Treprostinil Reconstitutes Mitochondrial Organisation and Structure in Idiopathic Pulmonary Fibrosis Cells.

Idiopathic pulmonary fibrosis (IPF) presents as an incurable change in the lung tissue and mitochondrial dysfunction of unknown origin. Treprostinil, a prostacyclin analogue, has been suggested for IPF therapy. This study assessed the effect of treprostinil on the cAMP signalling and mitochondrial activity in healthy lung fibroblasts and fibroblast-like cells from IPF patients. Six control fibroblast strains and six fibroblast-like IPF cell strains were isolated and expanded from freshly resected lung tissue. The cells were grown to confluence before being treated with either transforming growth factor (TGF)-ß1, treprostinil, their combination, or a vehicle for up to 2 days. Mitochondria-regulating proteins were analysed using Western blotting and immunofluorescence, and the mitochondria were analysed using cytochrome C, mitochondrial cytochrome C oxidase II (MTCO2), and MTCO4. The IPF cells showed an increased rate of damaged mitochondria, which were significantly reduced when the cells were treated with treprostinil over 24 h. In the control cells, treprostinil prevented TGF-ß-induced mitochondrial damage. Treatment with treprostinil modified the expression of several mitochondria-regulating proteins. In both cell types, treprostinil upregulated the expression of PTEN, p21(Waf1/Cip1), beclin1, LC3 II, parkin, PINK1, MTCO2, and MTCO4. In contrast, treprostinil downregulated the phosphorylation of mTOR and the expression of p62, mitofusin1, and mtiofusin2 in IPF cells. This might explain the reduced mitochondrial damage observed in treprostinil-treated IPF cells and suggest an improvement in the mitochondrial function in IPF. In this study, treprostinil improved mitochondrial impairment in vitro, which might, in part, explain the beneficial clinical effects documented in patients.

Severe Asthma Remissions Induced by Biologics Targeting IL5/IL5r: Results from a Multicenter Real-Life Study.

Add-on biological therapy has proven to be effective in many patients with severe eosinophilic asthma. In this observational multicenter retrospective study, we report the results obtained with mepolizumab and benralizumab in severe asthmatics treated for 12 months in a real-life setting. In these patients, peripheral eosinophil levels, pulmonary function trends, exacerbation rates, systemic corticosteroid use, and symptom control were evaluated during the observation period, to understand which patients met all the criteria in order to be considered in disease remission. The percentage of remittent patients was 30.12% in the mepolizumab-treated subgroup, while in the benralizumab-treated subgroup, patients in complete disease remission were 40%, after 12 months. The results of this study confirm the efficacy of anti-IL-5 biologic drugs in the treatment of severe eosinophilic asthma in a real-life setting.

Eicosapentaenoic Acid Extraction from Nannochloropsis gaditana using Carbon Dioxide at Supercritical Conditions.

This research shows that carbon dioxide supercritical fluid (CO2-SF) is an emerging technology for the extraction of high interest compounds for applications in the manufacturing of pharmaceuticals, nutraceuticals, and cosmetics from microalgae. The purpose of this study is to recover fatty acids (FAs) and, more precisely, eicosapentaenoic acid (EPA) from Nannochloropsis gaditana biomass by CO2-SF extraction. In the paper, the effect of mechanical pre-treatment was evaluated with the aim of increasing FAs recovery. Extraction was performed at a pressure range of 250⁻550 bars and a CO2 flow rate of 7.24 and 14.48 g/min, while temperature was fixed at 50 or 65 °C. The effect of these parameters on the extraction yield was assessed at each extraction cycle, 20 min each, for a total extraction time of 100 min. Furthermore, the effect of biomass loading on EPA recovery was evaluated. The highest EPA extraction yield, i.e., 11.50 mg/g, corresponding to 27.4% EPA recovery, was obtained at 65 °C and 250 bars with a CO2 flow rate of 7.24 g/min and 1.0 g biomass loading. The increased CO2 flow rate from 7.24 to 14.48 g/min enhanced the cumulative EPA recovery at 250 bars. The purity of EPA could be improved by biomass loading of 2.01 g, even if recovery was reduced.

Hybrid Geopolymers from Fly Ash and Polysiloxanes.

The preparation and characterization of innovative organic-inorganic hybrid geopolymers, obtained by valorizing coal fly ash generated from thermoelectric power plants, is reported for the first time. These hybrid materials are prepared by simultaneously reacting fly ash and dimethylsiloxane oligomers at 25 °C in a strongly alkaline environment. Despite their lower density, the obtained materials are characterized by highly improved mechanical properties when compared to the unmodified geopolymer obtained without the use of polysiloxanes, hence confirming the effectiveness of the applied synthetic strategy which specifically aims at obtaining hybrid materials with better mechanical properties in respect to conventional ones. This study is an example of the production of new materials by reusing and valorizing waste raw resources and by-products, thus representing a possible contribution towards the circular economy.

Extraction of Bioactive Compounds Using Supercritical Carbon Dioxide.

Microalgae Dunaliella salina contains useful molecules such as ß-carotene and fatty acids (FAs), which are considered high value-added compounds. To extract these molecules, supercritical carbon dioxide was used at different operative conditions. The effects of mechanical pre-treatment (grinding speed at 0⁻600 rpm; pre-treatment time of 2.5⁻7.5 min) and operating parameters for extraction, such as biomass loading (2.45 and 7.53 g), pressure (100⁻550 bars), temperature (50⁻75 °C) and CO2 flow rate (7.24 and 14.48 g/min) by varying the extraction times (30⁻110 min) were evaluated. Results showed that the maximum cumulative recovery (25.48%) of ß-carotene was achieved at 400 bars and 65 °C with a CO2 flow rate of 14.48 g/min, while the highest purity for stage (55.40%) was attained at 550 bars and 65 °C with a CO2 flow rate of 14.48 g/min. The maximum recovery of FAs, equal to 8.47 mg/g, was achieved at 550 bars and 75 °C with a CO2 flow rate of 14.48 g/min. Moreover, the lowest biomass loading (2.45 g) and the first extraction cycle (30 min) allowed the maximum extraction of ß-carotene and FAs.

Selective Extraction of ω-3 Fatty Acids from Nannochloropsis sp. Using Supercritical CO2 Extraction.

In this article, microalgae Nannochloropsis sp. was used for fatty acid (FA) extraction, using a supercritical fluid-carbon dioxide (SF-CO2) extraction method. This study investigated the influence of different pre-treatment conditions by varying the grinding speed (200-600 rpm), pre-treatment time (2.5-10 min), and mixing ratio of diatomaceous earth (DE) and Nannochloropsis sp. biomass (0.5-2.0 DE/biomass) on FAs extraction. In addition, the effect of different operating conditions, such as pressure (100-550 bar), temperature (50-75 °C), and CO2 flow rate (7.24 and 14.48 g/min) on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) recovery, was analyzed. Experimental data evidenced that, keeping constant the extraction conditions, the pre-treatment step enhanced the FAs extraction yield up to 3.4 fold, thereby the maximum extracted amount of FAs (61.19 mg/g) was attained with the pre-treatment with a ratio of DE/biomass of 1 at 600 rpm for 5 min. Moreover, by increasing both SF-CO2 pressure and temperature, the selectivity towards EPA was enhanced, while intermediate pressure and lower pressure promoted DHA recovery. The highest amount of extracted EPA, i.e., 5.69 mg/g, corresponding to 15.59%, was obtained at 75 °C and 550 bar with a CO2 flow rate of 14.48 g/min, while the maximum amount of extracted DHA, i.e., ~0.12 mg/g, equal to 79.63%, was registered at 50 °C and 400 bar with a CO2 flow rate of 14.48 g/min. Moreover, the increased CO2 flow rate from 7.24 to 14.48 g/min enhanced both EPA and DHA recovery.

Supercritical Fluid Extraction of Lutein from Scenedesmus almeriensis.

Lutein has several benefits for human health, playing an important role in the prevention of age-related macular degeneration (AMD), cataracts, amelioration of the first stages of atherosclerosis, and some types of cancer. In this work, the Scenedesmus almeriensis microalga was used as a natural source for the supercritical fluid (SF) extraction of lutein. For this purpose, the optimization of the main parameters affecting the extraction, such as biomass pre-treatment, temperature, pressure, and carbon dioxide (CO2) flow rate, was performed. In the first stage, the effect of mechanical pre-treatment (diatomaceous earth (DE) and biomass mixing in the range 0.25-1 DE/biomass; grinding speed varying between 0 and 600 rpm, and pre-treatment time changing from 2.5 to 10 min), was evaluated on lutein extraction efficiency. In the second stage, the influence of SF-CO2 extraction parameters such as pressure (25-55 MPa), temperature (50 and 65 °C), and CO2 flow rate (7.24 and 14.48 g/min) on lutein recovery and purity was investigated. The results demonstrated that by increasing temperature, pressure, and CO2 flow rate lutein recovery and purity were improved. The maximum lutein recovery (~98%) with purity of ~34% was achieved operating at 65 °C and 55 MPa with a CO2 flow rate of 14.48 g/min. Therefore, optimum conditions could be useful in food industries for lutein supplementation in food products.

Management of Bradyarrhythmias in Heart Failure: A Tailored Approach.

Patients with heart failure (HF) may develop a range of bradyarrhythmias including sinus node dysfunction, various degrees of atrioventricular block, and ventricular conduction delay. Device implantation has been recommended in these patients, but the specific etiology should be sought as it may influence the choice of the type of device required (pacemaker vs. implantable cardiac defibrillator). Also, pacing mode must be carefully set in patients with heart failure (HF) and left ventricular systolic dysfunction.In this chapter, we summarize the knowledge required for a tailored approach to bradyarrhythmias in patients with heart failure.

Supercritical Carbon Dioxide Extraction of Astaxanthin, Lutein, and Fatty Acids from Haematococcus pluvialis Microalgae.

Haematococcus pluvialis microalgae in the red phase can produce significant amounts of astaxanthin, lutein, and fatty acids (FAs), which are valuable antioxidants in nutraceutics and cosmetics. Extraction of astaxanthin, lutein, and FAs from disrupted biomass of the H. pluvialis red phase using carbon dioxide (CO2) in supercritical fluid extraction (SFE) conditions was investigated using a bench-scale reactor in a semi-batch configuration. In particular, the effect of extraction time (20, 40, 60, 80, and 120 min), CO2 flow rate (3.62 and 14.48 g/min) temperature (50, 65, and 80 °C), and pressure (100, 400, and 550 bar.) was explored. The results show the maximum recovery of astaxanthin and lutein achieved were 98.6% and 52.3%, respectively, at 50 °C and 550 bars, while the maximum recovery of FAs attained was 93.2% at 65 °C and 550 bars.

Extraction of Astaxanthin and Lutein from Microalga Haematococcus pluvialis in the Red Phase Using CO2 Supercritical Fluid Extraction Technology with Ethanol as Co-Solvent.

Astaxanthin and lutein, antioxidants used in nutraceutics and cosmetics, can be extracted from several microalgal species. In this work, investigations on astaxanthin and lutein extraction from Haematococcus pluvialis (H. pluvialis) in the red phase were carried out by means of the supercritical fluid extraction (SFE) technique, in which CO2 supercritical fluid was used as the extracting solvent with ethanol as the co-solvent. The experimental activity was performed using a bench-scale reactor in semi-batch configuration with varying extraction times (20, 40, 60, and 80 min), temperatures (50, 65, and 80 °C) and pressures (100, 400, and 550 bar). Moreover, the performance of CO2 SFE with ethanol was compared to that without ethanol. The results show that the highest astaxanthin and lutein recoveries were found at 65 °C and 550 bar, with ~18.5 mg/g dry weight (~92%) astaxanthin and ~7.15 mg/g dry weight (~93%) lutein. The highest astaxanthin purity and the highest lutein purity were found at 80 °C and 400 bar, and at 65 °C and 550 bar, respectively.

Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodeling.

BACKGROUND: In asthma remodeling airway smooth muscle cells (ASMCs) contribute to airway wall thickness through increased proliferation, migration, and extracellular matrix deposition. Previously, we described that protein arginine methyltransferase 1 (PRMT1) participates in airway remodeling in pulmonary inflammation in E3 rats. OBJECTIVE: We sought to define the asthma-specific regulatory mechanism of PRMT1 in human ASMCs. METHODS: ASMCs from healthy subjects and asthmatic patients were activated with platelet-derived growth factor (PDGF)-BB. PRMT1 was localized by means of immunohistochemistry in human lung tissue sections and by means of immunofluorescence in isolated ASMCs. PRMT1 activity was suppressed by the pan-PRMT inhibitor AMI-1, signal transducer and activator of transcription 1 (STAT1) was suppressed by small interfering RNA, and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) was suppressed by PD98059. MicroRNAs (miRs) were assessed by using real-time quantitative PCR and regulated by miR mimics or inhibitors. RESULTS: PRMT1 expression was significantly increased in lung tissue sections and in isolated ASMCs of patients with severe asthma. PDGF-BB significantly increased PRMT1 expression through ERK1/2 MAPK and STAT1 signaling in control ASMCs, whereas in ASMCs from asthmatic patients, these proteins were constitutively expressed. ASMCs from asthmatic patients had reduced miR-19a expression, causing upregulation of ERK1/2 MAPK, STAT1, and PRMT1. Inhibition of PRMT1 abrogated collagen type I and fibronectin deposition, cell proliferation, and migration of ASMCs from asthmatic patients. CONCLUSIONS: PRMT1 is a central regulator of tissue remodeling in ASMCs from asthmatic patients through the pathway: PDGF-BB-miR-19a-ERK1/2 MAPK and STAT1. Low miR-19a expression in ASMCs from asthmatic patients is the key event that results in constitutive increased PRMT1 expression and remodeling. Therefore PRMT1 is an attractive target to limit airway wall remodeling in asthmatic patients.

Anticholinergic drugs in asthma therapy.

PURPOSE OF REVIEW: Current guidelines recommend a stepwise approach for pharmacological therapy aimed to achieve and maintain asthma control. Despite these recommendations, at least 50% of patients continue to be uncontrolled with risk of asthma exacerbations that can often be serious and are associated with deterioration of quality of life. In recent years, the interest in anticholinergic bronchodilators, which have been primarily used in the treatment of chronic obstructive pulmonary disease, has increased patients with uncontrolled asthma. This review analyzes the mechanisms for the proposed clinical use of anticholinergic bronchodilators as an adjunctive therapy in asthma. RECENT FINDINGS: Based on existing and recent evidence, the use of anticholinergic bronchodilators, particularly long-acting muscarinic antagonists (LAMAs), plays an important role as add-on therapy in patients uncontrolled on existing therapies. In particular, the use of anticholinergics in asthma may have a role in patients intolerant to long-acting ß2 agonist, in patients with certain pharmacogenetic profiles and in those patients with asthma symptoms mostly at night. SUMMARY: Data from clinical trials and from real-life confirm the safety and efficacy of LAMAs, especially tiotropium, in patients who remain uncontrolled despite the use of inhaled corticosteroid therapy.

[Thunderstorm and asthma outbreaks during pollen season]. / Temporali e attacchi d'asma durante le stagioni polliniche.

An increasing body of evidence shows the occurrence of asthma epidemics, sometimes also severe, during thunderstorms in the pollen season in various geographical zones. The main hypothesis explaining association between thunderstorms and asthma claims that thunderstorms can concentrate pollen grains at ground level; these grains may then release allergenic particles of respirable size in the atmosphere after their rupture by osmotic shock. During the first 20-30 minutes of a thunderstorm, patients suffering from pollen allergy may inhale a high concentration of the allergenic material dispersed into the atmosphere, which can, in turn, induce asthmatic reactions, often severe. Subjects without asthma symptoms but affected by seasonal rhinitis can also experience an asthma attack. All subjects affected by pollen allergy should be alerted to the danger of being outdoors during a thunderstorm in the pollen season, as such events may be an important cause of severe bronchial obstruction. Considering this background, it is useful to predict thunderstorms during pollen season and, thus, to prevent thunderstorm-related clinical event. However, it is also important to focus on therapy, and it is not sufficient that subjects at risk of asthma follow a correct therapy with bronchodilators, but they also need to inhale corticosteroids, using both in case of emergency.

Impact of Continuous Positive Airway Pressure Therapy on Atrial Electromechanical Delay in Obesity-Hypoventilation Syndrome Patients.

BACKGROUND: Obesity-hypoventilation syndrome (OHS) is defined as daytime hypercapnia and hypoxemia in obese patients with sleep-disordered breathing. We evaluated the electrocardiographic P-wave duration and dispersion (PD) and echocardiographic noninvasive indicators of atrial conduction heterogeneity in OHS patients and the impact of CPAP on atrial conduction and atrial fibrillation incidence. METHODS AND RESULTS: We enrolled 50 OHS patients and 50 sex- and age-matched obese subjects as control. Study population underwent cardiologic evaluation and polysomnography before enrollment, at 1- and 6-month follow-ups after CPAP therapy. The OHS group showed a significant increase in inter-atrial (35.2 ± 8 milliseconds vs. 20.1 ± 2.7 milliseconds, P < 0.0001), intra-left (30.5 ± 7.2 milliseconds vs. 16.5 ± 2 milliseconds, P < 0.0001), and intra-right atrial electromechanical delays (AEMD)(24.8 ± 10 milliseconds vs. 15 ± 2.6 milliseconds, P < 0.0001) as well as in Pmax (130 ± 7.4 milliseconds vs. 97 ± 7.2 milliseconds, P = 0.002) and PD (56.5 ± 8.5 milliseconds vs. 31 ± 7.2 milliseconds, P = 0.002) compared to the control group. Significant improvement was noted after 6 months of CPAP therapy in inter-atrial (35.2 ± 8 milliseconds vs. 24.5 ± 6.3 milliseconds, P < 0.0001), intra-left (30.5 ± 7.2 milliseconds vs. 20.6 ± 5 milliseconds, P = 0.003), and intra-right AEMD (24.8 ± 10 milliseconds vs. 17 ± 7.5 milliseconds, P < 0.0001), as well as in Pmax (130 ± 7.4 milliseconds vs. 95 ± 10 milliseconds, P < 0.0001) and in PD (56.5 ± 8.5 milliseconds vs. 32.5 ± 6 milliseconds, P < 0.0001) in the OHS group. External loop recorder monitoring detected paroxysmal AF in 19 OHS patients (38%) with significant reduction in paroxysmal AF episodes (12 ± 6 vs. 47 ± 12, P < 0.0001) after 6-month CPAP therapy. CONCLUSION: Our findings showed a significant increase of electrocardiographic and echocardiographic indexes of atrial conduction heterogeneity in OHS patients. The CPAP therapy, having a positive impact on atrial conduction time, seems to reduce AF incidence in OHS patients.

Far field R-wave sensing in Myotonic Dystrophy type 1: right atrial appendage versus Bachmann's bundle region lead placement.

Aim of the present study was to investigate far field R-wave sensing (FFRS) timing and characteristics in 34 Myotonic Dystrophy type 1 (DM1) patients undergoing dual chamber pacemaker implantation, comparing Bachmann's bundle (BB) stimulation (16 patients) site with the conventional right atrial appendage (RAA) pacing site (18 patients). All measurements were done during sinus rhythm and in supine position, with unipolar (UP) and bipolar (BP) sensing configuration. The presence, amplitude threshold (FFRS trsh) and FFRS timing were determined. There were no differences between both atrial sites in the Pmin and Pmean values of sensed P-wave amplitudes, as well as between UP and BP sensing configurations. The FFRS trsh was lower at the BB region in comparison to the RAA site. The mean BP FFRS trsh was significantly lower than UP configuration in both atrial locations. There were no significant differences in atrial pacing threshold, sensing threshold and atrial lead impedances at the implant time and at FFRS measurements. Bachmann's bundle area is an optimal atrial lead position for signal sensing as well as conventional RAA, but it offers the advantage of reducing the oversensing of R-wave on the atrial lead, thus improving functioning of standard dual chamber pacemakers in DM1 patients.

Impact of biologics on lung hyperinflation in patients with severe asthma.

BACKGROUND: In asthma, inflammation affects both the proximal and distal airways and can cause significant hyperinflation, which is thought to be a major cause of dyspnea. METHODS: This is a retrospective observational study evaluating the effect of three months of treatment with different biologic drugs (benralizumab, dupilumab and omalizumab) on pulmonary hyperinflation in a cohort of patients with severe asthma already receiving regular triple inhaled therapy. Changes in RV, RV/TLC ratio, FRC and FRC/TLC ratio were the primary efficacy measures. Secondary outcomes included FEV1, FVC, FEV1/FVC ratio, IC, IC/TLC ratio, asthma control test, the percentage of eosinophils in the blood and fractional FENO. RESULTS: Benralizumab led to significant changes (p < 0.001) in RV, RV/TLC, FRC, and FRC/TLC. Dupilumab demonstrated a notable reduction in RV (p = 0.017) and RV/TLC (p = 0.002), but the decreases in FRC and FRC/TLC were merely numerical and not as pronounced as those induced by benralizumab. Omalizumab's positive impact on RV (p = 0.057) and RV/TLC (p = 0.085), as well as FRC (p = 0.202) and FRC/TLC (p = 0.096), was also predominantly numerical, with a tendency towards efficacy, albeit excluding the effect on FRC. Treatment with biologics resulted in improvements in all other lung function parameters assessed and a decrease in FENO levels. CONCLUSION: This study, although limited by small sample size, lack of a placebo control, and unbalanced group sizes, suggests that biological agents are effective in reducing lung hyperinflation even after a relatively short treatment.

Quality of life and work functionality in severe asthma patients: the impact of biological therapies.

BACKGROUND: Severe asthma can cause poor health status, poor health-related quality of life (HRQoL) and an impaired functioning at work. However, to date, limited data are available on the impact of the biological therapies on such outcomes. Therefore, aim of the present study was to prospectively assess the clinical, quality of life and work functionality issues in severe asthma patients both at baseline and after 6 months of biological therapies and determine which individual, pathological and occupational factors can influence such parameters. METHODS: Fifty-two patients were enrolled between December 2022 and June 2023. Patients' personal, clinical, functional and occupational features were assessed. The Short Form Health Survey (SF-12), the Work Productivity and Activity Impairment (WPAI) questionnaire and the Work Ability Index (WAI) were employed to assess HRQoL, the employee's productivity and perception of work ability, respectively. RESULTS: Among the enrolled patients, 30 (57.70%) were employed. Biological therapy induced a significant improvement in clinical and functional parameters, e.g., FEV1% (72 ± 12 vs.87 ± 13%; 72 ± 14 vs. 86 ± 14%), FVC% (92 ± 11 vs. 101 ± 11%; 90 ± 13 vs. 98 ± 14%) and FEV1/FVC (62 ± 11 vs. 71 ± 8%; 64 ± 9 vs. 70 ± 8%) in workers and non-workers, respectively (P < 0.001). Comparably, the perception of life quality significantly improved, as physical and mental health scores, in the overall cohort, increased from 40.7 ± 10.3 and 48.5 ± 8.5 to 46.8 ± 8.6 and 51.6 ± 6.4, respectively (P < 0.001). The work ability perception significantly improved from a moderate to a good one (34 ± 6 vs. 40 ± 6, P = 0.001). A significant reduction in the absenteeism (19 ± 15 vs. 3 ± 11%; P < 0.001) and presenteeism rate (53 ± 24 vs. 29 ± 26%; P < 0.001), and an improvement in daily (40 ± 27.5% vs. 28.9 ± 24.7%, P < 0.001, in the overall population) and work activities (57 ± 25 vs. 29 ± 27%, P < 0.001) was determined. Gender, age, symptoms control and pulmonary functionality were correlated with the physical and mental health perception, daily activity impairment and work ability. CONCLUSIONS: Our study pointed out that biological therapies improved clinical, general life and occupational outcomes in patients with severe asthma. The correlation between clinical aspects and psychological and occupational issues suggest the relevance for a multidisciplinary management of the disease for an effective participation of patients in the world of work.

Long-term inhaled corticosteroid treatment in patients with chronic obstructive pulmonary disease, cardiovascular disease, and a recent hospitalised exacerbation: The ICSLIFE pragmatic, randomised controlled study.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) frequently have cardiovascular comorbidities, increasing the risk of hospitalised COPD exacerbations (H-ECOPDs) or death. This pragmatic study examined the effects of adding an inhaled corticosteroid (ICS) to long-acting bronchodilator(s) (LABDs) in patients with COPD and cardiac comorbidities who had a recent H-ECOPD. METHODS: Patients >60 years of age with COPD and ≥1 cardiac comorbidity, within 6 months after discharge following an H-ECOPD, were randomised to receive LABD(s) with or without ICS, and were followed for 1 year. The primary outcome was the time to first rehospitalisation and/or all-cause death. RESULTS: The planned number of patients was not recruited (803/1032), limiting the strength of the conclusions. In the intention-to-treat population, 89/403 patients (22.1 %) were rehospitalised or died in the LABD group (probability 0.257 [95 % confidence interval 0.206, 0.318]), vs 85/400 (21.3 %) in the LABD+ICS group (0.249 [0.198, 0.310]), with no difference between groups in time-to-event (hazard ratio 1.116 [0.827, 1.504]; p = 0.473). All-cause and cardiovascular mortality were lower in patients receiving LABD(s)+ICS, with relative reductions of 19.7 % and 27.4 %, respectively (9.8 % vs 12.2 % and 4.5 % vs 6.2 %), although the groups were not formally statistically compared for these endpoints. Fewer patients had adverse events in the LABD+ICS group (43.0 % vs 50.4 %; p = 0.013), with 4.9 % vs 5.4 % reporting pneumonia adverse events. CONCLUSIONS: Results suggest addition of ICS to LABDs did not reduce the time-to-combined rehospitalisation/death, although it decreased all-cause and cardiovascular mortality. ICS use was not associated with an increased risk of adverse events, particularly pneumonia.