Individualized survival predictions using state space model with longitudinal and survival data.

Monitoring disease progression often involves tracking biomarker measurements over time. Joint models (JMs) for longitudinal and survival data provide a framework to explore the relationship between time-varying biomarkers and patients' event outcomes, offering the potential for personalized survival predictions. In this article, we introduce the linear state space dynamic survival model for handling longitudinal and survival data. This model enhances the traditional linear Gaussian state space model by including survival data. It differs from the conventional JMs by offering an alternative interpretation via differential or difference equations, eliminating the need for creating a design matrix. To showcase the model's effectiveness, we conduct a simulation case study, emphasizing its performance under conditions of limited observed measurements. We also apply the proposed model to a dataset of pulmonary arterial hypertension patients, demonstrating its potential for enhanced survival predictions when compared with conventional risk scores.

Initial combination therapy with macitentan and tadalafil in patients with pulmonary arterial hypertension, with and without cardiac comorbidities.

AIMS: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities. METHODS AND RESULTS: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups. CONCLUSIONS: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups.

Association of risk assessment at diagnosis with healthcare resource utilization and health-related quality of life outcomes in pulmonary arterial hypertension.

We aimed to describe the clinical characteristics, healthcare resource utilization (HCRU) and costs, health-related quality of life (HRQoL), and survival for patients with pulmonary arterial hypertension (PAH), stratified by 1-year mortality risk at diagnosis. Adults diagnosed with PAH at the Sheffield Pulmonary Vascular Disease Unit between 2012 and 2019 were included. Patients were categorized as low, intermediate, or high risk for 1-year mortality at diagnosis. Demographics, clinical characteristics, comorbidities, HCRU, costs, HRQoL, and survival were analyzed. Overall, 1717 patients were included: 72 (5%) at low risk, 941 (62%) at intermediate risk, and 496 (33%) at high risk. Low-risk patients had lower HCRU prediagnosis and 1-year postdiagnosis than intermediate- or high-risk patients. Postdiagnosis, there were significant changes in HCRU, particularly inpatient hospitalizations and accident and emergency (A&E) visits among high-risk patients. At 3 years postdiagnosis, HCRU for all measures was similar across risk groups. Low-risk patients had lower EmPHasis-10 scores (indicating better HRQoL) at diagnosis and at 1-year follow-up compared with intermediate- and high-risk patients; only the score in the high-risk group improved. Median overall survival decreased as risk category increased in analyzed subgroups. Low-risk status was associated with better 1-year survival and HRQoL compared with intermediate- and high-risk patients. HCRU decreased in high-risk patients postdiagnosis, with the most marked reduction in A&E admissions. The pattern of decreased per-patient inpatient hospitalizations and A&E visits at 3 years postdiagnosis suggests that a diagnosis of PAH helps to decrease HCRU in areas that are key drivers of costs.

Attitudes and barriers to pulmonary arterial hypertension screening in systemic sclerosis patients: A survey of UK-based rheumatologists.

Objectives: The objectives were to explore rheumatologists' current clinical screening practices of pulmonary arterial hypertension in patients with systemic sclerosis in the United Kingdom and to identify barriers to screening and consider potential solutions. Methods: A survey of 31 questions was developed and included six sections: clinician demographics, the importance of screening, screening practices, barriers to screening, treatment and patient education. The survey was disseminated among rheumatologists working in the United Kingdom. Results: Forty-four rheumatologists working in the United Kingdom participated in the study, and the majority completed all the questions. Around one-third (37.0%) worked in specialised systemic sclerosis units (university or general hospitals (54.5% and 45.4%, respectively)). The majority recognised that systemic sclerosis-pulmonary arterial hypertension is a major cause of morbidity and mortality. Over half (60.0%) reported using the DETECT algorithm to screen for systemic sclerosis-pulmonary arterial hypertension, although other algorithms were also sometimes used. All of the respondents utilised transthoracic echocardiogram, and almost all (95.0%) performed pulmonary function tests for screening purposes. Various challenges and barriers were identified relating to systemic sclerosis-pulmonary arterial hypertension screening, with the difficulty in interpreting results from other hospitals and extended wait times for diagnostic tests being the most reported (76.0% and 74.0%, respectively). Most respondents agreed that access to key investigations (87.0%), ongoing clinician education (82.0%), multidisciplinary meetings (79.5%) and a better understanding of proposed screening algorithms (79.5%) could be potential solutions. Conclusion: Screening patients with systemic sclerosis for pulmonary arterial hypertension is crucial to improve survival, but variable practices exist among UK rheumatologists. Solutions include educating healthcare professionals on guidelines, sharing information between centres and integrating care services.

Two prospective, multicenter studies for the identification of biomarker signatures for early detection of pulmonary hypertension (PH): The CIPHER and CIPHER-MRI studies.

A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA-based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER-MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N-terminal pro-brain natriuretic peptide (NT-proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta-analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC-confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80-0.89] for microRNA-alone and 0.90 [0.86-0.93] for microRNA+NT-proBNP, and the corresponding specificities were 0.33 [0.24-0.44] and 0.28 [0.20-0.39]. Of 80 CIPHER-MRI participants with evaluable data, 7 were considered PH-positive by cMRI whereas 52 were considered PH-positive by the microRNA signature. Due to low specificity, the CIPHER miRNA-based signature for PH (either with or without NT-proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis.

A systematic review of artificial intelligence tools for chronic pulmonary embolism on CT pulmonary angiography.

Background: Chronic pulmonary embolism (PE) may result in pulmonary hypertension (CTEPH). Automated CT pulmonary angiography (CTPA) interpretation using artificial intelligence (AI) tools has the potential for improving diagnostic accuracy, reducing delays to diagnosis and yielding novel information of clinical value in CTEPH. This systematic review aimed to identify and appraise existing studies presenting AI tools for CTPA in the context of chronic PE and CTEPH. Methods: MEDLINE and EMBASE databases were searched on 11 September 2023. Journal publications presenting AI tools for CTPA in patients with chronic PE or CTEPH were eligible for inclusion. Information about model design, training and testing was extracted. Study quality was assessed using compliance with the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Results: Five studies were eligible for inclusion, all of which presented deep learning AI models to evaluate PE. First study evaluated the lung parenchymal changes in chronic PE and two studies used an AI model to classify PE, with none directly assessing the pulmonary arteries. In addition, a separate study developed a CNN tool to distinguish chronic PE using 2D maximum intensity projection reconstructions. While another study assessed a novel automated approach to quantify hypoperfusion to help in the severity assessment of CTEPH. While descriptions of model design and training were reliable, descriptions of the datasets used in training and testing were more inconsistent. Conclusion: In contrast to AI tools for evaluation of acute PE, there has been limited investigation of AI-based approaches to characterising chronic PE and CTEPH on CTPA. Existing studies are limited by inconsistent reporting of the data used to train and test their models. This systematic review highlights an area of potential expansion for the field of AI in medical image interpretation.There is limited knowledge of A systematic review of artificial intelligence tools for chronic pulmonary embolism in CT. This systematic review provides an assessment on research that examined deep learning algorithms in detecting CTEPH on CTPA images, the number of studies assessing the utility of deep learning on CTPA in CTEPH was unclear and should be highlighted.

Comparison of Contemporary Risk Scores in All Groups of Pulmonary Hypertension: A Pulmonary Vascular Research Institute GoDeep Meta-Registry Analysis.

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. RESEARCH QUESTION: Are risk scores originally developed for PAH predictive in PH groups 1 through 4? STUDY DESIGN AND METHODS: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including Registry to Evaluate Early and Long-Term PAH Disease Mangement (REVEAL) Lite 2, REVEAL 2.0, ESC/ERS 2022, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 3-strata, and COMPERA 4-strata. RESULTS: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (interquartile range, 33-52 mm Hg) and pulmonary vascular resistance of 7 Wood units (WU) (interquartile range, 4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH). INTERPRETATION: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT05329714; URL: www. CLINICALTRIALS: gov.

Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies.

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Comparison of cardiac magnetic resonance imaging, functional and haemodynamic variables in pulmonary arterial hypertension: insights from REPAIR.

Background: Measures that can detect large treatment effects are important for monitoring therapeutic effectiveness. The 2022 European Society of Cardiology/European Respiratory Society guidelines highlight the importance of imaging in monitoring disease status and treatment response in pulmonary arterial hypertension (PAH). Are the standardised treatment effect sizes (STES) of cardiac magnetic resonance imaging (cMRI) comparable with functional and haemodynamic variables? Methods: REPAIR (ClinicalTrials.gov: NCT02310672) was a prospective, multicentre, single-arm, open-label, 52-week phase 4 study evaluating the effect of macitentan 10 mg, with or without a phosphodiesterase 5 inhibitor (PDE5i), on right ventricular (RV) remodelling, cardiac function and cardiopulmonary haemodynamics. Both cMRI and functional assessments were performed at screening and at weeks 26 and 52; haemodynamic measurements were conducted at screening and week 26. In this post hoc analysis, STES were estimated using the parametric Cohen's d and non-parametric Cliff's delta tests. Results: At week 26, large STES (Cohen's d) were observed for 10 of the 20 cMRI variables assessed, including the prognostic measures of RV and left ventricular stroke volume and RV ejection fraction and the haemodynamic trial end-point, pulmonary vascular resistance; medium STES were observed for 6-min walk distance (6MWD). The STES were consistent in treatment-naïve patients and those escalating therapy and maintained at week 52. Similar results were obtained using the non-parametric Cliff's delta method. Conclusions: The treatment effect of macitentan, alone or in combination with a PDE5i, was comparable for several cMRI and haemodynamic variables with prognostic value in PAH, and greater than that of 6MWD in patients with PAH, highlighting the emerging relevance of cMRI in PAH.

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.

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.

Pulmonary Embolism (PE) to Chronic Thromboembolic Pulmonary Disease (CTEPD): Findings from a Survey of UK Physicians.

Chronic thromboembolic pulmonary disease (CTEPD) is a complication of pulmonary embolism (PE). We conducted an online survey of UK PE-treating physicians to understand practices in the follow-up of PE and awareness of CTEPD. The physicians surveyed (N = 175) included 50 each from cardiology, respiratory and internal medicine, plus 25 haematologists. Most (89%) participants had local guidelines for PE management, and 65% reported a PE follow-up clinic, of which 69% were joint clinics. Almost half (47%) had a protocol for the investigation of CTEPD. According to participants, 129 (74%) routinely consider a diagnosis of CTEPD and 97 (55%) routinely investigate for CTEPD, with 76% of those 97 participants investigating in patients who are symptomatic at 3 months and 22% investigating in all patients. This survey demonstrated variability in the follow-up of PE and the awareness of CTEPD and its investigation. The findings support the conduct of a national audit to understand the barriers to the timely detection of CTEPD.

Risk assessment and real-world outcomes in chronic thromboembolic pulmonary hypertension: insights from a UK pulmonary hypertension referral service.

OBJECTIVES: This study was conducted to evaluate the ability of risk assessment to predict healthcare resource utilisation (HCRU), costs, treatments, health-related quality of life (HRQoL) and survival in patients diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). DESIGN: Retrospective observational study. SETTING: Pulmonary hypertension referral centre in the UK. PARTICIPANTS: Adults diagnosed with CTEPH between 1 January 2012 and 30 June 2019 were included. Cohorts were retrospectively defined for operated patients (received pulmonary endarterectomy (PEA)) and not operated; further subgroups were defined based on risk score (low, intermediate or high risk for 1-year mortality) at diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographics, clinical characteristics, comorbidities, treatment patterns, HRQoL, HCRU, costs and survival outcomes were analysed. RESULTS: Overall, 683 patients were analysed (268 (39%) operated; 415 (61%) not operated). Most patients in the operated and not-operated cohorts were intermediate risk (63%; 53%) or high risk (23%; 31%) at diagnosis. Intermediate-risk and high-risk patients had higher HCRU and costs than low-risk patients. Outpatient and accident and emergency visits were lower postdiagnosis for both cohorts and all risk groups versus prediagnosis. HRQoL scores noticeably improved in the operated cohort post-PEA, and less so in the not-operated cohort at 6-18 months postdiagnosis. Survival at 5 years was 83% (operated) and 49% (not operated) and was lower for intermediate-risk and high-risk patients compared with low-risk patients. CONCLUSIONS: Findings from this study support that risk assessment at diagnosis is prognostic for mortality in patients with CTEPH. Low-risk patients have better survival and HRQoL and lower HCRU and costs compared with intermediate-risk and high-risk patients.

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

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

Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results.

INTRODUCTION: The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. METHODS: REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland-Altman analyses. RESULTS: The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland-Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of - 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. CONCLUSIONS: A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. TRIAL REGISTRATION NUMBER: REPAIR NCT02310672.

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.

Multicenter Standardization of Phase-Resolved Functional Lung MRI in Patients With Suspected Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media. PURPOSE: To assess the feasibility and image quality of PREFUL-MRI in a multicenter setting in suspected CTEPH. STUDY TYPE: This is a prospective cohort sub-study. POPULATION: Forty-five patients (64 ± 16 years old) with suspected CTEPH from nine study centers. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST). ASSESSMENT: Lung signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL-MRI (QDPPREFUL ) was compared to QDP from the established dynamic contrast-enhanced MRI technique (QDPDCE ). Furthermore, QDPPREFUL was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups. STATISTICAL TESTS: t-Test, one-way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%. RESULTS: Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion -4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDPPREFUL was significantly correlated with QDPDCE (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDPPREFUL = 33.9 ± 17.2%). DATA CONCLUSION: PREFUL-MRI could be considered as a non-invasive method for imaging regional lung perfusion in multicenter studies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 1.

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.

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

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

Pulmonary hypertension associated with lung disease: new insights into pathomechanisms, diagnosis, and management.

Patients with chronic lung diseases, particularly interstitial lung disease and chronic obstructive pulmonary disease, frequently develop pulmonary hypertension, which results in clinical deterioration, worsening of oxygen uptake, and an increased mortality risk. Pulmonary hypertension can develop and progress independently from the underlying lung disease. The pulmonary vasculopathy is distinct from that of other forms of pulmonary hypertension, with vascular ablation due to loss of small pulmonary vessels being a key feature. Long-term tobacco exposure might contribute to this type of pulmonary vascular remodelling. The distinct pathomechanisms together with the underlying lung disease might explain why treatment options for this condition remain scarce. Most drugs approved for pulmonary arterial hypertension have shown no or sometimes harmful effects in pulmonary hypertension associated with lung disease. An exception is inhaled treprostinil, which improves exercise capacity in patients with interstitial lung disease and pulmonary hypertension. There is a pressing need for safe, effective treatment options and for reliable, non-invasive diagnostic tools to detect and characterise pulmonary hypertension in patients with chronic lung disease.