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BACKGROUND: The coronary artery calcium score (CACS) and ratio of the pulmonary artery to aorta diameters (PA:A ratio) measured from chest CT scans have been established as predictors of cardiovascular events and chronic obstructive pulmonary disease (COPD) exacerbations, respectively. However, little is known about the reciprocal relationship between these predictors and outcomes. Furthermore, the prognostic implications of COPD subtypes on clinical outcomes remain insufficiently characterized. RESEARCH QUESTION: How can these two chest CT-derived parameters predict subsequent cardiovascular events and COPD exacerbations in different COPD subtypes? STUDY DESIGN AND METHODS: Using COPDGene study data, we assessed prospective cardiovascular disease (CVD) and COPD exacerbation risk in COPD subjects (Global Initiative for Chronic Obstructive Lung Disease spirometric grades 2-4), focusing on CACS and PA:A ratio at study enrollment, with logistic regression models. These outcomes were analyzed in three COPD subtypes: 1,042 Non-emphysema-predominant COPD (NEPD; low attenuation area at -950 Hounsfield units [LAA-950]<5%), 1,324 Emphysema-predominant COPD (EPD; LAA-950≥10%), and 465 Intermediate Emphysema COPD (IE; 5≤LAA-950<10%). RESULTS: Our study indicated significantly higher overall risk for cardiovascular events in subjects with higher CACS (≥median; Odds Ratio (OR): 1.61, 95% Confidence Interval (CI)=1.30-2.00) and increased COPD exacerbations in those with higher PA:A ratios (≥1; OR: 1.80, 95% CI=1.46-2.23). Notably, NEPD subjects showed a stronger association between these indicators and clinical events compared to EPD (with CACS/CVD, NEPD vs. EPD, OR 2.02 vs. 1.41; with PA:A ratio/COPD exacerbation, NEPD vs. EPD, OR 2.50 vs. 1.65); the difference in odds ratios between COPD subtypes was statistically significant for CACS/CVD. INTERPRETATION: Two chest CT parameters, CACS and PA:A ratio, hold distinct predictive values for cardiovascular events and COPD exacerbations that are influenced by specific COPD subtypes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00608764.
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The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.
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BACKGROUND: Cardiovascular disease (CVD) is the most important comorbidity in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations not only contribute to COPD progression but may also elevate the risk of CVD. This study aimed to determine whether COPD exacerbations increase the risk of subsequent CVD events using up to 15 years of prospective longitudinal follow-up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. METHODS AND RESULTS: The COPDGene study is a large, multicenter, longitudinal investigation of COPD, including subjects at enrollment aged 45 to 80 years with a minimum of 10 pack-years of smoking history. Cox proportional hazards models and Kaplan-Meier survival curves were used to assess the risk of a composite end point of CVD based on the COPD exacerbation rate. Frequent exacerbators exhibited a higher cumulative incidence of composite CVD end points than infrequent exacerbators, irrespective of the presence of CVD at baseline. After adjusting for covariates, frequent exacerbators still maintained higher hazard ratios (HRs) than the infrequent exacerbator group (without CVD: HR, 1.81 [95% CI, 1.47-2.22]; with CVD: HR, 1.92 [95% CI, 1.51-2.44]). This observation remained consistently significant in moderate to severe COPD subjects and the preserved ratio impaired spirometry population. In the mild COPD population, frequent exacerbators showed a trend toward more CVD events. CONCLUSIONS: COPD exacerbations are associated with an increased risk of subsequent cardiovascular events in subjects with and without preexisting CVD. Patients with COPD experiencing frequent exacerbations may necessitate careful monitoring and additional management for subsequent potential CVD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00608764.
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Doenças Cardiovasculares , Progressão da Doença , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Estudos Longitudinais , Idoso de 80 Anos ou mais , Medição de Risco , Incidência , Fatores de Risco , Estudos Prospectivos , Estados Unidos/epidemiologia , Fatores de TempoRESUMO
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.
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Antagonistas Adrenérgicos beta , Infarto do Miocárdio , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/complicações , Antagonistas Adrenérgicos beta/uso terapêutico , Masculino , Feminino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Idoso , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Longitudinais , Hospitalização/estatística & dados numéricosRESUMO
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.
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Cuidadores , Cuidados Paliativos , Doença Pulmonar Obstrutiva Crônica , Qualidade de Vida , Idoso , Feminino , Humanos , Masculino , Cuidadores/psicologia , Vida Independente , Tutoria/métodos , Cuidados Paliativos/métodos , Cuidados Paliativos/organização & administração , Projetos Piloto , Doença Pulmonar Obstrutiva Crônica/terapia , Doença Pulmonar Obstrutiva Crônica/enfermagem , Telefone , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
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.
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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.
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MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Humanos , Cádmio/metabolismo , Anoctamina-1/genética , Anoctamina-1/metabolismo , Células Epiteliais/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/genética , Proteínas de Neoplasias/metabolismo , Transportadores de Sulfato/metabolismo , Antiporters/metabolismoAssuntos
Terapia Cognitivo-Comportamental , Doença Pulmonar Obstrutiva Crônica , Humanos , Depressão/terapia , Depressão/psicologia , Intervenção Psicossocial , Ansiedade/terapia , Ansiedade/psicologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/terapia , Doença Pulmonar Obstrutiva Crônica/psicologiaRESUMO
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.
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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.
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Doenças Cardiovasculares , Sistema Cardiovascular , Doença Pulmonar Obstrutiva Crônica , Humanos , Doenças Cardiovasculares/epidemiologia , Progressão da DoençaRESUMO
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.
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Bronquite Crônica , Doença Pulmonar Obstrutiva Crônica , Humanos , Bronquite Crônica/cirurgia , Estudos de Viabilidade , Qualidade de Vida , Progressão da Doença , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
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.
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Metoprolol , Doença Pulmonar Obstrutiva Crônica , Humanos , Antagonistas Adrenérgicos beta/efeitos adversos , Progressão da Doença , Metoprolol/efeitos adversos , Morbidade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoAssuntos
Bronquiectasia , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Bronquiectasia/complicações , Bronquiectasia/diagnóstico por imagem , Tomografia Computadorizada por Raios X , SíndromeRESUMO
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.
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Multimorbidade , Doença Pulmonar Obstrutiva Crônica , Humanos , Sindemia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Comorbidade , PulmãoRESUMO
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.