Pulmonary Vascular Disease Research Articles

Effect of Eccentric Cycling on Oxygen Uptake and Hemodynamics in Patients With Pulmonary Vascular Disease: A Randomized Controlled Crossover Trial

BackgroundEccentric cycling exercise (ECC) allows training at low metabolic costs and may therefore be valuable for patients with precapillary pulmonary hypertension (PH) due to pulmonary vascular disease (PVD). Research QuestionThe aim of this study was to compare the ventilatory and circulatory responses to ECC versus conventional cycling (CON) in patients with PVD. Study Design and MethodsThis was a randomized controlled crossover trial in which patients diagnosed with PVD, defined as either pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH), performed CON and ECC cycling tests at identical submaximal work-rates, following stepwise incremental protocols. Oxygen uptake (V’O2) and additional cardiorespiratory responses were measured breath-by-breath by ergospirometry. Hemodynamic parameters such as systolic pulmonary artery pressure (sPAP) and tricuspid annular plain systolic excursion (TAPSE) were measured by echocardiography. Results33 patients (19 PAH, 14 CTEPH, 13 females, 50±15 years) were included. At identical work-rates during ECC compared to CON, V’O2 was significantly lower by - 200 ml/min (-40%, 95CI: -272 to -129, p<0.01), minute ventilation by -5.5 l/min (-30%, 95CI: -9.2 to -3.1, p<0.01), and sPAP by -12 mmHg (-20%, 95CI: -20 to -4 p<0.01). Right ventricular–arterial coupling, as measured by TAPSE/sPAP, was 0.11 mm/mmHg higher (+31%, 95CI: 0.04 to 0.18, p<0.01). No adverse events occurred. InterpretationThe current study supports the hypothesis that ECC is a feasible and well-tolerated exercise modality for PVD patients, with lower O2 demand and a reduced load on the right ventricle. Future studies should investigate whether ECC improves exercise capacity, muscle force and possibly hemodynamics during prolonged rehabilitation programs in patients with PVD.

Evaluation of feline heartworm disease based on gross necropsy, serology, pulmonary histopathology, and radiographic evidence in adult shelter cats in northeastern Alabama

Background: Veterinary knowledge regarding feline heartworm has been increasing significantly over the past two decades. Necropsy surveys of shelter cats have shown feline adult heartworm infection prevalence to be 5–20% of the rate in unprotected dogs; however, other studies have shown feline heartworm antibody prevalence up to 33%, reflecting higher exposure rates and potential immature adult infections. Thus, the true prevalence of feline heartworm infection is likely underestimated due to the limitations of current diagnostic techniques, inadequate testing protocols, and the high likelihood of cats exhibiting transient clinical signs or dying without confirmation of infection. Diagnosing Feline Heartworm Disease (FHWD), also referred to as Heartworm Associated Respiratory Disease (HARD), is one of the conundrums of veterinary medicine. The purpose of this study was to evaluate and characterize the occurrence of Heartworm Associated Respiratory Disease [HARD] in shelter cats, naturally-infected with D.immitis.MethodsFifty shelter cats slated for euthanasia between December 2009 and June 2010 were investigated by gross necropsy, radiography, serology, and lung histopathology using techniques that have been established in experimental models of cat heartworm infection. The relationship between pulmonary vascular disease and serological markers for heartworm was also examined using correlations and statistical modeling. Serology included standard heartworm antigen test and a commonly used heartworm antibody test. Also included were heat-treated heartworm antigen test and two additional heartworm antibody tests previously evaluated on experimentally-infected cats.ResultsNone of the cats were heartworm antibody (HW Ab) positive on a commonly used HW Ab test used by many reference laboratories even though 20% of the study cats were heartworm antigen (HW Ag) positive on heat-treated samples. Two additional HW Ab test were positive on 26% and 22% of the study cats. The combination of heat-treated HW Ag, HW Ab tests, and histopathology indicated 34% of the study cats had HARD.ConclusionsUtilizing both, the above tests, and thoracic radiographs, enhanced the ability to predict vascular disease, possibly caused by infection with immature and adult heartworms and supported the premise that cats develop heartworm disease at the same rate as dogs.Graphical

Long-term survival and clinical outcomes of delayed chest closure following lung transplantation

PurposesDelayed chest closure (DCC) is a widely accepted procedure in the context of lung transplantation (LTx); yet there are few reports detailing its long-term survival and clinical outcomes.MethodsWe reviewed the medical records of recipients who underwent deceased-donor lung transplantation (LTx) at Tohoku University Hospital. Long-term survival, including overall survival, freedom from chronic lung allograft dysfunction (CLAD), and CLAD-free survival and the clinical outcomes of graft function and physical performance and constitution were reviewed in recipients with DCC.ResultsBetween 2009 and 2022, 116 patients underwent LTx, 33 of whom (28.4%) required DCC. The intra—and post-operative courses of the recipients who required DCC were more complicated than those of the recipients who underwent primary chest closure (PCC), with frequent volume reduction surgery and longer periods of invasive mechanical ventilation. Pulmonary vascular disease was considered a risk factor for these complications and DCC. Nonetheless, long-term survival and graft functions were comparable between the DCC and PCC groups. The physical performance and constitution of recipients who required DCC continued to improve, and by 2 years after transplantation, exhibited almost no difference from those who underwent PCC.ConclusionsIn view of the profoundly complicated intra- and post-operative courses, DCC should be performed cautiously and only when clinically indicated, despite which it can result in equivalent long-term survival and acceptable outcomes to PCC.

PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONGENITAL HEART DISEASE: RATIONALE FOR MANAGEMENT ALGORITHM BASED ON A LITERATURE REVIEW

The substantial progress achieved in cardiology and paediatric cardiac surgery has led to a considerable increase of life expectancy of patients with congenital heart disease (CHD), and at the same time to growing number of adult patients developing pulmonary arterial hypertension (PAH) associated with congenital heart defects. Nowadays guidelines were developed and updated for PAH, but no expert recommendations exist for effective management of PAH associated with CHD. Thus, it is important to develop an algorithm for managing these patients, based on international standards and a comprehensive understanding of prognostic markers of worsening the course of pulmonary arterial hypertension (PAH), considering local cardiac tertiary hospitals' capabilities.&#x0D; The aim. To highlight the pathophysiology and clinical characteristics of PAH-CHD patients, identify prognostic markers for its onset and progression, and develop a management algorithm for patients.&#x0D; Results. The article presents the pathophysiology of PAH-CHD, the mechanisms of right ventricle adaptation to pressure overload, which determine the functional abilities of patients and prognosis, PAH formation, and progression after defects correction. The accurate identification of stages in PAH-CHD (volume overload, mixed, stage of pulmonary vascular disease) is essential for the timely determination of surgical intervention, selecting conservative treatment strategies, and predicting the outcomes of surgical defect correction. The type of defect, its size, and the volume of blood flow through the defect influence the onset and progression of PH-CHD. We review the pathophysiology and clinical features of PAH-CHD, as well as the reasons for the late diagnosis of heart failure at the stage of severe decompensation and irreversible remodelling of the lung vessels when diuretic therapy is not effective enough and inotropic support, circulatory mechanical support and heart / lung complex transplantation are required. The necessity of developing new scales for stratifying the risk of PAH-CHD is justified considering the particularities of the disease course and cardiac hemodynamic in different anatomical types of the defects. Based on this literature review, at the Municipal Enterprise «Dnipropetrovsk Regional Clinical Center for Diagnostics and Treatment» of the Dnipropetrovsk Regional Council» the algorithm for managing patients with PAH-CHD was devised and implemented into clinical practice.&#x0D; Conclusions. PAH is a common complication of CHD. The prevalence of PAH-CHD is substantial and it can manifest and progress even in patients with previously corrected heart defects. To effectively manage patients with PAH-CHD, an algorithm has been devised and implemented in clinical practice. It includes factors that have demonstrated associations with poor prognosis which are more than two hospitalizations for HF in the last year, pulmonary vascular resistance (PVR) (or index of PVR), mean pressure in the pulmonary artery, pulmonary capillary wedge pressure, left ventricular ejection fraction, heart failure with a reduced ejection fraction, right ventricle heart failure, NYHA FC, high risk of atrial fibrillation or flutter, 6-minute walking test distance, NTproBNP, highly sensitive C-reactive protein, B-lines on lung ultrasound, glomerular filtration rate, haemoglobin, platelet count, sodium, Model for End-Stage Liver Disease scale.

Pulmonary Hypertension in Systemic Sclerosis.

Systemic sclerosis is a multisystem connective tissue disease that is associated with substantial morbidity and mortality. Visceral organ involvement is common in patients with systemic sclerosis and occurs independently of skin manifestations. Pulmonary hypertension (PH) is an important and prevalent complication of systemic sclerosis. The clinical classification of PH cohorts conditions with similar pathophysiological mechanisms into one of five groups. While patients with systemic sclerosis can manifest with a spectrum of pulmonary vascular disease, notable clinical groups include group 1 pulmonary arterial hypertension (PAH) associated with connective tissues disease, PAH with features of capillary/venous involvement, group 2 PH associated with left heart disease, and group 3 PH associated with interstitial lung disease. Considerable efforts have been made to advance screening methods for PH in systemic sclerosis including the DETECT and ASIG (Australian Scleroderma Interest Group) composite algorithms. Current guidelines recommend annual assessment of the risk of PAH as early recognition may result in attenuated hemodynamic impairment and improved survival. The treatment of PAH associated with systemic sclerosis requires a multidisciplinary team including a PH specialist and a rheumatologist to optimize immunomodulatory and PAH-specific therapies. Several potential biomarkers have been identified and there are several promising PAH therapies on the horizon such as the novel fusion protein sotatercept. This chapter provides an overview of PH in systemic sclerosis, with a specific focus on group 1 PAH.

Surviving birth at high altitude.

This Symposium Review examines challenges to surviving birth and infancy at high altitudes. Chronic exposure to the environmental hypoxia of high altitudes increases the incidence of maternal vascular disorders of pregnancy characterized by placental insufficiency, restricted fetal growth and preterm delivery, and impairs pulmonary vascular health during infancy. While each condition independently contributes to excess morbidity and mortality in early life, evidence indicates vascular disorders of pregnancy and infantile pulmonary vascular dysfunction are intertwined. By integrating our recent scientific and clinical observations in Bolivia with existing literature, we propose potential avenues to reduce the infant mortality burden at high altitudes and reduce pulmonary vascular disease in highland neonates, and emphasize the need for further research to address unresolved questions.

Deep Learning Model for Prediction of Bronchopulmonary Dysplasia in Preterm Infants Using Chest Radiographs

Bronchopulmonary dysplasia (BPD) is common in preterm infants and may result in pulmonary vascular disease, compromising lung function. This study aimed to employ artificial intelligence (AI) techniques to help physicians accurately diagnose BPD in preterm infants in a timely and efficient manner. This retrospective study involves two datasets: a lung region segmentation dataset comprising 1491 chest radiographs of infants, and a BPD prediction dataset comprising 1021 chest radiographs of preterm infants. Transfer learning of a pre-trained machine learning model was employed for lung region segmentation and image fusion for BPD prediction to enhance the performance of the AI model. The lung segmentation model uses transfer learning to achieve a dice score of 0.960 for preterm infants with ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le$$\\end{document} 168 h postnatal age. The BPD prediction model exhibited superior diagnostic performance compared to that of experts and demonstrated consistent performance for chest radiographs obtained at ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le$$\\end{document} 24 h postnatal age, and those obtained at 25 to 168 h postnatal age. This study is the first to use deep learning on preterm chest radiographs for lung segmentation to develop a BPD prediction model with an early detection time of less than 24 h. Additionally, this study compared the model’s performance according to both NICHD and Jensen criteria for BPD. Results demonstrate that the AI model surpasses the diagnostic accuracy of experts in predicting lung development in preterm infants.

Cardiopulmonary exercise test to detect cardiac dysfunction from pulmonary vascular disease

BackgroundCardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease.MethodsWe reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O2·pulseAT/O2·pulserest with RHC-determined SVAT/SVrest. We evaluated the sensitivity and specificity of O2·pulseAT/O2·pulserest to detect SVAT/SVrest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRVpeak) with SVAT/SVrest.ResultsFrom July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O2·pulse and SV at rest and at AT. O2·pulseAT/O2·pulserest correlated highly with SVAT/SVrest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRVpeak did not (r = -0.09, 95% CI -0.47, 0.33; p = 0.69). The AUROC to detect SVAT/SVrest below the LLN was significantly higher for O2·pulseAT/O2·pulserest (0.92, SE 0.04; p = 0.0002) than for TRVpeak (0.69, SE 0.10; p = 0.12). O2·pulseAT/O2·pulserest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SVAT/SVrest.ConclusionsCPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O2·pulseAT/O2·pulserest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism.

The role of immune cells and inflammation in pulmonary hypertension: mechanisms and implications.

Pulmonary hypertension (PH) is a malignant disease with progressive increase of pulmonary vascular pressure, which eventually leads to right heart failure. More and more evidences show that immune cells and inflammation play an important role in the occurrence and development of PH. In the context of pulmonary vascular diseases, immune cells migrate into the walls of the pulmonary vascular system. This leads to an increase in the levels of cytokines and chemokines in both the bloodstream and the surrounding tissues of the pulmonary vessels. As a result, new approaches such as immunotherapy and anti-inflammatory treatments are being considered as potential strategies to halt or potentially reverse the progression of PH. We reviewed the potential mechanisms of immune cells, cytokines and chemokines in PH development. The potential relationship of vascular cells or bone morphogenetic protein receptor 2 (BMPR2) in immune regulation was also expounded. The clinical application and future prospect of immunotherapy were further discussed.

Association of Male Sex With Worse Right Ventricular Function and Survival in Pulmonary Hypertension in the Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics Cohort

BackgroundSex-based differences are important in the development and progression of pulmonary arterial hypertension (PAH). However, it is not established whether these differences are generalizable to all forms of pulmonary hypertension (PH). Research QuestionTo assess sex-based differences in right ventricular (RV) function and transplant-free survival in subjects with PH from the PVDOMICS cohort. Study Design and MethodsSubjects with PH enrolled in PVDOMICS cohort study underwent right heart catheterization, cardiac MRI, and echocardiogram. A multivariable linear regression model was used to investigate the interactive effect between sex and pulmonary vascular resistance (PVR) on RV ejection fraction (EF). Effects of sex, RVEF, and PVR on transplant-free survival were assessed using a Cox proportional hazards model. Results750 subjects with PH (62.8% female) were enrolled, including 397 subjects with Groups 2-5 PH. Group 1 was most predominantly female (73.4%). Men had multiple markers of worse RV function with significantly lower RVEF (Adjusted difference 5.5%, 95% CI: 3.2-7.8%, P<0.001) on cardiac MRI and lower RV fractional shortening (Adjusted difference 4.0%, 95% CI: 2.3 to 5.8%, P<0.001) and worse RV free wall longitudinal strain (Adjusted difference 2.4%, 95% CI: 1.2 to 3.6%, P<0.001) on echocardiogram. There was significant interaction between PVR and sex on RVEF with largest sex-based differences in RVEF noted at mild to moderate PVR elevation. Male sex was associated with decreased transplant-free survival (adjusted HR 1.46, 95% CI: 1.07 to 1.98, P=0.02), partially mediated by differences in RVEF (P=0.003). InterpretationIn subjects with PH in PVDOMICS, female sex is more common, while male sex is associated with worse RV function and decreased transplant-free survival, most notably at mild to moderate elevation of PVR.

Is General Anesthesia for Peripheral Vascular Surgery Correlated with Impaired Outcome in Patients with Cardiac Comorbidity? A Closer Look into the Nationwide Danish Cohort

ObjectiveGeneral anesthesia (GA) may impair outcome after vascular surgery. The use of anticoagulant medication is often used in patients with cardiac comorbidity. Regional anesthesia (RA) requires planning of discontinuation before neuraxial blockade(s) in this subgroup. The aim was to describe the effect of anesthesia choice on outcome after vascular surgery in patients with known cardiac comorbidity. DesignRetrospective cohort study. SettingDanish hospitals. Participants6302 patients with known cardiac comorbidity, defined as ischemic heart disease, valve disease, pulmonary vascular disease, heart failure, and cardiac arrhythmias, undergoing lower extremity vascular surgery between 2005 and 2017. InterventionsGA versus RA. Measurements and Main ResultsData were extracted from national registries. GA was defined as anesthesia with mechanical ventilation. Multivariable regression models were used to describe the incidence of postoperative complications as well as 30-day mortality, hypothesizing a better outcome after RA. The rate of RA decreased from 48% in 2005 to 20% in 2017. The number of patients with ≥1 complications was 9.7 vs 6.2% (p <.001) and 30-day mortality was 6.0 vs 3.4% (p <.001) after GA. After adjusting for baseline differences, odds ratio (OR) was significantly lower for medical complications (cardiac, pulmonary, renal, new dialysis, intensive care unit and other medical complications) (OR 0.97 (0.95-0.98)) and 30-day mortality (OR 0.98 (0.97-0.99)) after RA. ConclusionsRA may be associated with a better outcome than GA after lower extremity vascular surgery, in patients with cardiac comorbidity. Prioritizing RA, despite the inconvenience of discontinuing anticoagulants, may be recommended.

Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome.

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than nondeployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the subjects in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease. Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice. SO2 exposure led to increased formation of isolevuglandins (isoLGs) adducts and superoxide dismutase 2 (SOD2) acetylation in endothelial cells, which were attenuated by treatment with the isoLG scavenger 2-hydroxybenzylamine acetate (2-HOBA). In addition, 2-HOBA treatment or Siruin-3 overexpression in a transgenic mouse model prevented vascular remodeling following SO2 exposure. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress appears to mediate PV remodeling in this model. Together, these findings provide new insights regarding the critical mechanisms underlying PDRS.NEW & NOTEWORTHY We developed a mice model of "post-deployment respiratory syndrome" (PDRS), a condition in Veterans with unexplained exertional dyspnea. Our model successfully recapitulates many of the pathological and physiological features of the syndrome, revealing involvement of the ROS-isoLGs-Sirt3-SOD2 pathway in pulmonary vasculature pathology. Our study provides additional knowledge about effects and long-term consequences of sulfur dioxide exposure on the respiratory system, serving as a valuable tool for future PDRS research.

Updated Clinical Classification and Hemodynamic Definitions of Pulmonary Hypertension and Its Clinical Implications.

Pulmonary hypertension (PH) refers to a pathologic elevation of the mean pulmonary artery pressure (mPAP) and is associated with increased morbidity and mortality in a wide range of medical conditions. These conditions are classified according to similarities in pathophysiology and management in addition to their invasive hemodynamic profiles. The 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension present the newest clinical classification system and includes significant updates to the hemodynamic definitions. Pulmonary hypertension is now hemodynamically defined as an mPAP > 20 mmHg, reduced from the previous threshold of ≥25 mmHg, due to important insights from both normative and prognostic data. Pulmonary vascular resistance has been extended into the definition of pre-capillary pulmonary hypertension, with an updated threshold of >2 Wood Units (WU), to help differentiate pulmonary vascular disease from other causes of increased mPAP. Exercise pulmonary hypertension has been reintroduced into the hemodynamic definitions and is defined by an mPAP/cardiac output slope of >3 mmHg/L/min between rest and exercise. While these new hemodynamic thresholds will have a significant impact on the diagnosis of pulmonary hypertension, no evidence-based treatments are available for patients with mPAP between 21-24 mmHg and/or PVR between 2-3 WU or with exercise PH. This review highlights the evidence underlying these major changes and their implications on the diagnosis and management of patients with pulmonary hypertension.

Effects of 5-Week Oral Acetazolamide on Incremental Cycling Exercise in Pulmonary Arterial and Chronic Thromboembolic Pulmonary Hypertension: A Randomized Placebo-Controlled, Double-Blinded, Crossover Trial

Introduction: Acetazolamide (AZA) improves nocturnal and daytime blood oxygenation in patients with pulmonary vascular disease (PVD), defined as pulmonary arterial and distal chronic thromboembolic pulmonary hypertension (CTEPH), and may improve exercise performance. Methods: We investigated the effect of 5 weeks of AZA (250 mg bid) versus placebo on maximal load during incremental cycling ramp exercise in patients with PVD studied in a randomized controlled, double-blind, crossover design, separated by > 2 weeks of washout. Results: Twenty-five patients (12 pulmonary arterial hypertension, 13 CTEPH, 40% women, age 62 ± 15 years) completed the trial according to the protocol. Maximum load was similar after 5 weeks of AZA versus placebo (113 ± 9 vs. 117 ± 9 watts [W]), mean difference −4 W (95% CI: −9 to 1, p = 0.138). With AZA, maximum (max)-exercise partial pressure of O₂ (PaO₂) was significantly higher by 1.1 kPa (95% CI: 0.5–1.8, p = 0.003), while arterial pH and partial pressure of CO₂ were significantly lower. Gas exchange threshold was reached at a higher load with AZA (108 ± 8 W vs. 97 ± 8 W) and was therefore delayed by 11 W (95% CI: 3–19, p = 0.013), while the ventilatory equivalent for O₂ and CO₂ were significantly higher at both the max-exercise and gas exchange threshold with AZA versus placebo. Conclusion: AZA for 5 weeks did not significantly change maximum exercise capacity in patients with PVD despite a significant increase in PaO₂. The beneficial effects of increased blood oxygenation may have been diminished by increased ventilation due to AZA-induced metabolic acidosis and increased dyspnea.

Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study

In the post-pandemic era, growing apprehension exists regarding the potential sequelae of COVID-19. However, the risks of respiratory diseases following SARS-CoV-2 infection have not been comprehensively understood. This study aimed to investigate whether COVID-19 increases the long-term risk of respiratory illness in patients with COVID-19. In this longitudinal, population-based cohort study, we built three distinct cohorts age 37-73 years using the UK Biobank database; a COVID-19 group diagnosed in medical records between January 30th, 2020 and October 30th, 2022, and two control groups, a contemporary control group and a historical control group, with cutoff dates of October 30th, 2022 and October 30th, 2019, respectively. The follow-up period of all three groups was 2.7 years (the median (IQR) follow-up time was 0.8 years). Respiratory outcomes diagnosed in medical records included common chronic pulmonary diseases (asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer. For the data analysis, we calculated hazard ratios (HRs) along with their 95% CIs using Cox regression models, following the application of inverse probability weights (IPTW). A total of 3 cohorts were included in this study; 112,311 individuals in the COVID-19 group with a mean age (±SDs) of 56.2 (8.1) years, 359,671 in the contemporary control group, and 370,979 in the historical control group. Compared with the contemporary control group, those infected with SARS-CoV-2 exhibited elevated risks for developing respiratory diseases. This includes asthma, with a HR of 1.49 and a 95% CI 1.28-1.74; bronchiectasis (1.30; 1.06-1.61); COPD (1.59; 1.41-1.81); ILD (1.81; 1.38-2.21); PVD (1.59; 1.39-1.82); and lung cancer (1.39; 1.13-1.71). With the severity of the acute phase of COVID-19, the risk of pre-described respiratory outcomes increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time. Additionally, the HR of lung cancer for 0-6 month follow-up was 3.07 (CI 1.73-5.44), and the association of lung cancer with COVID-19 disease disappeared at 6-12 month follow-up (1.06; 0.43-2.64) and at 12-24 months (1.02; 0.45-2.34). Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of asthma (3.0; 1.32-6.84), COPD (3.07; 1.42-6.65), ILD (3.61; 1.11-11.8), and lung cancer (3.20; 1.59-6.45). Similar findings were noted when comparing with a historical cohort serving as a control group, including asthma (1.31; 1.13-1.52); bronchiectasis (1.53; 1.23-1.89); COPD (1.41; 1.24-1.59); ILD (2.53; 2.05-3.13); PVD (2.30; 1.98-2.66); and lung cancer (2.23; 1.78-2.79). Our research suggests that patients with COVID-19 may have an increased risk of developing respiratory diseases, and the risk increases with the severity of infection and reinfection. Even during the 24-month follow-up, the risk of asthma and bronchiectasis continued to increase. Hence, implementing appropriate follow-up strategies for these individuals is crucial to monitor and manage potential long-term respiratory health issues. Additionally, the increased risk in lung cancer in the COVID-19 individuals was probably due to the diagnostic tests conducted and incidental diagnoses. The National Natural Science Foundation of China of China Regional Innovation and Development Joint Foundation; National Natural Science Foundation of China; Program for High-level Foreign Expert Introduction of China; Natural Science Foundation for Distinguished Young Scholars of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital; VA Clinical Merit and ASGE clinical research funds.

Health-Related Quality of Life Across the Spectrum of Pulmonary Hypertension

BackgroundHealth related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension (PAH). However, little is known about HRQOL in other forms of pulmonary hypertension (PH). Research QuestionDoes HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system? Study Design and MethodsThis cross-sectional study included PH patients from PVDOMICS (Pulmonary Vascular Disease Phenomics). HRQOL was assessed using emPHasis-10 (e-10), Medical Outcomes Survey Short Form-36 (SF-36; physical component (PCS) and mental component (MCS)), and Minnesota Living with Heart Failure Questionnaire (MLHF). Pearson’s correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups adjusting for demographics, disease prevalence, functional class, and hemodynamics. Cox proportional hazard models were used to assess associations between HRQOL and survival across WSPH groups. ResultsAmong 691 PH patients, HRQOL correlated with functional class and six-minute walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the SF-36 MCS. When compared to Group 1, Group 2 subjects had significantly worse HRQOL (e-10: 29 vs 24, p=0.001, PCS: 32.9 ± 8 vs 38.4 ± 10, p<0.0001, MLHF: 50 vs 38, p=0.003). Group 3 subjects similarly had worse e-10 (31 vs 24, p<0.0001) and PCS scores (33.3 ± 9 vs 38.4 ± 10, p<0.0001) compared to Group 1, which persisted in multivariable models (p<0.05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3. InterpretationHRQOL is depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but hemodynamic disease severity poorly estimates the impact of PH on patient’s lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of pulmonary hypertension.

Spectral analysis of non-contrast fluoroscopy for evaluation of pulmonary perfusion: Feasibility and sensitivity testing with a phantom.

Oscillating x-ray attenuation in the lungs provides an opportunity to evaluate pulmonary perfusion without contrast. Recent intensity-based methods have been compared to pulmonary scintigraphy and CT angiography but lack rigorous phantom studies. A new method to quantify the periodic signal amplitude was employed using spectral analysis. Performance was characterized using a water phantom capable of creating an oscillating x-ray attenuation at physiologic amplitudes. Feasibility in detecting abnormal perfusion was performed on a volunteer with pulmonary vascular disease and compared to pulmonary angiography, the clinical gold standard. For each fluoroscopic acquisition, the normalized temporal signal from each pixel was decomposed into its frequency components using Fourier transformation, and the spectral amplitude, defined as the x-ray pulsatility index (XPI), was determined at the desired frequency using a band-pass filter. XPI was displayed as a pixel-wise parametric colormap. Based on XPI maps generated using two human volunteers, a water bath phantom was constructed with a fluctuating fluid height and a 1cm diameter pulsatility defect. Contrast-to-noise (CNR) of the defect was measured using fluoroscopy images acquired at variable fluid height fluctuation (0.1-1.9mm) and oscillation frequency (30-60bpm). Various sampling frame rates (3-30 fps) and acquisition durations (1.8-8s) using truncated datasets were reconstructed from full datasets. Fluoroscopic images were obtained in a patient just prior to pulmonary angiography in the same projection. XPI maps in human subjects showed high signal to background contrast with high central XPI measuring up to 0.5. Phantom experiments revealed CNR was linearly correlated to fluid height change (r2=0.998). CNR is proportional to increasing sampling frame rate and increasing acquisition duration as expected with Fourier analysis. XPI map displayed multifocal perfusion defects in good agreement with pulmonary angiography. Spectral analysis is an accurate and sensitive method to detect small changes in periodic x-ray attenuation using a short fluoroscopic acquisition. This method demonstrated good agreement to pulmonary angiography and shows promise for clinical imaging of pulmonary perfusion using standard fluoroscopic methods.

SOCS5, targeted by miR-155-5p, plays a negative regulatory role in pulmonary hypertension through inhibiting JAK2/STAT3 signaling pathway

Pulmonary hypertension (PH) is a chronic pulmonary vascular disease and causes massive deaths. Here, we intended to investigate the function and mechanism of SOCS5 in PH. We engineered a hypoxia-induced PH model in mice. HE staining were implemented to evaluate pathological alterations in the lung tissues. The potential mechanism of SOCS5 in regulating hypoxia-induced pulmonary artery smooth muscle cell (PASMC) function was explored in vitro. RT-qPCR and western blot revealed that the level of SOCS5 was decreased both in PH mice and hypoxia-induced HPASMCs. Functional assays were performed for confirming the role of SOCS5 in modulating the cell phenotype and JAK2/STAT3 pathway in HPASMCs. Results revealed that overexpression of SOCS5 suppressed proliferation, migration and contraction of HPASMCs and negatively regulated the JAK2/STAT3 signaling pathway in HPASMCs under hypoxia in vitro, while knockdown of SOCS5 accelerated it. As evidenced by mechanism studies, SOCS5 was targeted and regulated by miR-155-5p, hence affecting on HPASMC proliferation, migration and contraction. These outcomes indicated that the decreased level of SOCS5 in hypoxia-induced HPASMCs promoted the cell proliferation, cell migration, and cell contraction through activating JAK2/STAT3 signaling pathway. Moreover, SOCS5 was targeted by miR-155-5p. All in all, our work hinted that miR-155-5p/SOCS5/JAK2/STAT3 axis played a crucial part in PH.

Clinical phenogroup diversity and multiplicity: Impact on mechanisms of exercise intolerance in heart failure with preserved ejection fraction.

We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits. Individuals with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow-up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously-proposed, non-exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08-2.79 for 0-1 vs. ≥2 phenogroup traits present). Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non-cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome.

Endothelium-specific SIRT7 targeting ameliorates pulmonary hypertension through Krüpple-like factor 4 deacetylation.

Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by a high mortality rate. Pulmonary arterial endothelium cells (PAECs) serve as a primary sensor of various environmental cues, such as shear stress and hypoxia, but PAEC dysfunction may trigger vascular remodelling during the onset of PH. This study aimed to illustrate the role of Sirtuin 7 (SIRT7) in endothelial dysfunction during PH and explore the potential therapeutic strategy for PH. SIRT7 levels were measured in human and murine experimental PH samples. Bioinformatic analysis, immunoprecipitation, and deacetylation assay were used to identify the association between SIRT7 and Krüpple-like factor 4 (KLF4), a key transcription factor essential for endothelial cell (EC) homeostasis. Sugen5416 + hypoxia (SuHx)-induced PH mouse models and cell cultures were used for the study of the therapeutic effect of SIRT7 for PH. SIRT7 level was significantly reduced in lung tissues and PAECs from PH patients and the SuHx-induced PH mouse model as compared with healthy controls. Pulmonary endothelium-specific depletion of Sirt7 increased right ventricular systolic pressure and exacerbated right ventricular hypertrophy in the SuHx-induced PH model. At the molecular level, we identified KLF4 as a downstream target of SIRT7, which deacetylated KLF4 at K228 and inhibited the ubiquitination-proteasome degradation. Thus, the SIRT7/KLF4 axis maintained PAEC homeostasis by regulating proliferation, migration, and tube formation. PAEC dysfunction was reversed by adeno-associated virus type 1 vector-mediated endothelial overexpression of Sirt7 or supplementation with nicotinamide adenine dinucleotide (NAD)+ intermediate nicotinamide riboside which activated Sirt7; both approaches successfully reversed PH phenotypes. The SIRT7/KLF4 axis ensures PAEC homeostasis, and pulmonary endothelium-specific SIRT7 targeting might constitute a PH therapeutic strategy.