CD109 Attenuates Bleomycin-induced Pulmonary Fibrosis by Inhibiting TGF-ß Signaling.

Pulmonary fibrosis is a fatal condition characterized by fibroblast and myofibroblast proliferation and collagen deposition. TGF-ß plays a pivotal role in the development of pulmonary fibrosis. Therefore, modulation of TGF-ß signaling is a promising therapeutic strategy for treating pulmonary fibrosis. To date, however, interventions targeting TGF-ß have not shown consistent efficacy. CD109 is a GPI-anchored glycoprotein that binds to TGF-ß receptor I and negatively regulates TGF-ß signaling. However, no studies have examined the role and therapeutic potential of CD109 in pulmonary fibrosis. The purpose of this study was to determine the role and therapeutic value of CD109 in bleomycin-induced pulmonary fibrosis. CD109-transgenic mice overexpressing CD109 exhibited significantly attenuated pulmonary fibrosis, preserved lung function, and reduced lung fibroblasts and myofibroblasts compared with wild-type (WT) mice. CD109-/- mice exhibited pulmonary fibrosis comparable to WT mice. CD109 expression was induced in variety types of cells, including lung fibroblasts and macrophages, upon bleomycin exposure. Recombinant CD109 protein inhibited TGF-ß signaling and significantly decreased ACTA2 expression in human fetal lung fibroblast cells in vitro. Administration of recombinant CD109 protein markedly reduced pulmonary fibrosis in bleomycin-treated WT mice in vivo. Our results suggest that CD109 is not essential for the development of pulmonary fibrosis, but excess CD109 protein can inhibit pulmonary fibrosis development, possibly through suppression of TGF-ß signaling. CD109 is a novel therapeutic candidate for treating pulmonary fibrosis.

CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation.

Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing T-helper cell type 2 (Th2) skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109-deficient mice (CD109-/-) were sensitized with house dust mite or ovalbumin and compared with wild-type mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared with wild-type mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109-/- mice had a poor ability to induce cytokine production in ex vivo DC-T cell cocultures with high expression of RUNX3 (runt-related transcription factor 3), resulting in suppression of Th2 differentiation. Adoptive transfer of bone marrow-derived CD109-/- DCs loaded with house dust mite failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma.

Prognostic significance of radiological pleuroparenchymal fibroelastosis in Mycobacterium avium complex lung disease: a multicentre retrospective cohort study.

BACKGROUND: Mycobacterium avium complex (MAC) causes chronic respiratory infectious diseases with diverse clinical features and prognoses. Pleuroparenchymal fibroelastosis (PPFE) is a rare disease characterised by pleural fibrosis with subjacent intra-alveolar fibrosis and alveolar septal elastosis, with unique chest high-resolution CT (HRCT) features (radiological PPFE). An association between recurrent respiratory infections and PPFE formation has been hypothesised; however, the clinical significance of PPFE in MAC lung disease remains unclear. METHODS: This retrospective, multicentre study investigated the prevalence of radiological PPFE in patients with MAC lung disease and its association with clinical features and outcomes. Radiological PPFE was diagnosed on the basis of HRCT findings. Prognostic factors were identified using Cox proportional hazards and Fine-Gray models. RESULTS: Of 850 consecutive patients with definite MAC lung disease, 101 (11.9%) exhibited radiological PPFE. Patients with radiological PPFE had unique characteristics, such as lower body mass index, lower survival rate (5-year cumulative survival rate, 63.1% vs 91.7%; p<0.001) and a higher incidence of respiratory-related death (5-year cumulative incidence, 31.1% vs 3.6%; p<0.001), than those without radiological PPFE. In the multivariable analysis, the presence of radiological PPFE was independently associated with all-cause mortality (adjusted HR, 4.78; 95% CI, 2.87 to 7.95; p<0.001) and respiratory-related death (adjusted HR, 3.88; 95% CI, 2.14 to 7.01; p<0.001). INTERPRETATION: This large-scale study demonstrated that in patients with MAC lung disease, radiological PPFE was common, a phenotype associated with unique clinical features and poor prognosis, particularly respiratory-related death. The specific management of this subgroup should be established.

Impact of antifibrotic therapy on lung cancer development in idiopathic pulmonary fibrosis.

Patients with idiopathic pulmonary fibrosis (IPF) are at a high risk of lung cancer (LC). Antifibrotic therapy slows disease progression and possibly prolongs survival. However, whether antifibrotic therapy affects LC development in patients with IPF remains unknown. This multicentre retrospective study evaluated 345 patients with IPF. The incidence and prevalence of LC were significantly lower in patients with IPF receiving antifibrotic therapy than those not receiving. Subsequently, LC-related mortality was significantly lower in patients with IPF receiving antifibrotic therapy. These results suggest that antifibrotic therapy was possibly associated with a reduced risk of LC development in patients with IPF, which may be partly associated with its survival benefit.

Frequency, proportion of PF-ILD, and prognostic factors in patients with acute exacerbation of ILD related to systemic autoimmune diseases.

BACKGROUND: Acute exacerbation (AE) of systemic autoimmune disease-related interstitial lung diseases (SAID-ILD) is less common than AE of idiopathic pulmonary fibrosis (IPF) and the details of AE-SAID-ILD have not been elucidated, but the prognosis is similarly devastating. This study was undertaken to determine the incidences of AE-ILD in each SAID and to elucidate the proportion of progressive fibrosing (PF)-ILD in AE-SAID-ILD. METHODS: We retrospectively analysed data for patients with SAID-ILD who were diagnosed and observed at our hospital between 1999 and 2020. RESULTS: Two hundred and thirty-two patients with SAID-ILD were enrolled, with a mean observation period of 100.2 months. AE-SAID-ILD was found in 25 patients (10.78%), mainly in patients with RA (17 patients, 68%) and elderly male patients with a smoking history. The overall incidence of AE-SAID-ILD was 1.29%/person-year, and the incidence for each SAID was as follows: RA 2.193, microscopic polyarteritis (MPA) 3.203, systemic sclerosis (SSc) 2.277, primary Sjögren syndrome 0.426, and polymyositis/dermatomyositis 0.222. The incidence of AE of RA/MPA/SSc-ILD was significantly higher than that of other AE-SAID-ILD (p < 0.001). Five of 25 patients (20%) fulfilled the criteria for PF-ILD. The 90-day survival rate was 48.0%, and a higher neutrophil count at AE (HR 13.27, 95%CI 2.447-246, p = 0.001) and early commencement of long-duration direct haemoperfusion with a polymyxin B-immobilised fibre column (HR 0.105, 95%CI 0.005-0.858, p = 0.035) were significant prognostic factors. CONCLUSIONS: The incidence of AE-SAID-ILD was significantly higher in patients with RA, MPA, or SSc than in patients with other SAID. Furthermore, even in patients with AE-SAID-ILD, the proportion of PF-ILD just before AE was not high (20%).

Cause of mortality and sarcopenia in patients with idiopathic pulmonary fibrosis receiving antifibrotic therapy.

BACKGROUND AND OBJECTIVE: Recent research has highlighted the fundamental role of sarcopenia, characterized by loss of skeletal muscle mass and strength, with a risk of poor outcomes. AFT preserves lung function by preventing the annual decline in FVC and is associated with improved outcomes in patients with IPF. However, altered cause of death and prognostic implications of sarcopenia in patients with IPF receiving AFT remain unknown. METHODS: This study comprised two cohorts of patients with IPF receiving AFT, historical cohort of IPF patients without AFT and controls. The cause of mortality was compared with a historical cohort. Sarcopenia was assessed by measuring the ESMCSA and ESMMA via CT. RESULTS: Patients with IPF had smaller ESMCSA and lower ESMMA but similar BMI than controls, suggesting patients with IPF had skeletal muscle loss without any obvious body weight loss. The most common cause of mortality in patients receiving AFT was chronic respiratory failure, accounting for approximately 60%, and decreased proportions of LC were found. Subsequently, low ESMCSA was an independent prognostic factor associated with worse survival rates. Furthermore, combined assessment of ESMCSA , %FVC predicted and BMI values provided clear prognostic distinction. CONCLUSION: Patients with IPF receiving AFT showed skeletal muscle loss without obvious weight loss. These patients mostly died by chronic respiratory failure, and skeletal muscle wasting has prognostic significance, suggesting that preventing sarcopenia as well as preserving lung function are important for managing these patients.

Switching antifibrotics in patients with idiopathic pulmonary fibrosis: a multi-center retrospective cohort study.

BACKGROUND: Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated. METHODS: This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses. RESULTS: The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7-35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p < 0.0001). In propensity-score matched analyses that were adjusted to age, sex, FVC (%), history of acute exacerbation, and usage of long-term oxygen therapy, the Switch-IPF cohort had significantly longer survival times than the Non-Switch-IPF group (median 67.2 vs. 41.3 months, p = 0.0219). The second-line antifibrotic therapy showed similar survival probabilities than those in first-line antifibrotic therapy in multistate model analyses. CONCLUSION: Switching antifibrotics is feasible and may improve prognosis in patients with IPF. A further prospective study will be required to confirm clinical implication of switching the antifibrotics.

Different Impact of Resting Heart Rate on Adverse Events in Paroxysmal and Sustained Atrial Fibrillation　- The Fushimi AF Registry.

BACKGROUND: Heart rate (HR) is an important factor in atrial fibrillation (AF); however, it remains unclear whether the impact of HR differs between paroxysmal AF and sustained (persistent and permanent) AF.Methods and Results:The association of resting HR during AF with adverse events (composite of all-cause death, hospitalization for heart failure, stroke/systemic embolisms, myocardial infarction, and arrhythmic events) in 1,064 paroxysmal and 1,610 sustained AF patients from the Fushimi AF Registry were investigated. These patients were divided into 4 groups based on their resting HR; ≥110 beats/min (bpm), 80-109 bpm, 60-79 bpm, and <60 bpm. The number of patients in each group was 486, 400, 172, and 22 for paroxysmal AF, and 205, 734, 645, and 71 for sustained AF, respectively. Among patients with sustained AF, a HR ≥110 bpm was associated with a higher incidence of adverse events at 1 year and during the entire follow up (median of 1,833 days) (hazard ratio [95% confidence interval] compared with a HR of 60-79 bpm: 1.90 [1.31-2.72] at 1 year, 1.38 [1.10-1.72] during the entire follow up). Patients with a HR <60 bpm showed higher incidence of adverse events at 1 year; however, the incidence of adverse events did not differ among all HR groups of paroxysmal AF. CONCLUSIONS: Baseline HR was associated with adverse events in sustained AF, but not in paroxysmal AF.

Impact of Valvular Heart Disease on Mortality, Thromboembolic and Cardiac Events in Japanese Patients With Atrial Fibrillation　- The Fushimi AF Registry.

BACKGROUND: There is a growing burden of valvular heart disease (VHD) and atrial fibrillation (AF) due to population aging, but data regarding the characteristics and outcomes of patients with AF and concomitant VHD are lacking.Methods and Results:The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto. Among 3,566 patients with available echocardiographic data, 20% had VHD, consisting of 131 valvular AF (VAF: 3.7%) and 583 nonvalvular AF with VHD (NVAF-VHD: 16.3%). Here, VAF was defined as AF with mitral stenosis or a prosthetic heart valve. AF patients with VHD were older, had more comorbidities with a higher CHADS2 score, and were prescribed oral anticoagulants more frequently than those without VHD. After adjusting for confounders, VHD was not associated with stroke or systemic embolism, all-cause mortality, or cardiac death. NVAF-VHD was significantly associated with an increased risk of hospitalization for heart failure (adjusted hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.16-1.78), whereas VAF was not (HR, 1.28; 95% CI, 0.86-1.92). Among all types of VHD, aortic valve diseases were associated with a higher risk of cardiac events, whereas mitral valve diseases were not. CONCLUSIONS: Although VHD did not significantly affect thromboembolism or mortality, it affected cardiac events depending on type, with aortic valve diseases having higher risk, in Japanese patients with AF.

Progression From Paroxysmal to Sustained Atrial Fibrillation Is Associated With Increased Adverse Events.

Background and Purpose- Atrial fibrillation (AF) is a common arrhythmic disorder among the elderly and sometimes progresses from paroxysmal to sustained (persistent or permanent) types. Clinical outcomes of patients with progression of AF were unknown. This study assessed the characteristics of patients with AF progression and the impact of AF progression on various clinical events. Methods- The Fushimi AF Registry is a community-based prospective survey of the patients with AF in Fushimi-ku, Kyoto. Analyses were performed on 4045 patients, which included 1974 paroxysmal AF (PAF; 48.8%) and 2071 sustained (persistent or permanent) AF (SAF; 51.2%) at baseline. Results- During the median follow-up period of 1105 days, progression of AF occurred in 252 patients with PAF (4.22 per 100 person-years). Multivariate Cox regression analysis demonstrated that progression of AF was significantly associated with an increased risk of ischemic stroke or systemic embolism (adjusted hazard ratio [HR], 4.10; 95% CI, 1.95-8.24; P<0.001 [versus PAF without progression]; adjusted HR, 2.20; 95% CI, 1.11-4.00; P=0.025 [versus SAF]) during progression period from paroxysmal to sustained forms. The risk after the progression was equivalent to SAF (adjusted HR, 1.54; 95% CI, 0.78-2.75; P=0.201 [versus SAF]). AF progression was significantly associated with a higher risk of hospitalization for heart failure (adjusted HR, 2.70; 95% CI, 1.55-4.52; P<0.001 [versus PAF without progression]; adjusted HR, 1.81; 95% CI, 1.08-2.88; P=0.026 [versus SAF]). Conclusions- Progression of AF was associated with increased risk of clinical adverse events during arrhythmia progression period from PAF to SAF among Japanese patients with AF. The risk of adverse events was transiently elevated during progression period from PAF to SAF and declined to the level equivalent to SAF after the progression. Clinical Trial Registration- URL: http://www.umin.ac.jp/ctr/ . Unique identifier: UMIN000005834.

Current Status, Time Trends and Outcomes of Combination Therapy With Oral Anticoagulant and Antiplatelet Drug in Patients With Atrial Fibrillation　- The Fushimi AF Registry.

BACKGROUND: The combination of oral anticoagulant (OAC) and antiplatelet drug (APD) increases the bleeding risk in atrial fibrillation (AF). Non-vitamin K antagonist OAC (NOAC) have been increasingly used since 2011. We investigated current status, time trends and outcomes of AF patients using combination therapy in 2011-2017. Methods and Results: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Of 2,378 patients with OAC at enrollment, 521 (22%) received combination therapy, while 1,857 (78%) received OAC alone. When compared with OAC alone, combination therapy patients had more comorbidities, but approximately 30% had no atherosclerotic disease. From 2011 to 2017, the prevalence of combination therapy decreased from 26% to 14%. The prevalence of NOAC increased in those on combination therapy. Off-label under-dosing of NOAC increased year by year, especially in combination therapy. During follow-up, the incidence of major bleeding (hazard ratio [HR], 1.42; 95% CI: 1.03-1.95) and stroke/systemic embolism (HR, 1.48; 95% CI: 1.09-2.00) was higher in the combination therapy than in the OAC alone group. CONCLUSIONS: In Japanese AF patients receiving OAC, the prevalence of combination therapy decreased, with the proportion of NOAC use increasing in 2011-2017. Many patients, however, received off-label NOAC under-dosing, especially in the combination therapy group. Patients with combination therapy had higher incidences of major bleeding as well as stroke/systemic embolism, compared with OAC monotherapy.

Effectiveness and safety of morphine administration for refractory dyspnoea among hospitalised patients with advanced heart failure: the Morphine-HF study.

OBJECTIVES: Morphine is effective in alleviating dyspnoea in patients with cancer. We aimed to investigate the effectiveness and safety of morphine administration for refractory dyspnoea in patients with advanced heart failure (HF). METHODS: We conducted a multicentre, prospective, observational study of hospitalised patients with advanced HF in whom morphine was administered for refractory dyspnoea. Morphine effectiveness was evaluated by dyspnoea intensity changes, assessed regularly by both a quantitative subjective scale (Visual Analogue Scale (VAS; graded from 0 to 100 mm)) and an objective scale (Support Team Assessment Schedule-Japanese (STAS-J; graded from 0 to 4 points)). Safety was assessed by vital sign changes and new-onset severe adverse events, including nausea, vomiting, constipation and delirium based on the Common Terminology Criteria for Adverse Events. RESULTS: From 15 Japanese institutions between September 2020 and August 2022, we included 28 hospitalised patients with advanced HF in whom morphine was administered (mean age: 83.8±8.7 years, male: 15 (54%), New York Heart Association class IV: 26 (93%) and mean left ventricular ejection fraction: 38%±19%). Both VAS and STAS-J significantly improved from baseline to day 1 (VAS: 67±26 to 50±31 mm; p=0.02 and STAS-J: 3.3±0.8 to 2.6±1.1 points; p=0.006, respectively), and thereafter the improvements sustained through to day 7. After morphine administration, vital signs including blood pressure, pulse rate and oxygen saturation did not change, and no new-onset severe adverse events occurred through to day 7. CONCLUSIONS: This study suggested acceptable effectiveness and safety for morphine administration in treating refractory dyspnoea in hospitalised patients with advanced HF.

Radiological and histopathological features and treatment response by subtypes of interstitial pneumonia with autoimmune features: A prospective, multicentre cohort study.

BACKGROUND: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF. METHODS: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated. RESULTS: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002). CONCLUSIONS: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF.

Proteinuria is independently associated with heart failure events in patients with atrial fibrillation: the Fushimi AF registry.

AIMS: Previous studies have shown that proteinuria is independently associated with the incidence of atrial fibrillation (AF), and is also associated with the incidence of cardiovascular events such as stroke and thromboembolism in patients with AF. However, the association of proteinuria with heart failure (HF) events in patients with AF remains unclear. METHODS AND RESULTS: The Fushimi AF Registry is a community-based prospective study of patients with AF. Of the entire cohort of 4489 patients, 2164 patients had available data of proteinuria. We compared the clinical background and outcomes between patients with proteinuria (n = 606, 28.0%) and those without (n = 1558, 72.0%). Patients with proteinuria were older and had a higher prevalence of major co-morbidities. During the median follow-up of 5.0 years, the incidence rates of HF events (composite of cardiac death or HF hospitalization) were higher in patients with proteinuria than those without (4.1% vs. 2.1% person-year, P < 0.01). Multivariate analyses revealed that proteinuria was an independent risk factor of the incidence of HF events [adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.13-1.74]. This association was consistent among the various subgroups, except for the age subgroup in which there was a significant interaction (P < 0.01) between younger (<75 years) (unadjusted HR: 3.03, 95% CI: 2.12-4.34) and older (≥75 years) patients (unadjusted HR: 1.59, 95% CI: 1.23-2.05). CONCLUSION: Our community-based large prospective cohort suggests that proteinuria is independently associated with the incidence of HF events in Japanese patients with AF.

Involvement of autophagy in exacerbation of eosinophilic airway inflammation in a murine model of obese asthma.

Obesity is a common comorbidity in patients with asthma, and obese asthma patients present the most refractory phenotype among patients with severe asthma. Similar to the observations in non-obese asthma patients, clinical studies have revealed heterogeneity in obese asthma patients, including the occurrences of T helper (Th)2-high and Th2-low phenotypes. However, the mechanisms underlying obesity-related asthma are not completely understood. Though macroautophagy/autophagy is involved in asthma and obesity, its role in obesity-associated asthma is unknown. We hypothesized that autophagy is involved in the pathogenesis of obese asthma. For our investigations, we used high-fat diet-induced Atg5 (autophagy related 5)-deficient mice and epithelial cell-specific atg5-/- (Scgb1a1/CCSP-atg5-/-) obesity-induced mice. House dust mite (HDM)-sensitized atg5-/- obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of atg5-/- obese mice showed increased levels of Th2 cells but not ILC2s together with elevated expression of Th2 cytokines in the lung. In response to the HDM challenge, activated epithelial autophagy was observed in lean but not obese WT mice. Epithelium-specific deletion of Atg5 induced eosinophilic inflammation in Scgb1a1/CCSP-atg5-/- obese mice, and genetic analyses of epithelial cells from HDM-immunized atg5-/- obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized atg5-/- mice developed TSLP- and IL33-dependent eosinophilic inflammation and AHR. Our results suggest that autophagy contributes to the exacerbation of eosinophilic inflammation in obese asthma. Modulations of autophagy may be a therapeutic target in obesity-associated asthma.Abbreviations: AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; Cdyn: dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; RL: lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type.

Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF. METHODS: Thirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated. RESULTS: The serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = -0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012). CONCLUSION: The serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF.

Iatrogenic ventricular fibrillation caused by inappropriately synchronized cardioversion in a patient with pre-excited atrial fibrillation: A case report.

Direct-current (DC) cardioversion is effective at terminating arrhythmias in an emergency. During treatment, energy delivery synchronizing with the QRS complex is essential to avoid ventricular fibrillation (VF) caused by a shock on the T wave, which is the vulnerable period of ventricular repolarization. However, distinguishing the QRS from the T wave is difficult in some patients with abnormal, irregular, and varying QRS complexes. We report the case of a 45-year-old man who had iatrogenic VF caused by inappropriate synchronization with the T wave during cardioversion of pre-excited atrial fibrillation due to high ventricular rates and varying R wave amplitude affected by an accessory pathway. .

Prognostic significance of natriuretic peptide levels in atrial fibrillation without heart failure.

OBJECTIVES: Natriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice. METHODS: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fraction<40%) using the data of B-type natriuretic peptide (BNP, n=388) or N-terminal pro-B-type natriuretic peptide (NT-proBNP, n=771) at enrolment. BNPs were converted to NT-proBNP using a conversion formula. We divided the patients according to quartiles of NT-proBNP levels and compared the backgrounds and outcomes. RESULTS: Of 1159 patients (mean age: 72.1±10.2 years, median CHA2DS2-VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169-1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA2DS2-VASc scores and had more OAC prescription (all p<0.001). Kaplan-Meier curves demonstrated that NT-proBNP levels were significantly associated with higher incidences of stroke/systemic embolism, all-cause death and HF hospitalisation during a median follow-up period of 5.0 years (log rank, all p<0.001). Multivariable Cox regression analyses revealed that NT-proBNP levels were an independent predictor of adverse outcomes even after adjustment by various confounders. CONCLUSION: NT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value. TRIAL REGISTRATION NUMBER: UMIN000005834.

Combined assessment of the GAP index and body mass index at antifibrotic therapy initiation for prognosis of idiopathic pulmonary fibrosis.

Antifibrotic therapy (AFT) slows disease progression in patients with idiopathic pulmonary fibrosis (IPF). The Gender-Age-Physiology (GAP) index, was developed based on data at IPF diagnosis before the introduction of AFT and has not been evaluated in the AFT context. Further, recent advances have revealed the importance of body-composition factors in prognosis of IPF treated with AFT. This multi-centre, retrospective study aimed to evaluate the GAP index and body mass index (BMI) at the time of AFT initiation for predicting prognosis in patients with IPF. This study included two patient cohorts of IPF receiving AFT, Hamamatsu cohort (n = 110) and Seirei cohort (n = 119). The distribution of GAP stages I, II, and III was 38.2%, 43.6%, and 18.2%, respectively, in Hamamatsu cohort; in Seirei cohort, it was 41.2%, 50.4%, and 8.4%, respectively. In both cohorts, the GAP index distinctly classified prognosis into three groups (log-rank test). Interestingly, a lower BMI showed prognostic value independent of the GAP index in multivariate analyses. Subsequently, combining the GAP index with BMI at AFT initiation successfully divided the patients with IPF into four distinct prognoses. Assessment of the GAP index and BMI measurement at AFT initiation are important for predicting prognosis in patients with IPF.

Late-onset Hereditary ATTR Amyloidosis with a Novel p.P63S (P43S) Transthyretin Variant.

The patient was an 82-year-old Japanese man with no family history suggestive of amyloidosis. He developed bilateral leg edema and shortness of breath and was referred to our hospital. An electrocardiogram showed atrial fibrillation with right bundle branch block. Echocardiography showed concentric LV hypertrophy. An endomyocardial biopsy showed severe ATTR amyloid deposits. A genetic analysis of the transthyretin (TTR) gene revealed a heterozygous c.187C>T missense variant resulting in p.P63S (P43S). In silico analyses predicted that this variant only modestly altered the structure and function of the TTR protein. The p.P63S variant might be associated with an elderly-onset cardiac-dominant ATTRv phenotype.