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.

CD147 Plasma Levels in Hospitalised Patients with Covid-19 Pneumonia Predict Illness Severity and In-Hospital Mortality.

COVID-19 and infectious diseases have been included in strategic development goals (SDG) of United Nations (UN). The CD147 receptor is one of several receptors for the SARS-CoV-2 spike protein that could mediate Covid-19 viral infection of host cells. It has been recently proposed to regulate viral invasion and dissemination among lymphocytes and progenitor/stem cells. A soluble by-product of CD147 (sCD147) exists in plasma and has been previously identified as a marker of diabetes and platelet activation. We examined plasma sCD147 levels in 161 Covid-19 patients at hospital admission. We demonstrated significantly higher plasma sCD147 levels in Covid-19 patients, which correlated with plasma multiorgan dysfunction biomarkers interleukin-6, creatinine and Troponin I. Importantly, sCD147 admission levels were associated with Covid-19 severity and survival, carrying potential value as a biomarker in hospitalized patients with Covid-19 infection.

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.

Right ventricular functional recovery assessment with stress echocardiography and cardiopulmonary exercise testing after pulmonary embolism: a pilot prospective multicentre study.

BACKGROUND: Data on right ventricular (RV) exercise adaptation following acute intermediate and high-risk pulmonary embolism (PE) remain limited. This study aimed to evaluate the symptom burden, RV functional recovery during exercise and cardiopulmonary exercise parameters in survivors of intermediate and high-risk acute PE. METHODS: We prospectively recruited patients following acute intermediate and high-risk PE at four sites in Australia and UK. Study assessments included stress echocardiography, cardiopulmonary exercise testing (CPET) and ventilation-perfusion (VQ) scan at 3 months follow-up. RESULTS: Thirty patients were recruited and 24 (median age: 55 years, IQR: 22) completed follow-up. Reduced peak oxygen consumption (VO2) and workload was seen in 75.0% (n=18), with a persistent high symptom burden (mean PEmb-QoL Questionnaire 48.4±21.5 and emPHasis-10 score 22.4±8.8) reported at follow-up. All had improvement in RV-focused resting echocardiographic parameters. RV systolic dysfunction and RV to pulmonary artery (PA) uncoupling assessed by stress echocardiography was seen in 29.2% (n=7) patients and associated with increased ventilatory inefficiency (V̇E/V̇CO2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen desaturation (93.2% vs 98.4%, p=0.01) and reduced peak oxygen pulse (p=0.036) compared with controls. Five out of seven patients with RV-PA uncoupling demonstrated persistent bilateral perfusion defects on VQ scintigraphy consistent with chronic thromboembolic pulmonary vascular disease. CONCLUSION: In our cohort, impaired RV adaptation on exercise was seen in almost one-third of patients. Combined stress echocardiography and CPET may enable more accurate phenotyping of patients with persistent symptoms following acute PE to allow timely detection of long-term complications.

Chaotic breathing in post-COVID-19 breathlessness: a key feature of dysfunctional breathing can be characterised objectively by approximate entropy.

Post-COVID-19 breathing pattern disorder can be characterised by application of nonlinear statistical modelling of exercise ventilatory data https://bit.ly/3WlBc7e.

Right ventricular responses to CPAP therapy in obstructive sleep apnea: CMR analysis of the MOSAIC randomized trial.

Effects of continuous positive airway pressure (CPAP) on right ventricular (RV) function in patients with untreated mild-to-moderate obstructive sleep apnea (OSA) are unclear. In this exploratory analysis of cardiac magnetic resonance (CMR)-derived indices of RV function in patients with minimally symptomatic OSA from the MOSAIC randomized control trial we found no effect of CPAP on RV CMR parameters. In those with lower RV ejection fraction and higher RV end-diastolic volume (EDV) at baseline, CPAP treatment appeared to improve RV function with a significant reduction in both RV EDV and RV end-systolic volume although between-group effects were not observed. These data suggest potential merit in a larger randomized study of CPAP in patients with mild-to-moderate OSA and a greater breadth of RV dysfunction.

Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension is a life-limiting complication of interstitial lung disease (ILD-PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD-PH was associated with improved survival. METHODS: Consecutive incident patients with ILD-PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow-up and survival data modelled by Bayesian methods. RESULTS: The diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non-specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint-modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity-matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: -0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04). CONCLUSION: PDE5i treatment in ILD-PH should be investigated by a prospective randomized trial.

Heightened ventilatory response during stair climbing in individuals with dysfunctional breathing.

This prospective cohort study confirms that patients with dysfunctional breathing experience dyspnoea and an abnormal breathing pattern when faced with undertaking everyday exercise challenges, such as climbing stairs https://bit.ly/3OEWwPM.

Right Ventricle Remodeling in Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed, but potentially curable pulmonary vascular disease. The increased pulmonary vascular resistance in CTEPH is caused by unresolved proximal thrombus and secondary microvasculopathy in the pulmonary vasculature, leading to adaptive and maladaptive remodeling of the right ventricle (RV), eventual right heart failure, and death. Knowledge on the RV remodeling process in CTEPH is limited. The progression to RV failure in CTEPH is a markedly slower process. A detailed understanding of the pathophysiology and underlying mechanisms of RV remodeling may facilitate early diagnosis and the development of targeted therapy. While ultrasound, magnetic resonance imaging, right heart catheterization, and serum biomarkers have been used to assess cardiac function, the current treatment strategies reduce the afterload of the right heart, but are less effective in improving the maladaptive remodeling of the right heart. This review systematically summarizes the current knowledge on adaptive and maladaptive remodeling of the right heart in CTEPH from molecular mechanisms to clinical practice.

Right heart strain assessment on CTPA following acute pulmonary embolism: Interobserver variability between expert radiologists and physicians.

BACKGROUND: Accuracy of right heart strain (RHS) measured on computed tomography pulmonary angiogram (CTPA) scans by non-radiologists is unknown. We assessed inter-observer variability of four RHS features and determined the accuracy of measurements by respiratory physicians. METHOD: 1560 consecutive patients with acute PE were identified, and those who had a CTPA and an echocardiogram within 24-h included. CTPAs were independently scored prospectively by two radiologists, two thoracic physicians and a specialist registrar. Inter-observer variability was assessed, and diagnostic accuracy compared to echocardiography. RESULTS: 182 patients (median age 62.8 years, IQR 49.8-71.5) with acute PE (7.7% high-risk, 40.7% intermediate high-risk, 31.3% intermediate low-risk and 20.3% low-risk) were included. Right ventricle to left ventricle diameter ratio (RV:LV) measurement had low inter-observer variability among the radiologists and non-radiologists with interclass correlation coefficient (ICC) of 0.95 (95%CI 0.92-0.97) and 0.96 (95%CI 0.94-0.97) respectively. RV:LV ratio had high diagnostic accuracy compared to RV dilatation on echocardiography (AUC 0.89, 95%CI 0.84-0.94 for radiologists and AUC 0.84, 95%CI 0.77-0.90 for non-radiologists). Main pulmonary artery to ascending aorta diameter ratio (MPA:Ao) measurement also had excellent agreement amongst the radiologists and non-radiologists (ICC 0.93 (95%CI 0.88-0.96) and 0.92 (95%CI 0.81-0.96) respectively). Significant variability was seen in the assessment of subjective features of RHS (leftward bowing of interventricular septum and contrast reflux into inferior vena cava) amongst the non-radiologists. CONCLUSION: RV:LV and MPA:Ao diameter ratios on CTPA measured by non-radiologists have low inter-observer variability and good agreement with radiologists, and can be reliably used where an expert report is unavailable.

The Effect of Borderline Pulmonary Hypertension on Survival in Chronic Lung Disease.

BACKGROUND: The impact of the new "borderline" hemodynamic class for pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP], 21-24 mm Hg and pulmonary vascular resistance, [PVR], ≥3 wood units, [WU]) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is unclear. OBJECTIVES: The aim of this study was to assess the effect of borderline PH (BLPH) on survival in COPD and ILD patients. METHOD: Survival was analyzed from retrospective data from 317 patients in 12 centers (Italy, Spain, UK) comparing four hemodynamic groups: the absence of PH (NoPH; mPAP <21 mm Hg or 21-24 mm Hg and PVR <3 WU), BLPH (mPAP 21-24 mm Hg and PVR ≥3 WU), mild-moderate PH (MPH; mPAP 25-35 mm Hg and cardiac index [CI] ≥2 L/min/m2), and severe PH (SPH; mPAP ≥35 mm Hg or mPAP ≥25 mm Hg and CI <2 L/min/m2). RESULTS: BLPH affected 14% of patients; hemodynamic severity did not predict survival when COPD and ILD patients were analyzed together. However, survival in the ILD cohort for any PH level was worse than in NoPH (3-year survival: NoPH 58%, BLPH 32%, MPH 28%, SPH 33%, p = 0.002). In the COPD cohort, only SPH had reduced survival compared to the other groups (3-year survival: NoPH 82%, BLPH 86%, MPH 87%, SPH 57%, p = 0.005). The mortality risk correlated significantly with mPAP in ILD (hazard ratio [HR]: 2.776, 95% CI: 2.057-3.748, p < 0.001) and notably less in COPD patients (HR: 1.015, 95% CI: 1.003-1.027, p = 0.0146). CONCLUSIONS: In ILD, any level of PH portends worse survival, while in COPD, only SPH presents a worse outcome.

Direct oral anticoagulants for cancer-associated venous thromboembolisms: a systematic review and network meta-analysis.

BACKGROUND: Several recent randomised controlled trials (RCT) have investigated the use of direct oral anticoagulants (DOAC) in the treatment of malignancy-associated venous thromboembolism (VTE). AIMS: This meta-analysis combines all RCT data to determine the risks of recurrent VTE and bleeding with DOAC in patients with malignancy-associated VTE compared with low-molecular-weight heparin (LMWH). METHODS: The study followed PRISMA guidelines. MEDLINE, EMBASE and CENTRAL were systematically searched from inception to 1 April 2020. References of reviews and relevant conference proceedings were searched by hand. Two authors independently evaluated study eligibility, extracted data and assessed risk of bias. Direct and indirect meta-analyses were performed. RESULTS: In four RCT with low risk of bias (2907 patients), high certainty evidence suggested that DOAC had a 37% reduction in risk of recurrent VTE compared with LMWH (direct pooled risk ratio (RR) 0.63; 95% confidence interval (CI) 0.44-0.91; I2 = 28%). No significant difference was observed in the risk of major bleeding with DOAC compared with LMWH (RR 1.31; 95% CI 0.83-2.07; I2 = 22%; moderate certainty evidence), including in patients in gastrointestinal and genitourinary malignancy. An increased risk of combined major or clinically relevant non-major bleeding was seen with DOAC (RR 1.52; 95% CI 1.09-2.12; I2 = 51%; low certainty evidence). Apixaban had the highest probability of being ranked the most effective and least bleeding risk among the DOAC. CONCLUSION: DOAC are effective in treating malignancy associated VTE; however, caution is required in patients with high risk of bleeding. Apixaban had lower risk of bleeding compared to other DOAC in this population.

Use of direct oral anticoagulants for acute pulmonary embolisms in obesity: a propensity-matched, multicentre case-control study.

Assessment of efficacy and safety of DOACs in treatment of pulmonary embolisms in obese patients provides reassurance that treatment with DOACs carries similar rates of recurrent VTE and bleeding complications to warfarin https://bit.ly/2VdrSXX.

Impact of cyanosis on ventilatory responses during stair climb exercise in Eisenmenger syndrome and idiopathic pulmonary arterial hypertension.

Studies assessing exercise ventilatory responses during real-life exercise in pulmonary arterial hypertension (PAH) which include patients with cyanotic congenital heart disease are scarce. We assessed the ventilatory response to stairclimbing in patients with idiopathic PAH (IPAH) and congenital heart disease-associated PAH with Eisenmenger (EIS) physiology compared to healthy controls. Fifteen adults with IPAH, six EIS and 15 age and body mass index (BMI) matched controls were prospectively recruited. Participants completed spirometry and a self-paced stair-climb (48 steps) with portable cardiopulmonary exercise testing (CPET) equipment in-situ. Borg dyspnoea scores were measured at rest and on stair-climb cessation. Both IPAH and EIS groups had amplified ventilatory responses compared to Controls. The rate of increase in minute ventilation (VE) was exaggerated in EIS driven by an early increase in tidal volume (Tv) and more gradual increase in respiratory rate (RR). Peak Tv, RR, Tv: forced vital capacity (FVC) ratio, VE/VCO2 slope and stairclimb duration were significantly higher in EIS and IPAH compared to controls despite similar baseline spirometry and change in oxygen uptake on exercise. A decline in end-tidal carbon dioxide (CO2) and arterial oxygen saturations in early exercise distinguished EIS and IPAH patients. Significant correlations were observed between peak exercise Borg score and stair-climb time (r = 0.73, p = 0.002), peak end-tidal CO2 (r = -0.73, p = 0.001), peak VE (r = 0.53, p = 0.008), peak RR (r = 0.42, p = 0.011) and VE/VCO2 slope (r = 0.54, p = 0.001). Patients with IPAH and EIS have exaggerated ventilatory responses to stair-climbing compared to the controls with more severe levels of dyspnoea perception in Eisenmenger syndrome for equivalent oxygen uptake and work.

Sarcoidosis associated pulmonary hypertension: an update.

PURPOSE OF REVIEW: Sarcoidosis associated pulmonary hypertension (SAPH) is a well-recognised complication, associated with a seven-fold increase in mortality. This comprehensive review will summarise these recent developments and proposes the use of a phenotype-based management approach in SAPH. RECENT FINDINGS: Recent registry-based studies have highlighted the adverse outcomes associated with SAPH and shown that reduced 6-min walk distance and diffusion capacity for carbon monoxide are predictive of poor prognosis. There is increasing interest in methods for early detection of SAPH, although whether early diagnosis impacts on survival remains uncertain. The pathophysiology underpinning SAPH is complex and often incorporates multiple mechanisms. Once the diagnosis is confirmed, understanding the underlying phenotypes of SAPH is key to providing the most effective management plan. There is some evidence that treating patients with precapillary PH with pulmonary vasodilators may improve some haemodynamic and quality life measures. However, more work is needed to determine whether mortality is affected. SUMMARY: SAPH is associated with worsened survival. A range of phenotypes are recognised in SAPH. Multimodality risk assessment in patients with SAPH is likely to be important and is an area that requires further work. Published evidence for pulmonary vasodilator therapies in SAPH with a Pulmonary arterial hypertension-like phenotype is encouraging so far, but multiple confounding factors affects the quality of the evidence. The role of immunosuppressive agents for improving pulmonary pressures is unclear. Urgent controlled trials are needed.

Physiological demands of singing for lung health compared with treadmill walking.

INTRODUCTION: Participating in singing is considered to have a range of social and psychological benefits. However, the physiological demands of singing and its intensity as a physical activity are not well understood. METHODS: We compared cardiorespiratory parameters while completing components of Singing for Lung Health sessions, with treadmill walking at differing speeds (2, 4 and 6 km/hour). RESULTS: Eight healthy adults were included, none of whom reported regular participation in formal singing activities. Singing induced acute physiological responses that were consistent with moderate intensity activity (metabolic equivalents: median 4.12, IQR 2.72-4.78), with oxygen consumption, heart rate and volume per breath above those seen walking at 4 km/hour. Minute ventilation was higher during singing (median 22.42 L/min, IQR 16.83-30.54) than at rest (11 L/min, 9-13), lower than 6 km/hour walking (30.35 L/min, 26.94-41.11), but not statistically different from 2 km/hour (18.77 L/min, 16.89-21.35) or 4 km/hour (23.27 L/min, 20.09-26.37) walking. CONCLUSIONS: Our findings suggest the acute metabolic demands of singing are comparable with walking at a moderately brisk pace, hence, physical effects may contribute to the health and well-being benefits attributed to singing participation. However, if physical training benefits result remains uncertain. Further research including different singing styles, singers and physical performance impacts when used as a training modality is encouraged. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registry (NCT04121351).