The association of cardiovascular disease with respiratory disease and impact on outcome.

Paul Carter, MBChB;1,2 Jakub Lagan, LEKARZ;3,4 Christien Fortune, MBChB;3 Deepak L Bhatt, MD;5 Jørgen Vestbo, DrMedSci;4,6 Robert Niven, MBChB;4,6 Nazia Chaudhuri, PhD;4,6 Erik B Schelbert, MD;7-9 Rahul Potluri, MBChB;1 Christopher A Miller, PhD.3,4,10

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Affiliations1. ACALM Study Unit in collaboration with Aston Medical School, Aston University,

Birmingham.2. Cambridge Epidemiology Unit. Worts' Causeway, University of Cambridge, Cambridge CB1

8RN.3. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine

and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL.

4. Manchester University NHS Foundation Trust, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT.

5. Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, MA

6. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL

7. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA8. UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh,

PA, USA9. Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA10. Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative

Medicine, School of Biology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT

Funding: Dr Lagan is funded by a Clinical Research Training Fellowship from the British Heart Foundation (FS/17/47/32805). Dr Miller is funded by a Clinician Scientist Award (CS-2015-15-003) from the National Institute for Health Research. Dr Vestbo is supported by the National Institute for Health Research Manchester Biomedical Research Centre.

DisclosuresThe views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee

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funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, PLx Pharma, Takeda. Dr Nazia Chaudhuri discloses the following relationships - Advisory Board: Roche. Research grants: Roche and Boehringer Ingelheim. Professor Jørgen Vestbo discloses the following relationships - Consultancy for COPD Phase 2 and 3 program and payment for lectures including service in speaker bureau for GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer-Ingelheim, Novartis and AstraZeneca.

Address for correspondenceDr. Christopher A. Miller, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PLTelephone: 0044 161 291 2034. Fax: 0044 161 291 2389Email: Christopher.Miller@manchester.ac.ukTweet: Lung disease is associated with cardiovascular diseases, which contribute significantly to all-cause mortality, independent of shared risk factorsTwitter handle: @DLBHATTMD

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ABSTRACTBackground: The relationship between respiratory diseases and individual cardiovascular diseases, and the impact of cardiovascular diseases on mortality in patients with respiratory disease, are unclear.

Objectives: To determine the relationship between chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease (ILD), and individual cardiovascular diseases, and evaluate the impact of individual cardiovascular diseases on all-cause mortality in respiratory conditions.

Methods: Cohort study of all patients admitted to seven National Health Service hospitals across the North West of England, between January 1st 2000 and March 31st 2013 with relevant respiratory diagnoses, with age and gender matched control groups. Results: 31,646 COPD, 60,424 asthma and 1,662 ILD patients were included. Control groups comprised 158,230, 302,120 and 8,310 patients respectively (total follow up 2,968,182 patient-years). COPD was independently associated with ischemic heart disease (IHD), heart failure (HF), atrial fibrillation and peripheral vascular disease, all of which were associated with all-cause mortality (e.g. odds ratio for the association of COPD with HF 2.18 [95% confidence interval 2.08-2.26]; hazard ratio (HR) for the contribution of HF to mortality in COPD 1.65 [1.61-1.68]). Asthma was independently associated with IHD, and multiple cardiovascular diseases contributed to mortality (e.g. HF HR 1.81 [1.75-1.87]). ILD was independently associated with IHD and HF, both of which were associated with mortality. Patients with lung disease were less likely to receive coronary revascularization.

Conclusions: Lung disease is independently associated with cardiovascular diseases, particularly IHD and HF, which contribute significantly to all-cause mortality. However, patients with lung disease are less likely to receive coronary revascularization.

CONDENSED / UNSTRUCTURED ABSTRACT:The relationship between respiratory diseases and individual cardiovascular diseases, and their impact on patient outcome, is unclear. We conducted a cohort study of patients with chronic obstructive pulmonary disease, asthma and interstitial lung disease (2,968,182 patient-years follow-up). Lung disease was independently associated with cardiovascular diseases, particularly ischemic heart disease and heart failure, which contributed significantly to all-cause mortality, independent of shared risk factors. However, patients with lung disease were less likely to receive coronary revascularization.

KEY WORDSIschemic heart disease, heart failure, chronic obstructive pulmonary disease, asthma, interstitial lung fibrosis

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ABBREVIATIONSACALM - Algorithm for Comorbidities, Associations, Length of stay, and MortalityAF – Atrial fibrillationCABG - Coronary artery bypass graftingCI – Confidence intervalCKD - Chronic kidney diseaseCOPD – Chronic obstructive pulmonary diseaseIHD - Ischemic heart diseaseILD - Interstitial lung diseaseNHS - National Health ServicePCI - Percutaneous coronary interventionPVD - Peripheral vascular diseaseT1DM - Type 1 diabetes mellitus

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INTRODUCTION

Respiratory and cardiovascular disease frequently co-exist. Whilst shared risk factors are common,

it has become clear that the association between chronic obstructive pulmonary disease (COPD) and

cardiovascular disease is independent of these risk factors; indeed, the relationship between severity

of airflow obstruction and cardiovascular disease prevalence and mortality is now well established

(1,2).

The relationships between asthma, characterised by variable airway obstruction, or interstitial lung

disease (ILD), characterised by restrictive lung function, with cardiovascular disease, are less well

defined. Furthermore, the association between respiratory diseases and individual cardiovascular

diseases, which comprise a range of conditions with differing mechanisms and manifestations, is

not well characterised. Moreover, while there are extensive data to show that lung diseases,

particularly COPD (3,4), adversely affect the prognosis of patients with cardiovascular diseases,

few studies have investigated the impact of individual cardiovascular diseases on mortality in

patients with lung diseases.

In this study we aimed to investigate the association between COPD, asthma and ILD, with

individual cardiovascular diseases, and evaluate the impact of individual cardiovascular diseases on

all-cause mortality in these lung conditions, using a large cohort of patients admitted to National

Health Service (NHS) hospitals across the North West of England, UK over a 13-year period.

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METHODS

Data sources and study population

The study population comprised all patients admitted to seven National Health Service (NHS)

hospitals across the North West of England, UK at least once between January 1st 2000 and March

31st 2013. Anonymised discharge data including diagnoses, comorbidities and procedures were

obtained from the NHS Local Health Authority computerized hospital activity analysis register. The

Algorithm for Comorbidities, Associations, Length of stay, and Mortality (ACALM) study protocol

was subsequently applied to transfer this raw data into an analyzable research database. The

ACALM protocol utilizes the concept of amalgamation of routinely collected data and advances the

concept of the use of big data in medical research, and has been as previously described in

numerous publications (5-7). The ACALM protocol eliminates the possibility of patients being

counted twice. First admission data are used for patients with multiple admissions.

The three study groups comprised all adult patients (≥ 18 years old) with a diagnosis of COPD,

asthma and ILD respectively. Patients were identified using International Classification of Disease

10th edition (ICD-10) and Office of Population Censuses and Surveys Classification of

Interventions and Procedures (OPCS-4) coding systems. Data regarding an additional study group

with asthma-COPD overlap (ACO) are presented in the supplemental file.

Age and sex matched control groups for each of the three study groups were formed independently

from the main study population. SPSS was used to randomly select patients without diagnoses of

COPD, asthma or ILD. Control groups were matched for sex in age deciles for each study group.

Control groups were made five times larger than their corresponding study groups.

Outcomes

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Cardiovascular diseases (hypertension, hyperlipidaemia, type 1 or type 2 diabetes mellitus, ischemic

heart disease (IHD), heart failure, atrial fibrillation, peripheral vascular disease or cerebrovascular

disease) and cardiac procedures (percutaneous coronary intervention (PCI) or coronary artery

bypass grafting (CABG)) were identified using ICD-10 and OPCS-4 coding as part of the ACALM

study protocol. In addition, diagnoses of the other conditions in the top 10 most common causes of

death in the UK aside from cardiovascular diseases and COPD (i.e. lung cancer, breast cancer,

colon cancer, pneumonia, chronic kidney disease (CKD) and dementia) were identified using ICD-

10 and OPCS-4 coding. Data regarding diagnoses of respiratory disease, cardiovascular disease and

the other common causes of death, as well as age, sex and ethnicity, were available for all patients.

The ACALM algorithm captures tobacco use from ICD-10 coding; however, the NHS hospital

activity analysis register usually records tobacco use using a separate demographic field. Therefore,

tobacco use is substantially under-recorded by the ACALM algorithm. We report tobacco use,

however it was excluded from regression analyses in the main manuscript. Multivariable regression

analysis that includes tobacco use is presented in the supplemental file.

Mortality status at the end of the study period (March 31st 2013) was determined by record linkage

to the National Health Tracing Services (NHS Strategic Tracing Service) which utilizes data from

the UK Office for National Statistics. Mortality status was available for all patients.

Statistical Analysis

Nominal baseline characteristics including the unadjusted prevalence of cardiovascular diseases

were compared between each respiratory group and their respective control group using Chi square

(χ2) tests. Continuous variables were compared using independent t tests. To determine the

relationship between each respiratory condition and cardiovascular disease, logistic regression was

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used to calculate odds ratios and 95% confidence intervals. Multivariable models included

adjustments for age, sex, ethnic group and the cardiovascular diseases, cardiac procedures and

common causes of death stated above. To determine the relationship between cardiovascular

disease and death in each respiratory condition, multivariable Cox regression models were used to

calculate hazard ratios (HR) and 95% confidence intervals adjusted for age, sex, ethnic group and

the other cardiovascular diseases, cardiac procedures and common causes of death stated above.

Kaplan-Meier curves were used to illustrate the impact of cardiovascular diseases on survival. All p

values were 2-sided and a level of less than 0.05 was considered significant. Analyses were

performed using SPSS version 21.0 (IBM).

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RESULTS

Study Population

Between January 1st 2000 and March 31st 2013, 1,220,024 patients were admitted to the seven

hospitals included in the study. Of these patients, 31,646 patients (2.59%) had COPD, 60,424

(4.95%) had asthma and 1,662 (0.14%) had ILD at baseline. Control groups comprised 158,230

patients, 302,120 patients and 8,310 patients for the COPD, asthma and ILD groups respectively.

Baseline characteristics of patients with each respiratory condition and their matched controls are

presented in Table 1. Mean follow up was 5.2 ± 3.6 years (2,968,182 patient-years).

COPD

The unadjusted prevalence of cardiovascular diseases was higher among patients with COPD than

among controls at baseline (Table 1). Rates of pneumonia and lung cancer were also higher.

In multivariable analysis (Table 2), COPD was independently associated with IHD (odds ratio [OR]

1.74; 95% confidence interval [CI] 1.69-1.80), heart failure (OR 2.17; 95% CI 2.08-2.26), AF (OR

1.39; 95% CI 1.34-1.44) and peripheral vascular disease (OR 1.85; 95% CI 1.74-2.00). COPD was

not independently associated with cerebrovascular disease (OR 0.97; 95% CI 0.92-1.03).

During study follow-up 16,812 patients (53.1%) with COPD died, compared with 46,873 (29.6%)

matched controls (p < 0.001). In multivariable Cox regression, IHD (HR 1.03; 95% CI 1.01-1.05),

heart failure (HR 1.65; 95% CI 1.61-1.68), AF (HR 1.08; 95% CI 1.06-1.10), cerebrovascular

disease (HR 1.84; 95% CI 1.80-1.89) and peripheral vascular disease (HR 1.32; 95% CI 1.27-1.37)

were independently associated with death in patients with COPD (Table 3 and Figure 1).

Despite the higher prevalence of IHD, patients with COPD were less likely to receive coronary

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revascularization, either via percutaneous coronary intervention (PCI) (OR 0.48; 95% CI 0.44-0.54)

or coronary artery bypass grafting (CABG) (OR 0.42; 95% CI 0.36-0.49), but coronary

revascularization was associated with a lower rate of death (PCI HR 0.35; 95% CI 0.32-0.39;

CABG HR 0.52; 95% CI 0.46-0.58)

Asthma

The unadjusted prevalence of hypertension, hyperlipidaemia, type II diabetes, IHD, heart failure,

and AF was higher among patients with asthma than among controls at baseline (Table 1). Rate of

pneumonia was also higher.

In multivariable analysis (Table 2), asthma was independently associated with IHD (OR 1.48; 95%

CI 1.44-1.53). Asthma was not independently associated with heart failure (OR 1.06; 95% CI 1.00-

1.12) or AF (OR 1.02; 95% CI 0.97-1.07) and was associated with lower rates of cerebrovascular

disease (OR 0.77; 95% CI 0.72-0.82) and peripheral vascular disease (OR 0.79; 95% CI 0.72-0.87).

During study follow-up 6,649 patients (11.0%) with asthma died, compared with 36,624 (12.1%)

matched controls (p < 0.001). In multivariable Cox regression, IHD (HR 1.04; 95% CI 1.01-1.07),

heart failure (HR 1.81; 95% CI 1.75-1.87), AF (HR 1.07; 95% CI 1.04-1.10), cerebrovascular

disease (HR 2.10; 95% CI 2.03-2.17) and peripheral vascular disease (HR 1.39; 95% CI 1.32-1.47)

were independently associated with death in patients with asthma (Table 3 and Figure 2).

Despite the higher prevalence of IHD, patients with asthma were less likely to receive coronary

revascularization, either via PCI (OR 0.75; 95% CI 0.70-0.82) or CABG (OR 0.60; 95% CI 0.53-

0.67), but coronary revascularization was associated with a lower rate of death (PCI HR 0.41; 95%

CI 0.37-0.47; CABG HR 0.57; 95% CI 0.50-0.65).

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ILD

The unadjusted prevalence of type II diabetes, IHD, heart failure and AF were higher among

patients with ILD than among controls at baseline (Table 1). Rates of pneumonia and lung cancer

were also higher.

In multivariable analysis (Table 2), ILD was independently associated with IHD (OR 1.57; CI 1.37-

1.81) and heart failure (OR 2.23; 95% CI 1.88-2.66). ILD was not independently associated with

AF (OR 1.10; 95% CI 0.93-1.30) or peripheral vascular disease (OR 1.09; 95% CI 0.78-1.52). ILD

was associated with lower rates of cerebrovascular disease (OR 0.61; 95% CI 0.47-0.78).

During study follow-up 1,149 patients (69.1%) with ILD died, compared with 2737 (32.9%)

matched controls (p < 0.001). In multivariable Cox regression, IHD (HR 1.10; 95% CI 1.02-1.19),

heart failure (HR 1.59; 95% CI 1.45-1.74), cerebrovascular disease (HR 1.89; 95% CI 1.70-2.09)

and peripheral vascular disease (HR 1.27; 95% CI 1.07-1.50) were independently associated with

death in patients with ILD (Table 3 and Figure 3).

Despite the higher prevalence of IHD, patients with ILD were less likely to receive coronary

revascularization, either via PCI (OR 0.42; 95% CI 0.25-0.71) or CABG (OR 0.47; 95% CI 0.25-

0.87), but coronary revascularization was associated with a lower rate of death (PCI HR 0.43; 95%

CI 0.28-0.66; CABG HR 0.43; 95% CI 0.26-0.70).

Asthma-COPD overlap

Results are presented in the supplemental file.

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Tobacco Use

Tobacco use was recorded in 9.2% of patients with COPD compared to 1.8% of the COPD control

population (5.11 fold higher). In patients with asthma, tobacco use was 5% compared to 2.7% in the

asthma control group (1.85 fold higher) and in patients with ILD, tobacco use was 2.8% compared

to 1.5% in the ILD control group (1.86 fold higher). Multivariable-adjusted associations of

cardiovascular diseases with each respiratory disease, including adjustment for tobacco use, are

presented in the supplemental file (Table S4).

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DISCUSSION

In this study, we found COPD, asthma and ILD to be strongly and independently associated with

cardiovascular diseases. Furthermore, cardiovascular diseases were independently and often

strongly associated with all-cause mortality in patients with lung diseases. Despite these findings,

patients with COPD, asthma and ILD were less likely to receive coronary revascularization than

patients without these lung conditions. Strengths of this study include its prospective design, large

sample, length of follow-up and completeness of mortality status. We used all-cause mortality

because cause of death reporting is often inaccurate in lung conditions (8).

The association between ILD and IHD seen in our study, by far the largest to investigate this

relationship, is in keeping with the findings of smaller previous studies (9,10). Importantly, our

study is the first to demonstrate that IHD is independently associated with all-cause mortality in

patients with ILD. Higher unadjusted rates of heart failure have been observed in patients with ILD

compared with patients without ILD (11), but our study is the first to demonstrate an independent

association between ILD and heart failure, and in addition, the first to show that heart failure is

independently associated with all-cause mortality in ILD, with an associated 1.6 fold increased risk.

We found ILD was not independently associated with AF, which is in keeping with a previous

smaller study by Hubbard et al (10), and additionally found, for the first time, that AF did not

contribute significantly to death in ILD. In the first study to investigate the relationship between

ILD and peripheral vascular disease, we found ILD was not associated with peripheral vascular

disease.

The association between asthma and IHD found in our study is in keeping with the findings of

recent meta-analyses (12,13). However, our study is the first to demonstrate that IHD is

independently associated with all-cause mortality in patients with asthma, albeit the association was

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relatively small. Unlike the study by Iribarren et al (14), we did not find an independent association

between asthma and heart failure, although the rate of heart failure in our asthma and asthma

control cohorts was 3.3 times higher than that in the study by Iribarren et al. We did find heart

failure conferred a highly increased risk of death. The relationship between asthma and

cerebrovascular disease has been inconsistent across previous studies and we found patients with

asthma had lower rates of cerebrovascular disease than non-asthmatic patients, after multivariable

adjustment (14,15). Our study is by far the largest to investigate the relationship between asthma

and peripheral vascular disease and asthma and AF, and the first to investigate their contribution to

mortality, showing that asthma is not independently associated with either condition, but both

contribute significantly to all-cause mortality.

The unadjusted prevalence and adjusted risk of IHD and heart failure in patients with COPD in our

study are in keeping with those reported in a recent systematic review (16). There is substantially

less data regarding the relationship between COPD and peripheral vascular disease, and COPD and

AF, but the independent associations with both peripheral vascular disease and AF found in our

study are in keeping with the findings of previous smaller studies (17,18). A variable relationship

has been observed across the published literature between COPD and cerebrovascular disease and

we did not find an independent association (17,19,20).

Our findings regarding the impact of IHD and heart failure on mortality in patients with COPD are

in keeping with those of Sidney et al (21), who found myocardial infarction and heart failure were

independently associated with all-cause mortality in patients with COPD, although Sidney et al did

not adjust for other causes of death and follow-up in our study was considerably longer. Our study

is the first to investigate the impact of AF and peripheral vascular disease on all-cause mortality in

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COPD, finding that AF and peripheral vascular disease are associated with 1.1- and 1.3-fold higher

risks of death respectively.

Population prevalence of tobacco use in UK adults is reported as 17.2% (22). Therefore, while we

were able to identify variations in tobacco use in patients with COPD, asthma, and ILD compared to

their respective control groups, tobacco use was substantially under-recorded, the reason for which

is described in the Methods section. Recent UK data found 89.4% of COPD patients had a current

or past history of smoking, which is 5.2 fold higher than the population prevalence (23). This is

very similar to the difference in tobacco use (5.1 fold higher) between COPD and COPD control

groups in our study. Similar findings are found in the Asthma and ILD groups. As such, the under-

reporting of tobacco use in our study appears to be consistent across the whole study population

rather than being disease specific. Nevertheless, the observed associations between lung diseases

and cardiovascular diseases persisted after adjusting for tobacco use.

The risk and impact of heart failure in lung disease was found to be particularly strong and is

independent of the increased risk of IHD. Myocardial inflammation occurring as part of systemic

inflammation, with subsequent interstitial myocardial fibrosis, which in turn leads to mechanical,

electrical and vasomotor dysfunction of the myocardium, is a widely held pathophysiological

hypothesis (24). Circulating inflammatory biomarkers are strongly associated with heart failure in

COPD (25). Myocardial injury (elevated troponin level) is observed in chronic stable COPD, the

magnitude of which is determined by immune activation (26), and inflammatory biomarkers are

independently associated with natriuretic peptide levels (27). López-Sánchez et al found patients

with COPD and LV diastolic dysfunction had significantly higher levels of circulating

inflammatory and fibrotic biomarkers compared to COPD patients without diastolic dysfunction

(28), and collagen remodeling biomarkers are associated with increased mortality (29).

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Interestingly, targeted anti-inflammatory therapy may reduce cardiovascular events and incident

lung cancer (30). However, the relationship between lung disease, inflammation and heart failure is

inconsistent and mechanisms extrinsic to the myocardium, such as reduced left ventricular pre-load

secondary to pulmonary dysfunction, increased after-load due to arterial stiffness and autonomic

dysfunction, have been proposed (31,32). In particular, COPD exacerbations are associated with

increased arterial stiffness and frequent exacerbations are associated with chronically elevated

arterial stiffness, possibly mediated by loss of elastic connective tissue (32).

The role of inflammation in ILD is less clear. Nevertheless, following the initial injury, many of the

molecular (e.g. transforming growth factor β, angiotensin II, endothelin-1, extracellular regulated

kinase 1/2 and matrix metalloproteinases), and cellular (proliferation and transdifferentiation of

fibroblasts, collagen secretion) fibrotic mechanisms are common to pulmonary and myocardial

tissue (33). Diastolic dysfunction is observed in ILD and it may be that myocardial fibrosis

contributes to the association between ILD and heart failure, although this requires investigation

(34). The nature of heart failure associated with lung disease (i.e. reduced versus preserved ejection

fraction) remains poorly characterised.

Multiple mechanisms have been proposed to explain the link between lung disease and IHD.

Subclinical atherosclerosis is observed early in the COPD disease process and is related to

circulating markers of systemic inflammation (35). Impaired endothelial-dependent and

independent vasodilatation is observed in patients with COPD without cardiovascular disease, the

severity of which is related to systemic inflammation (36). Vijayakumar et al demonstrated

increased arterial inflammation in patients with asthma using 18F-fluorodeoxyglucose positron

emission tomography, which remained significant after adjusting for traditional cardiovascular risk

factors, and which was related to severity of airflow obstruction (37). Plasma fibrinogen is

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chronically elevated in COPD and increases further during acute exacerbations, asthma is

associated with platelet activation and inhibition of fibrinolysis and clotting cascade activation is

observed in ILD (38). Nevertheless, the design and size of our study allows the relationship

between lung disease and other vascular disease (peripheral and cerebral) to be investigated

concurrently, and it shows that while there is a consistent association between the lung conditions

studied and IHD, the association with other vascular disease is inconsistent or indeed not present.

This suggests that if there is an underlying systemic process, it may have a differential effect

according to vascular location.

Despite the association with IHD and its impact on outcome, patients with the studied lung diseases

were less likely to undergo coronary revascularization than patients without lung diseases. Patients

with lung disease are generally underrepresented in trials and it may be that guidelines are

perceived to be less valid in this group (39). Elevated troponins may be attributed to decreased

oxygen supply (type 2 myocardial infarction) rather than a pathologic coronary artery process (type

I), albeit with similar associated risk. Patients with COPD have higher in hospital mortality and

higher rates of adverse cardiac events following PCI, and higher rates of postoperative pulmonary

infections and longer length of hospital stay following CABG, compared with patients without

COPD (40). Perhaps reflecting these data, in our study, patients receiving revascularization were

generally younger and had fewer co-morbidities (supplemental Table S5). While the SYNTAX

Score II generally favors PCI over CABG in patients with COPD, we found similarly low rates for

both (41).

There has been a long-standing debate about the safety of particularly long-acting beta-agonists in

asthma (42), with the FDA adding a black box warning in 2006. The FDA required large post-

marketing studies to evaluate this risk and following the findings from 4 studies including 41,297

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patients, the black box was removed in December 2017 (43). In COPD there has also been a

concern surrounding both the use of inhaled long-acting beta-agonists and long-acting

anticholinergics. The concern regarding beta-agonists were laid to rest by the SUMMIT trial (44,45)

and the TIOSPIR trial could not replicate the risk of cardiovascular death (46) suggested by a

previous meta-analysis (47).

Limitations

The study is limited by its observational cohort design. There may be residual confounding; in

particular, tobacco use was under-recorded as discussed, although a multivariable adjustment

including tobacco use was performed. The cardiovascular and respiratory diagnoses rely on the

disease coding of the individual hospitals involved, although these data are determined by the

diagnoses made by the treating physicians and are what the hospitals and the NHS use for

operational purposes (e.g. reimbursement and performance evaluation). Our data are limited to

hospitalized patients whereas most COPD and asthma exacerbations are treated in an outpatient

setting; thus, our findings are more likely to be driven by patients with more advanced lung disease.

Data regarding antihypertensive, lipid-lowering and smoking cessation therapy, as well as the type

of heart failure (i.e., reduced versus preserved ejection fraction) were not available.

Conclusions

In conclusion, in a large cohort study, we found that COPD, asthma and ILD were independently

associated with cardiovascular diseases, and, cardiovascular diseases were independently associated

with all-cause mortality in these lung conditions. Despite these findings, patients with COPD,

asthma and ILD were less likely to receive coronary revascularization than patients without these

lung conditions.

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Clinical perspectives

Competency in Medical Knowledge 1: COPD, ILD and asthma are independently associated with a

range of cardiovascular diseases, and, cardiovascular diseases are independently associated with all-

cause mortality in these lung conditions.

Competency in Medical Knowledge 2: Despite these associations, patients with lung conditions are

less likely to receive coronary revascularization.

Translational Outlook: Elucidation of the pathophysiological mechanisms underlying the

relationship between respiratory disease and cardiovascular disease is urgently required.

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24

FIGURE LEGENDS

Central illustration. Cardiovascular diseases associated with chronic obstructive pulmonary

disease (COPD), asthma and interstitial lung disease (ILD).

On multivariable analysis, COPD was independently associated with ischemic heart disease (IHD),

heart failure (HF), atrial fibrillation (AF) and peripheral vascular disease (PVD); asthma was

independently associated with IHD, and ILD was independently associated with IHD and HF.

Figure 1. The impact of cardiovascular diseases on all-cause mortality in chronic obstructive

pulmonary disease (COPD).

Between January 1st 2000 and March 31st 2013, 31,646 patients with COPD were admitted to seven

NHS hospitals across the North West of England, UK. During follow up of 5.2 ± 3.6 years, 16,812

patients (53.1%) died. Kaplan-Meier cumulative survival curves are used to illustrate the impact of

(A) ischemic heart disease, (B) heart failure, (C) atrial fibrillation, (D) cerebrovascular disease and

(E) peripheral vascular disease on survival. In multivariable analysis, ischemic heart disease, heart

failure, atrial fibrillation and peripheral vascular disease were independently associated with death.

Figure 2. The impact of cardiovascular diseases on all-cause mortality in asthma

Between January 1st 2000 and March 31st 2013, 60,424 patients with asthma were admitted to seven

NHS hospitals across the North West of England, UK. During follow up of 5.2 ± 3.6 years, 6,649

patients (11.0%) died. Kaplan-Meier cumulative survival curves are used to illustrate the impact of

(A) ischemic heart disease, (B) heart failure, (C) atrial fibrillation, (D) cerebrovascular disease and

(E) peripheral vascular disease on survival. In multivariable analysis, ischemic heart disease and

heart failure were independently associated with death.

25

Figure 3. The impact of cardiovascular diseases on all-cause mortality in interstitial lung

disease (ILD)

Between January 1st 2000 and March 31st 2013, 1,662 patients with ILD were admitted to seven

NHS hospitals across the North West of England, UK. During follow up of 5.2 ± 3.6 years, 1,149

patients (69.1%) died. Kaplan-Meier cumulative survival curves are used to illustrate the impact of

(A) ischemic heart disease, (B) heart failure, (C) atrial fibrillation, (D) cerebrovascular disease and

(E) peripheral vascular disease on survival. In multivariable analysis, ischemic heart disease and

heart failure were independently associated with death.

26

TABLES

Table 1. Baseline characteristics according to respiratory disease and matched controls.

COPD Asthma ILD

Characteristic Control

N = 158,230

COPD

N = 31,646

p value Control

N = 302,120

Asthma

N = 60,424

p value Control

N = 8,310

Fibrosis

N = 1,662

p value

Demographics

Age 70.0±12 70.3±12 48.6±20 48.5±20 71.3±12 71.5±12

Male 80,710 (51.0%) 16,142 (51.0%) 110,860 (36.7%) 22,172 (36.7%) 4,715 (56.7%) 943 (56.7%)

Ethnic Group

Caucasian

South Asian

Afro-Caribbean

Other

Unknown

133,209 (84.2%)

6,082 (3.8%)

2,383 (1.5%)

2828 (1.8%)

13,728 (8.7%)

28,527 (90.1%)

555 (1.8%)

175 (0.6%)

292 (0.9%)

2,097 (6.6%)

231,451 (76.6%)

24,604 (8.1%)

9,208 (3.0%)

11273 (3.7%)

25,584 (8.5%)

47,828 (79.2%)

5,343 (8.8%)

1,520 (2.5%)

1870 (3.1%)

3,863 (6.4%)

7,057 (84.9%)

304 (3.7%)

116 (1.4%)

135 (1.7%)

698 (8.4%)

1,427 (85.9%)

113 (6.8%)

17 (1.0%)

15 (0.9%)

90 (5.4%)

Cardiovascular disease

Hypertension

Hyperlipidaemia

T1DM

T2DM

IHD

53,396 (33.7%)

15,855 (10.0%)

2,253 (1.4%)

20,655 (13.1%)

28,380 (17.9%)

11,992 (37.9%)

3,051 (9.6%)

340 (1.1%)

4,879 (15.4%)

9,188 (29.0%)

<0.001

0.040

<0.001

<0.001

<0.001

50,243 (16.6%)

16,181 (5.4%)

3,287 (1.1%)

20,105 (6.7%)

24,149 (8.0%)

14,752 (24.4%)

4,478 (7.4%)

875 (1.4%)

5,945 (9.8%)

7,291 (12.1%)

<0.001

<0.001

<0.001

<0.001

<0.001

2,840 (34.2%)

799 (9.6%)

108 (1.3%)

1,133 (13.6%)

1,526 (18.4%)

575 (34.6%)

150 (9.0%)

17 (1.0%)

281 (16.9%)

452 (27.2%)

0.741

0.455

0.355

<0.001

<0.001

27

Heart Failure

AF

CKD

Cerebrovascular disease

PVD

PCI

CABG

10,076 (6.4%)

15,123 (9.6%)

6,275 (4.0%)

8,304 (5.2%)

3,750 (2.4%)

3,619 (2.3%)

2,153 (1.4%)

5,449 (17.2%)

5,444 (17.2%)

2,290 (7.2%)

1,932 (6.1%)

1,714 (5.4%)

418 (1.3%)

236 (0.7%)

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

7,617 (2.5%)

11,106 (3.7%)

4,653 (1.5%)

6,563 (2.2%)

3,010 (1.0%)

3,843 (1.3%)

1,859 (0.6%)

1,879 (3.1%)

2,504 (4.1%)

925 (1.5%)

1,119 (1.9%)

617 (1.0%)

829 (1.4%)

360 (0.6%)

<0.001

<0.001

0.866

<0.001

0.576

0.047

0.574

560 (6.7%)

896 (10.8%)

357 (4.3%)

512 (6.2%)

204 (2.5%)

180 (2.2%)

113 (1.4%)

295 (17.7%)

263 (15.8%)

149 (9.0%)

79 (4.8%)

52 (3.1%)

16 (1.0%)

12 (0.7%)

<0.001

<0.001

<0.001

0.026

0.113

0.001

0.033

Other disease

Pneumonia

Dementia

Breast Cancer

Lung Cancer

Colon Cancer

6,957 (4.4%)

7,157 (4.5%)

2,509 (1.6%)

2,676 (1.7%)

1,059 (0.7%)

4,870 (15.4%)

1,615 (5.1%)

543 (1.7%)

1,844 (5.8%)

195 (0.6%)

<0.001

<0.001

0.093

<0.001

0.287

5,818 (1.9%)

4,671 (1.5%)

3,532 (1.2%)

2,210 (0.7%)

871 (0.3%)

1,619 (2.7%)

615 (1.0%)

677 (1.1%)

399 (0.7%)

129 (0.2%)

<0.001

<0.001

0.308

0.059

0.001

422 (5.1%)

430 (5.2%)

122 (1.5%)

133 (1.6%)

57 (0.7%)

316 (19.0%)

83 (5.0%)

34 (2.0%)

83 (5.0%)

7 (0.4%)

<0.001

0.761

0.083

<0.001

0.217

Values presented are number and percentage, unless stated. Age is presented as mean years ± standard deviation.

28

Table 2: Multivariable-adjusted association of cardiovascular diseases with each respiratory disease.

COPD Asthma ILD

Odds ratio (95% CI) p value Odds ratio (95% CI) p value Odds ratio (95% CI) p value

Hypertension

Hyperlipidaemia

T1DM

T2DM

IHD

Heart Failure

AF

CKD

Cerebrovascular

PVD

PCI

CABG

1.089 (1.059-1.120)

0.876 (0.837-0.917)

0.662 (0.587-0.746)

1.034 (0.997-1.073)

1.742 (1.688-1.797)

2.167 (2.081-2.255)

1.391 (1.339-1.444)

1.229 (1.164-1.298)

0.973 (0.921-1.027)

1.849 (1.737-1.969)

0.484 (0.435-0.538)

0.422 (0.366-0.485)

<0.001

<0.001

<0.001

0.074

<0.001

<0.001

<0.001

<0.001

0.316

<0.001

<0.001

<0.001

1.656 (1.614-1.698)

1.053 (1.013-1.094)

1.055 (0.976-1.139)

1.295 (1.253-1.339)

1.483 (1.435-1.533)

1.057 (0.999-1.117)

1.016 (0.969-1.066)

0.828 (0.769-0.892)

0.767 (0.718-0.819)

0.792 (0.724-0.866)

0.753 (0.696-0.816)

0.597 (0.531-0.672)

<0.001

0.009

0.176

<0.001

<0.001

0.053

0.505

<0.001

<0.001

<0.001

<0.001

<0.001

0.950 (0.840-1.075)

0.929 (0.758-1.138)

0.709 (0.415-1.211)

1.195 (1.024-1.395)

1.571 (1.367-1.805)

2.234 (1.878-2.657)

1.100 (0.930-1.302)

1.586 (1.276-1.971)

0.606 (0.468-0.784)

1.088 (0.781-1.516)

0.418 (0.246-0.708)

0.469 (0.252-0.872)

0.417

0.475

0.209

0.024

<0.001

<0.001

0.267

<0.001

<0.001

0.617

0.001

0.017

29

Table 3: Multivariable Cox regression models of the contribution of cardiovascular diseases to mortality in patients with each

respiratory disease.

COPD Asthma ILD

No. of

patients

No. of deaths (%) HR p value No. of

patients

No. of deaths

(%)

HR p value No. of

patients

No. of deaths

(%)

HR p value

Total 31,646 16,812 (53.1%) 60,424 6 649 (11.0%) 1,662 1 149 (69.1%)

Hypertension

Hyperlipidaemia

T1DM

T2DM

IHD

Heart Failure

AF

CKD

Cerebrovascular

PVD

11,992

3,051

340

4,879

9,188

5,449

5,444

2,290

1,932

1,714

5,698 (47.5%)

972 (31.9%)

192 (56.5%)

2,546 (52.2%)

5,226 (56.9%)

4,219 (77.4%)

3,785 (69.5%)

1,632 (71.3%)

1,445 (74.8%)

1,079 (63.0%)

0.763 (0.750-0.776)

0.613 (0.592-0.635)

1.346 (1.265-1.433)

1.132 (1.107-1.157)

1.029 (1.009-1.050)

1.645 (1.608-1.684)

1.080 (1.057-1.103)

1.314 (1.277-1.352)

1.843 (1.796-1.891)

1.320 (1.271-1.371)

<0.001

<0.001

<0.001

<0.001

0.004

<0.001

<0.001

<0.001

<0.001

<0.001

14,752

4,478

875

5,945

7,291

1,879

2,504

925

1,119

617

2 671 (18.1%)

487 (10.9%)

197 (22.5%)

1 290 (21.7%)

1 802 (24.7%)

1 005 (53.5%)

940 (37.5%)

445 (48.1%)

550 (49.2%)

213 (34.5%)

0.790 (0.773-0.807)

0.614 (0.589-0.641)

1.612 (1.510-1.720)

1.252 (1.218-1.286)

1.039 (1.013-1.067)

1.808 (1.752-1.866)

1.070 (1.039-1.103)

1.553 (1.494-1.613)

2.098 (2.031-2.168)

1.394 (1.322-1.470)

<0.001

<0.001

<0.001

<0.001

0.003

<0.001

<0.001

<0.001

<0.001

<0.001

575

150

17

281

452

295

263

149

79

52

407 (70.8%)

83 (55.3%)

10 (58.8%)

192 (68.3%)

335 (74.1%)

241 (81.7%)

207 (78.7%)

114 (76.5%)

63 (79.7%)

32 (61.5%)

0.775 (0.723-0.830)

0.619 (0.538-0.712)

1.282 (0.969-1.695)

1.145 (1.049-1.250)

1.098 (1.016-1.187)

1.588 (1.448-1.742)

1.053 (0.966-1.148)

1.183 (1.053-1.328)

1.886 (1.702-2.090)

1.269 (1.072-1.503)

<0.001

<0.001

0.082

0.003

0.018

<0.001

0.239

0.005

<0.001

0.006

PCI 418 52 (12.4%) 0.353 (0.317-0.394) <0.001 829 54 (6.5%) 0.414 (0.367-0.466) <0.001 16 5 (31.3%) 0.427 (0.276-0.659) <0.001

CABG 236 37 (15.7%) 0.516 (0.461-0.579) <0.001 360 28 (7.8%) 0.573 (0.503-0.653) <0.001 12 3 (25%) 0.425 (0.259-0.700) 0.001

30