left ventricular diastolic dysfunction. This study compares 3 imaging modalities for LACI assessment and evaluates diagnostic performance for heart failure with preserved ejection fraction. Methods: We retrospectively included 1680 patients from 2 academic hospitals (Amsterdam UMC, The Netherlands, and ASPIRE registry). All underwent diagnostic right heart catheterization and cardiac magnetic resonance imaging (CMR); a subset additionally underwent cardiac computed tomography, and/or echocardiography. Patients were divided into derivation and validation cohorts. left atrial and left ventricular volumes were measured at end‐diastole. Agreement between imaging modalities was evaluated with Bland–Altman plots. The predictive performance of LACI for heart failure with preserved ejection fraction was evaluated using receiver operating characteristic analysis, with cut‐off values derived in the derivation cohort and tested unchanged in the validation cohort. Results: Assessment of LACI measurement accuracy across imaging modalities showed strong agreement between CMR and echocardiography. CMR LACI outperformed echocardiography (area‐under‐the‐curve=0.84 versus 0.65), while cardiac computed tomography tended to overestimate LACI. The derivation cohort identified LACI ≥36% on CMR as the optimal threshold (sensitivity: 64%, specificity: 83%), which was tested in the validation cohort (sensitivity: 58%, specificity: 82%). Conclusions: LACI ≥ 36%, particularly measured via CMR, shows strong diagnostic potential for heart failure with preserved ejection fraction as a noninvasive adjunct to current diagnostic strategies.

Background: Pulmonary arterial hypertension (PAH) is a severe, progressive disease of the small pulmonary arteries. These guidelines provide updated evidence-based recommendations for the treatment of PAH focusing on the latest scientific evidence on sotatercept, an activin signalling inhibitor targeting a novel pathway for the treatment of PAH, and on the role of right heart catheterisation (RHC) in the management of PAH patients during follow-up. Methods: A European Respiratory Society (ERS) Task Force, comprising global experts, methodologists and a patient representative, developed these clinical practice guidelines in accordance with ERS methodology and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. Four PICO (Patients, Intervention, Comparator, Outcomes) questions and one narrative question have been addressed. Recommendations: The Task Force recommends add-on treatment with sotatercept in PAH patients who already receive PAH drugs and are at intermediate-low, intermediate-high or high risk of death during follow-up; this recommendation is based on a high certainty of evidence available from randomised controlled trials (RCTs). In PAH patients at low risk of death, the Task Force does not provide a recommendation due to the low certainty of evidence and the limited number of such patients included in RCTs. To monitor safety and efficacy, patients receiving sotatercept should be treated in pulmonary hypertension centres and their management should include regular follow-up and appropriate examinations. To guide treatment strategy, the Task Force suggests performing RHC during follow-up in PAH patients who receive PAH drugs and are at intermediate-low, intermediate-high or high risk of death, when therapeutic consequences are expected. The Task Force does not provide a recommendation for this question in PAH patients at low risk of death, due to the very low certainty of evidence. Conclusion: The ERS guidelines on the treatment of PAH provide an updated evidence-based framework for the optimal management of patients with PAH.

Introduction: Although current international guidelines provide comprehensive evidence-based guidance for the management of pulmonary hypertension, clinicians are still regularly faced with uncertainty regarding correct diagnosis and optimal treatment. Methods: Ten diagnostic and management dilemmas were formulated by a panel of experts in the field of pulmonary hypertension. Current evidence was reviewed and a practical approach suggested for each dilemma. Results: Diagnostic and management dilemmas discussed include pulmonary hypertension with high cardiac output, idiopathic pulmonary arterial hypertension in the presence of cardiopulmonary comorbidities, pulmonary hypertension associated with left heart disease, pulmonary hypertension and obesity, chronic thromboembolic pulmonary hypertension mimics and Group 5 pulmonary hypertension associated with sarcoidosis, fibrosing mediastinitis and neurofibromatosis type 1. Conclusions: The suggested approaches are informed by a review of existing evidence and guidelines, as well as clinical experience.

Objectives: There are limited data comparing parameters reflecting gas transfer used to assess the likelihood of pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) and regarding the impact of transitioning to Global Lung Initiative (GLI)-predicted values. Methods: 632 patients with suspected SSc-associated PH were identified from the ASPIRE registry. Spirometry and computed tomography reports were reviewed to identify significant lung disease. Receiver operating characteristic curve analysis and correlations of the three markers of gas transfer with pulmonary arterial pressure were performed. Results: Correlations of GLI-derived values with mean pulmonary arterial pressure were diffusing capacity of the lung for carbon monoxide ( D _LCO )% r= −0.45, transfer coefficient of the lung for carbon monoxide ( K _CO )% r= −0.42 and forced vital capacity (FVC)%/ D _LCO % r=0.37. Correlations in patients without lung disease were D _LCO % r= −0.51, K _CO % r= −0.44, FVC%/ D _LCO % r=0.38, compared with patients with lung disease: D _LCO % r= −0.41, K _CO % r= −0.39, FVC%/ D _LCO % r=0.39. Area under the curve for the presence of PH in the overall study cohort was significantly superior for D _LCO % at 0.84 (optimal threshold 53%), compared with K _CO % 0.74 (60%) and FVC%/ D _LCO % was 0.74 (1.91), pD _LCO % and K _CO % were higher and consequently FVC%/ D _LCO % lower (pD _LCO performed as least as strongly as K _CO or FVC%/ D _LCO % in terms of correlations with mean pulmonary arterial pressure and diagnostic utility, regardless of the presence or absence of lung disease. Transitioning to GLI equations led to lower predicted spirometric volumes and higher D _LCO %. This should be considered when interpreting changes in values over time and when using screening algorithms.

Background and Objectives: Brain natriuretic peptide (BNP) and N‐terminal prohormone of BNP (NT‐proBNP) are important biomarkers in pulmonary arterial hypertension (PAH). However, results are rarely available at the time of clinical assessment. The reliability of NT‐proBNP/BNP point‐of‐care tests (POCT) in PAH patients and the stability of NT‐proBNP in posted blood samples, to simulate remote monitoring, was investigated. Methods: Group 1 PAH patients were prospectively recruited. A sample of 40 was required to demonstrate an intraclass correlation coefficient (ICC) of 0.94 with a 95% confidence interval width of < 0.1 for agreement between POCT and the laboratory standard. Blood samples were taken at two time‐points for laboratory and POCT NT‐proBNP/BNP. Separate samples were returned to the laboratory by post and some samples were assessed pre‐ and post‐exercise assessing the impact of exercise. Results: Forty‐one patients were enrolled with 56 study visits. NT‐proBNP laboratory and POCT ( n = 50) provided equivalent test results (Passing–Bablok slope = 1.08, CI = 0.97–1.19, intercept = 18.22, CI = −41.6 to 4.5) and ICC = 0.97. However, laboratory and POCT BNP ( n = 49), showed non‐equivalence (Passing–Bablok slope = 1.24, CI 1.11–1.31, intercept = −5.11, CI = −9.4 to −0.46), ICC = 0.96. POCT NT‐proBNP/BNP correctly classified 92% and 86% of cases, respectively against COMPERA 2.0 4‐risk‐strata thresholds. NT‐proBNP postal laboratory samples and immediately processed NT‐proBNP laboratory samples showed good agreement and exercise had no clinically significant effect on NT‐proBNP/BNP results. Laboratory BNP identified fewer patients as high risk compared to NT‐proBNP. BNP and NT‐proBNP risk status agreed at only 57% of visits ( p < 0.0009). Conclusions: These data support the use of POCT NT‐proBNP as a rapidly accessible and reliable alternative in clinical settings and highlight the potential of NT‐proBNP for remote monitoring via posted samples. Trial Registration: ClinicalTrials.gov registration: NCT05421949 image

BACKGROUND: Patients with pulmonary hypertension (PH) are classified based on disease pathogenesis and hemodynamic drivers. Classification informs treatment. The heart failure biomarker NT-proBNP (N-terminal pro-B-type natriuretic peptide) is used to help inform risk but is not specific to PH or sub-classification groups. There are currently no other biomarkers in clinical use to help guide diagnosis or risk. METHODS: We profiled a retrospective cohort of 1150 patients from 3 expert centers with PH and 334 non-PH symptomatic controls (disease controls) from the United Kingdom to measure circulating levels of 650 microRNAs (miRNAs) in serum. NT-proBNP (ELISA) and 326 well-detected miRNAs (polymerase chain reaction) were prioritized by feature selection using multiple machine learning models. From the selected miRNAs, generalized linear models were used to describe miRNA signatures to differentiate PH and pulmonary arterial hypertension from the disease controls, and pulmonary arterial hypertension, PH due to left heart disease, PH due to lung disease, and chronic thromboembolic pulmonary hypertension from other forms of PH. These signatures were validated on a UK test cohort and independently validated in the prospective CIPHER study (A Prospective, Multicenter, Noninterventional Study for the Identification of Biomarker Signatures for the Early Detection of Pulmonary Hypertension) comprising 349 patients with PH and 93 disease controls. RESULTS: NT-proBNP achieved a balanced accuracy of 0.74 and 0.75 at identifying PH and pulmonary arterial hypertension from disease controls with a threshold of 254 and 362 pg/mL, respectively but was unable to sub-categorize PH subgroups. In the UK cohort, miRNA signatures performed similarly to NT-proBNP in distinguishing PH (area under the curve of 0.7 versus 0.78), and pulmonary arterial hypertension (area under the curve of 0.73 versus 0.79) from disease controls. MicroRNA signatures outperformed NT-proBNP in distinguishing PH classification groups. External testing in the CIPHER cohort demonstrated that miRNA signatures, in conjunction with NT-proBNP, age, and sex, performed better than either NT-proBNP or miRNAs alone in sub-classifying PH. CONCLUSIONS: We suggest a threshold for NT-proBNP to identify patients with a high probability of PH, and the subsequent use of circulating miRNA signatures to help differentiate PH subgroups.

Introduction: Health-related quality of life (HRQoL) in pulmonary arterial hypertension (PAH) is valued as an outcome measure by patients, clinicians and regulators. The selection of patient-reported outcome measures (PROMs) for measurement of HRQoL in PAH clinical trials lacks systematic evaluation of their suitability, accuracy and reliability.Methods: We report a systematic review (PROSPERO ID: CRD42024484021) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of PROMs selected in PAH clinical trials. PROM measurement properties were then evaluated according to the 10-step COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and graded by recommendation for use. Finally, HRQoL was modelled into a conceptual framework using patient interviews and surveys.Results: Screening of 896 records identified 90 randomised controlled trials. 43 trials selected PROMs, of which 20 were sufficiently validated to detect meaningful change. Of these, eight trials were adequately powered, using either EuroQol-five dimensions-five levels (EQ-5D-5L), Short-Form-36 (SF-36) or the Living with Pulmonary Hypertension Questionnaire (LPHQ). The COSMIN evaluation recommended EmPHasis-10 and the LPHQ for use (grade A); whereas, SF-36 and EQ-5D-5L require further study (grade B). A conceptual framework of HRQoL was developed from literature comprising 8045 patients. This framework can be used to visualise the different HRQoL concepts measured by different PROMs.Conclusion: To improve patient-centred research, greater consistency in PROM selection is required. Three of 90 randomised controlled trials have selected COSMIN-recommended PROMs. Whilst the PROMs evaluated require development across the 10 areas of psychometric property measurement, EmPHasis-10 and the LPHQ can be recommended for use. The ratified conceptual framework can further support PROM selection by identifying the HRQoL concepts they are likely to capture.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is commonly evaluated using computed tomography pulmonary angiography (CTPA). We evaluated the frequency and impact of parenchymal and cardiac abnormalities on survival in CTEPH.Methods: Patients were identified from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) Registry. Kaplan–Meier analysis was used to assess survival.Results: 290 patients (55% female, mean±sdage 65±14 years) with CTEPH were included. Mosaic perfusion was noted in 83%, lung infarction in 73% and parenchymal lung disease in 28%. The severity of mosaic perfusion and lung infarction correlated with markers of disease severity (p<0.001). Whereas the presence of mosaic perfusion was associated with improved survival in all patients (p=0.03), it did not predict outcome in those undergoing pulmonary endarterectomy (PEA) (p=0.6) and those not undergoing PEA (p=0.22). The presence of lung infarction had no impact on mortality. The presence of co-existing lung disease was associated with a worse survival (p<0.008) in patients not undergoing PEA. Mosaic perfusion was less common in patients with parenchymal lung disease (65%) compared to those without parenchymal lung disease (90%), p<0.001. An increased right/left ventricular ratio and aortic diameter predicted a worse outcome (p<0.002).Conclusion: Lung parenchymal and cardiac changes on CTPA predict outcome in CTEPH. Co-existing parenchymal lung disease is not uncommon and when present may mask the presence of mosaic perfusion. This study highlights the importance of systematically evaluating the lung parenchyma and cardiac changes in patients with CTEPH.

Background: Exercise pulmonary hypertension (exercise PH) was defined by a mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope >3 mmHg·L⁻¹·min⁻¹between rest and exercise in the 2022 ESC/ERS PH guidelines. However, large, multi-center studies on the prognostic relevance of exercise hemodynamics and its added value to resting hemodynamics are missing.Patients and Methods: The PEX-NET (Pulmonary Hemodynamics during Exercise Network) registry enrolled patients who underwent clinically indicated right heart catheterizations both at rest and ergometer exercise from 23 PH-centers worldwide. In this retrospective analysis we included subjects with resting mPAP−1·min⁻¹had significantly worse survival compared to those with ≤3 mmHg·L⁻¹·min⁻¹(p=0.013; HR: 2.04 (95%CI:1.16–3.58)).Conclusion: The mPAP/CO slope is a robust and independent predictor of prognosis in patients with normal or mildly elevated resting pulmonary arterial pressure that provides prognostic information beyond resting hemodynamics and appears suitable to define exercise PH.