ß-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction.

Importance: While ß-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). Objective: To investigate whether ß-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Exposure: Prescription for any ß-blocker at hospital discharge. Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a ß-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with ß-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). Conclusions and Relevance: In this cohort study, ß-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of ß-blockers in patients with COPD and recent AMI.

Project EPIC (Empowering People to Independence in COPD): Study protocol for a hybrid effectiveness-implementation pilot randomized controlled trial of telephonic, geriatrics-palliative care nurse-coaching in older adults with COPD and their family caregivers.

BACKGROUND: EPIC (Empowering People to Independence in COPD) is a geriatric-palliative care telephonic, nurse coach intervention informed by Baltes' Theory of Successful Aging and adapted from the ENABLE (Educate, Nurture, Advise, Before Life Ends) intervention. EPIC, focused on improving independence, mobility, well-being, and COPD symptoms, has undergone formative and summative evaluation for adults with COPD. METHODS: The primary study aim is to assess the refined EPIC intervention's feasibility and acceptability via a pilot hybrid effectiveness-implementation randomized control trial in community-dwelling older adults with moderate to severe COPD and their family caregivers. The secondary aim is to explore the impact of EPIC on patient and caregiver outcomes. Older adults with COPD and their family caregivers (target N = 60 dyads) will be randomized to EPIC (intervention) or usual COPD care (control). EPIC includes six patient and four family caregiver weekly, telephone-based nurse coach sessions using a manualized curriculum (Charting Your Course), plus three monthly follow-up calls. Feasibility will be measured as completion of EPIC intervention and trial components (e.g., recruitment, retention, data collection). Acceptability will be evaluated using satisfaction surveys and post-study feedback interviews. A blinded data collector will assess exploratory outcomes (e.g., Life-Space mobility, quality of life, caregiver burden, emotional symptoms, loneliness, cognitive impairment, functional status, healthcare utilization) at baseline, 12, and 24 weeks. DISCUSSION: This intervention fills a gap in addressing the geriatrics and palliative care needs and equity for adults with COPD and their family caregivers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05040386.

The Effect of Chronic Altitude Exposure on COPD Outcomes in the SPIROMICS Cohort.

RATIONALE: Individuals with COPD have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. OBJECTIVES: Does residence at higher-altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, or mortality? METHODS: From the SPIROMICS cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n= 1,367) versus above 4,000 ft (1,219 m) elevation (n= 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. MEASUREMENTS AND MAIN RESULTS: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6MWD (-32.3 m, (-55.7 to -28.6)). There were no differences in patient-reported outcomes as defined by symptoms (CAT, mMRC), or health status (SGRQ). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (IRR 0.65, (0.46 to 0.90)). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (HR 1.25, (1.0 to 1.55)); however, this association was no longer significant when accounting for air pollution. CONCLUSIONS: Chronic altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. Additionally, chronic high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry.

Low dose cadmium exposure regulates miR-381-ANO1 interaction in airway epithelial cells.

Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death worldwide. Cigarette smoke which has approximately 2-3 µg of Cadmium (Cd) per cigarette contributes to the environmental exposure and development and severity of COPD. With the lack of a cadmium elimination mechanism in humans, the contribution of cadmium induced stress to lung epithelial cells remains unclear. Studies on cadmium responsive miRNAs suggest regulation of target genes with an emphasis on the critical role of miRNA-mRNA interaction for cellular homeostasis. Mir-381, the target miRNA in this study is negatively regulated by cadmium in airway epithelial cells. miR-381 is reported to also regulate ANO1 (Anoctamin 1) expression negatively and in this study low dose cadmium exposure to airway epithelial cells was observed to upregulate ANO1 mRNA expression via mir-381 inhibition. ANO1 which is a Ca2+-activated chloride channel has multiple effects on cellular functions such as proliferation, mucus hypersecretion and fibroblast differentiation in inflamed airways in chronic respiratory diseases. In vitro studies with cadmium at a high concentration range of 100-500 µM is reported to activate chloride channel, ANO1. The secretory epithelial cells are regulated by chloride channels like CFTR, ANO1 and SLC26A9. We examined "ever" smokers with COPD (n = 13) lung tissue sections compared to "never" smoker without COPD (n = 9). We found that "ever" smokers with COPD had higher ANO1 expression. Using mir-381 mimic to inhibit ANO1, we demonstrate here that ANO1 expression is significantly (p < 0.001) downregulated in COPD derived airway epithelial cells exposed to cadmium. Exposure to environmental cadmium contributes significantly to ANO1 expression.

Chronic obstructive pulmonary disease and cardiovascular disease: mechanistic links and implications for practice.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are both significant burdens on the healthcare system and often coexist. Mechanistic links between the two conditions and their clinical impact are increasingly understood. RECENT FINDINGS: Recent studies demonstrate multiple mechanisms by which the pathobiology of COPD may have negative effects on the cardiovascular system. These include extrapulmonary consequences of the COPD inflammatory state, cardiac autonomic dysfunction, which has been recently implicated in worsening respiratory symptoms and exacerbation risk, and mechanical effects of lung hyperinflation on left ventricular diastolic function.Clinical studies have consistently shown a high prevalence of CVD in COPD patients and worsened outcomes (and vice versa ). Exacerbations of COPD have also been demonstrated to dramatically increase the risk of cardiovascular events. While some safety concerns exist, medications for COPD and cardiovascular disease should be used in accordance with respective guidelines. However, real-world data show suboptimal management for patients with COPD and CVD. SUMMARY: COPD and cardiovascular disease have complicated interrelationships. Further mechanistic studies may lead to defining better targets for interventions. Education for medical professionals and implementation of novel screening protocols should be encouraged to fill in the gaps in clinical care for these patients.

Associations Between Coronary Artery Calcium Score and Exacerbation Risk in BLOCK-COPD.

Introduction: In 2019, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease study (BLOCK-COPD) evaluated the effect of metoprolol on exacerbation risk and mortality in a COPD population without indications for beta-blocker use. We hypothesized that an imaging metric of coronary artery disease (CAD), the coronary artery calcium (CAC) score, would predict exacerbation risk and identify a differential response to metoprolol treatment. Methods: The study population includes participants in the BLOCK-COPD study from multiple study sites. Participants underwent clinically indicated thoracic computed tomography (CT) scans ± 12 months from enrollment. The Weston scoring system quantified CAC. Adjusted Cox proportional hazards models evaluated for associations between CAC and time to exacerbation. Results: Data is included for 109 participants. The mean CAC score was 5.1±3.7, and 92 participants (84%) had CAC scores greater than 0. Over a median (interquartile range) follow-up time of 350 (280 to 352) days, there were 61 mild exacerbations and 19 severe/very severe exacerbations. No associations were found between exacerbations of any severity and CAC>0 or total CAC. Associations were observed between total CAC and CAC>0 in the left circumflex (LCx) and time to exacerbation of any severity (adjusted hazard ratio [aHR]=1.39, confidence interval [CI]: 1.08-1.79, p=0.01) and (aHR=1.96, 95% CI: 1.04-3.70, p=0.04), respectively. Conclusions: CAD is a prevalent comorbidity in COPD accounting for significant mortality. Our study confirms the high prevalence of CAD using the CAC score; however, we did not discover an association between CAC and exacerbation risk. We did find novel associations between CAC in the LCx and exacerbation risk which warrant further investigation in larger cohorts.

Bronchial rheoplasty for chronic bronchitis: 2-year results from a US feasibility study with RheOx.

INTRODUCTION: Chronic bronchitis (CB), a phenotype of chronic obstructive pulmonary disease (COPD) characterised by persistent cough and mucus hypersecretion, is associated with poor outcomes despite guideline-based treatment. Bronchial rheoplasty (BR) with the RheOx system delivers non-thermal pulsed electric fields to the lower airway epithelium and submucosa to reduce mucus producing cells. Early phase clinical trials including 1-year follow-up have demonstrated reduction in airway goblet cell hyperplasia and improvement in CB symptoms. METHODS: The current multicentre observational BR study enrolled 21 patients with CB at six centres in the USA, with bilateral treatment and 2-year follow-up. Entry criteria included elevated cough and sputum scores from COPD Assessment Test (CAT) and forced expiratory volume in one second<80% predicted. Safety was assessed by serious adverse event (SAE) incidence through 24 months. Clinical utility was evaluated using changes in the CAT, the St. George's Respiratory Questionnaire (SGRQ) and by comparing exacerbation rates before and following intervention. RESULTS: No procedure-related or device-related SAEs occurred. Mean (SD) changes from baseline in CAT at 12 and 24 months were -9.0 (6.7) (p<0.0001) and -5.6 (7.1) (p<0.0047) and in SGRQ were -16.6 (13.2) (p<0.0001) and -11.8 (19.2) (p<0.0227), respectively. There was a 34% reduction in moderate and a 64% reduction in severe COPD exacerbation events compared with the year prior to treatment. CONCLUSIONS: This study extends the findings from previous feasibility studies, demonstrating that BR can be performed safely and may significantly improve symptoms and health-related quality of life for patients with CB through 24 months. TRAIL REGISTRATION NUMBER: NCT03631472.

Association between P-pulmonale and respiratory morbidity in COPD: a secondary analysis of the BLOCK-COPD trial.

RATIONALE: Pulmonary hypertension (PH) in COPD confers increased risk of exacerbations (ECOPD). Electrocardiogram (ECG) indicators of PH are prognostic both in PH and COPD. In the Beta-Blockers for the Prevention of Acute Exacerbations of COPD (BLOCK-COPD) trial, metoprolol increased risk of severe ECOPD through unclear mechanisms. OBJECTIVE: We evaluated whether an ECG indicator of PH, P-pulmonale, would be associated with ECOPD and whether participants with P-pulmonale randomized to metoprolol were at higher risk of ECOPD and worsened respiratory symptoms given the potential detrimental effects of beta-blockers in PH. METHODS: ECGs of 501 participants were analyzed for P-pulmonale (P wave enlargement in lead II). Cox proportional hazards models evaluated for associations between P-pulmonale and time to ECOPD (all and severe) for all participants and by treatment assignment (metoprolol vs. placebo). Linear mixed-effects models evaluated the association between treatment assignment and P-pulmonale on change in symptom scores (measured by CAT and SOBQ). RESULTS: We identified no association between P-pulmonale and risk of any ECOPD or severe ECOPD. However, in individuals with P-pulmonale, metoprolol was associated with increased risk for ECOPD (aHR 2.92, 95% CI: 1.45-5.85). There was no association between metoprolol and ECOPD in individuals without P-pulmonale (aHR 1.01, 95% CI: 0.77-1.31). Individuals with P-pulmonale assigned to metoprolol experienced worsening symptoms (mean increase of 3.95, 95% CI: 1.32-6.58) whereas those assigned to placebo experienced a mean improvement in CAT score of -2.45 (95% CI: -0.30- -4.61). CONCLUSIONS: In individuals with P-pulmonale, metoprolol was associated with increased exacerbation risk and worsened symptoms. These findings may explain the findings observed in BLOCK-COPD.

COPD and multimorbidity: recognising and addressing a syndemic occurrence.

Most patients with chronic obstructive pulmonary disease (COPD) have at least one additional, clinically relevant chronic disease. Those with the most severe airflow obstruction will die from respiratory failure, but most patients with COPD die from non-respiratory disorders, particularly cardiovascular diseases and cancer. As many chronic diseases have shared risk factors (eg, ageing, smoking, pollution, inactivity, and poverty), we argue that a shift from the current paradigm in which COPD is considered as a single disease with comorbidities, to one in which COPD is considered as part of a multimorbid state-with co-occurring diseases potentially sharing pathobiological mechanisms-is needed to advance disease prevention, diagnosis, and management. The term syndemics is used to describe the co-occurrence of diseases with shared mechanisms and risk factors, a novel concept that we propose helps to explain the clustering of certain morbidities in patients diagnosed with COPD. A syndemics approach to understanding COPD could have important clinical implications, in which the complex disease presentations in these patients are addressed through proactive diagnosis, assessment of severity, and integrated management of the COPD multimorbid state, with a patient-centred rather than a single-disease approach.

Pulmonary emphysema subtypes defined by unsupervised machine learning on CT scans.

BACKGROUND: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations. METHODS: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined. RESULTS: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1, which is implicated in mucin hypersecretion (p=1.1 ×10-8). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome. CONCLUSION: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD.

Changes in Lung Volumes with Spirometric Disease Progression in COPD.

Background: Abnormal lung volumes representing air trapping identify the subset of smokers with preserved spirometry who develop spirometric chronic obstructive pulmonary disease (COPD) and adverse outcomes. However, how lung volumes evolve in early COPD as airflow obstruction develops remains unclear. Methods: To establish how lung volumes change with the development of spirometric COPD, we examined lung volumes from the pulmonary function data (seated posture) available in the U.S. Department of Veterans Affairs electronic health records (n=71,356) and lung volumes measured by computed tomography (supine posture) available from the COPD Genetic Epidemiology (COPDGene®) study (n=7969) and the SubPopulations and InterMediate Outcome Measures In COPD Study (SPIROMICS) (n=2552) cohorts, and studied their cross-sectional distributions and longitudinal changes across the airflow obstruction spectrum. Patients with preserved ratio-impaired spirometry (PRISm) were excluded from this analysis. Results: Lung volumes from all 3 cohorts showed similar patterns of distributions and longitudinal changes with worsening airflow obstruction. The distributions for total lung capacity (TLC), vital capacity (VC), and inspiratory capacity (IC) and their patterns of change were nonlinear and included different phases. When stratified by airflow obstruction using Global initiative for chronic Obstructive Lung Disease (GOLD) stages, patients with GOLD 1 (mild) COPD had larger lung volumes (TLC, VC, IC) compared to patients with GOLD 0 (smokers with preserved spirometry) or GOLD 2 (moderate) disease. In longitudinal follow-up of baseline GOLD 0 patients who progressed to spirometric COPD, those with an initially higher TLC and VC developed mild obstruction (GOLD 1) while those with an initially lower TLC and VC developed moderate obstruction (GOLD 2). Conclusions: In COPD, TLC, and VC have biphasic distributions, change in nonlinear fashions as obstruction worsens, and could differentiate those GOLD 0 patients at risk for more rapid spirometric disease progression.

Reduced quantity and function of pneumococcal antibodies are associated with exacerbations of COPD in SPIROMICS.

While hypogammaglobulinemia is associated with COPD exacerbations, it is unknown whether frequent exacerbators have specific defects in antibody production/function. We hypothesized that reduced quantity/function of serum pneumococcal antibodies correlate with exacerbation risk in the SPIROMICS cohort. We measured total pneumococcal IgG in n = 764 previously vaccinated participants with COPD. In a propensity-matched subset of n = 200 with vaccination within five years (n = 50 without exacerbations in the previous year; n = 75 with one, n = 75 with ≥2), we measured pneumococcal IgG for 23 individual serotypes, and pneumococcal antibody function for 4 serotypes. Higher total pneumococcal IgG, serotype-specific IgG (17/23 serotypes), and antibody function (3/4 serotypes) were independently associated with fewer prior exacerbations. Higher pneumococcal IgG (5/23 serotypes) predicted lower exacerbation risk in the following year. Pneumococcal antibodies are inversely associated with exacerbations, supporting the presence of immune defects in frequent exacerbators. With further study, pneumococcal antibodies may be useful biomarkers for immune dysfunction in COPD.

Association of Occupational Exposures and Chronic Obstructive Pulmonary Disease Morbidity.

OBJECTIVE: The aim of the study is to determine whether aggregate measures of occupational exposures are associated with chronic obstructive pulmonary disease (COPD) outcomes in the Subpopulations and Intermediate Outcome Measures in COPD study cohort. METHODS: Individuals were assigned to six predetermined exposure hazard categories based on self-reported employment history. Multivariable regression, adjusted for age, sex, race, current smoking status, and smoking pack-years determined the association of such exposures to odds of COPD and morbidity measures. We compared these with the results of a single summary question regarding occupational exposure. RESULTS: A total of 2772 individuals were included. Some exposure estimates, including "gases and vapors" and "dust and fumes" exposures resulted in associations with effect estimates over two times the estimated effect size when compared with a single summary question. CONCLUSIONS: Use of occupational hazard categories can identify important associations with COPD morbidity while use of single-point measures may underestimate important differences in health risks.