Competitive interaction between chronic obstructive pulmonary disease and CHA2DS2-VASc score in predicting incident atrial fibrillation

    Competitive interaction between chronic obstructive pulmonary disease and CHA2 DS2 -VASc score in predicting incident atrial fibrillation Maria Perticone, Angela Sciacqua, Giovanni Tripepi, Sofia Miceli, Salvatore Corrao, Giorgio Sesti, Francesco Perticone PII: DOI: Reference:

S0167-5273(17)34491-1 doi:10.1016/j.ijcard.2017.11.036 IJCA 25671

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

21 July 2017 13 October 2017 13 November 2017

Please cite this article as: Perticone Maria, Sciacqua Angela, Tripepi Giovanni, Miceli Sofia, Corrao Salvatore, Sesti Giorgio, Perticone Francesco, Competitive interaction between chronic obstructive pulmonary disease and CHA2 DS2 -VASc score in predicting incident atrial fibrillation, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.11.036

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ACCEPTED MANUSCRIPT Competitive interaction between chronic obstructive pulmonary disease and CHA2DS2VASc score in predicting incident atrial fibrillation

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Maria PERTICONE*1, Angela SCIACQUA*2, Giovanni TRIPEPI3, Sofia MICELI4, Salvatore

1University

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CORRAO5, Giorgio SESTI2, Francesco PERTICONE2

Magna Græcia, Department of Experimental and Clinical Medicine, Catanzaro,

2University

Magna Græcia, Department of Clinical and Surgical Sciences, Catanzaro, Italy

National Research Council-Institute of Clinical Physiology, Reggio Calabria, Italy

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Hospital Mater Domini, Catanzaro, Italy

5Department

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3CNR-IFC

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Italy

of Internal Medicine 2, National Relevance and High Specialization Hospital

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Trust, Palermo, Italy *

These authors equally contributed to the paper.

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All author take responsibility for all aspects of the reliability and freedom from bias of the

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data presented and their discussed interpretation. Correspondence to:

Prof. Francesco Perticone University Magna Græcia Department of Clinical and Surgical Sciences V.le Europa Loc. Germaneto 88100 Catanzaro – Italy Telephone: +39 0961 364 7149; Fax: +39 0961 364 7634; e-mail: [email protected]

Acknowledgement

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ACCEPTED MANUSCRIPT None.

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Conflict of interest

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The authors report no relationships that could be construed as a conflict of interest.

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Keywords

Atrial fibrillation; chronic obstructive pulmonary disease; CHA2DS2-VASc Score;

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cardiovascular risk

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ACCEPTED MANUSCRIPT ABSTRACT Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity

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and mortality, and an emerging risk factor for atrial fibrillation (AF). CHADS2 and CHA2DS2-

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VASc scores are significantly associated with incident AF independently of other risk factors. The aim of this study was to demonstrate a possible interaction between COPD and

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CHA2DS2-VASc in predicting incident AF.

Methods: This observational prospective cohort study included 4,322 Caucasians with

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cardiovascular risk factors, stratified by CHA2DS2-VASc score (>2 versus <2) and presence/absence of COPD. To detect AF appearance, patients underwent, every 6 months, physical examination, standard 12-lead electrocardiogram and routine laboratory tests. Results: COPD prevalence was significantly higher in patients with CHA2DS2-VASc>2

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versus CHA2DS2-VASc<2category (13.3% vs 10.5%, P=0.009). During the follow-up, 589

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cases of AF were documented (3.8 events/100 patients-year). COPD+ showed a significantly higher incidence of AF versus COPD- patients (17.4 vs 8.4 events/100 patients-year,

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P<0.0001). In Cox regression models both CHA2DS2-VASc score (HR=4.70, 95% CI=3.63-

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6.08) and COPD (HR=2.04, 95% CI=1.69-2.48) significantly predicted the incidence rate of AF; this was also confirmed introducing the two variables into the same Cox model. A significant competitive interaction between CHA2DS2-VASc and COPD was found in a Cox model in patients with CHA2DS2-VASc<2 (HR=8.45, 95% CI=5.20-13.74) than in those with CHA2DS2-VASc> 2. Conclusions: COPD is an independent ad strong predictor of incident AF. The presence of COPD increases the HR for incident AF about five times in patients with CHA2DS2VASc score <2, while the coexistence of a CHA2DS2Vasc score >2 minimizes the prognostic significance of COPD.

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ACCEPTED MANUSCRIPT INTRODUCTION Chronic obstructive pulmonary disease (COPD) is an important health problem,

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representing the third leading cause of death in developed countries in the last years [1,2]. In

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addition, this clinical condition is often associated with other multiple chronic comorbidities that have a negative impact on patients’ outcomes [3,4]; in particular, cardiovascular (CV)

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diseases greatly contribute to COPD-related mortality [5], despite COPD specific treatment [6,7].

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Atrial fibrillation (AF) represents the most common cardiac arrhythmia arising in adult and old subjects, conferring an increased risk for thromboembolic events and hospitalizations, with a significant impact on the health care economic costs [8-10]. Despite several clinical conditions have been recognized as risk factors for AF [11-13], we [14] and others [15] have

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recently demonstrated that CHADS2 [congestive heart failure, hypertension, age >75 years,

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type-2 diabetes, and previous stroke or transient ischemic attack (doubled)] and CHA2DS2VASc [congestive heart failure; hypertension; age >75 years (doubled); type-2 diabetes;

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previous stroke, transient ischemic attack (TIA), or thromboembolism (doubled); vascular

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disease; age 65 to 75 years; and sex category] scores, two validated schemas for assessing the risk for mortality and thromboembolic clinical events in AF patients, are significantly associated with incident AF independently of other risk factors. This is not surprising because these scores for thromboembolic events are constructed on the basis of different vascular risk factors and clinical conditions that are consistently associated with incident AF. In addition, recent evidences suggest that also breathing disorders, such as COPD, can be considered as emerging risk factors for AF [16-20], as well as influencing factors of its prognosis [21], but the pathophysiological mechanisms linking these diseases as well as the characteristics of patients sharing both AF and COPD remain still incompletely elucidated. It is likely that in patients with COPD, differently to other patients, the anatomo-functional substrate underlying

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ACCEPTED MANUSCRIPT AF is confined to the right atrium. In addition, consolidated evidences demonstrate that COPD is a clinical condition characterized by an inflammatory burden potentially affecting

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also anatomical and electrophysiological properties of left atrium with a significant increase

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of AF risk. Taken together, these evidences lead to hypothesize that COPD patients have an increased risk to develop AF.

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Thus, we designed present study to detect a possible interaction between COPD and CHA2DS2-VASc in predicting incident AF in a large cohort of Caucasian outpatients in the

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context of the “Catanzaro Atrial Fibrillation Project” [22].

Methods Study population

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We conducted an observational prospective cohort study that included 4,322 Caucasian

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outpatients, stratified by CHA2DS2-VASc score (>2 versus <2) and presence/absence of COPD, enrolled from January 1998 to December 2014 (2270 males and 2052 females, with a

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mean age of 59.2+11.7 years). All patients were referred to the University Hospital of

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Catanzaro for clinical evaluation and treatment of one or more of their CV risk factors. At the time of the enrollment all subjects underwent review of their medical history and physical examination with the measurement of anthropometrical parameters [weight, height, body mass index (BMI) and waist]. Patients with end-stage renal or malignant disease, thyroid dysfunction, cardiomyopathies, rheumatic and non-rheumatic valvular heart disease or prosthetic valves, were excluded from this study. At the enrollment none of the patient had experienced acute myocardial infarction (AMI) or stroke; thus, for vascular disease, we considered carotid atherosclerosis or peripheral artery disease, evaluated by ankle-brachial index (ABI).

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ACCEPTED MANUSCRIPT The ethical Committee of University Hospital of Catanzaro approved the protocol and informed written consent was obtained from all participants. All the investigations were

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performed according to the principles of the 1975 Declaration of Helsinki, and the study was

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conducted according to STROBE guidelines.

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Blood pressure measurements

Clinical evaluation of blood pressure (BP) was performed by a validated

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sphygmomanometer, with patients in the supine position, after 5 minutes of rest. The average of at least two of three consecutive measurements, obtained at intervals of 3 minutes, was considered for the analysis. Patients taking antihypertensive drugs or with a systolic BP (SBP) >140 mmHg and/or diastolic BP (DPB) >90 mmHg were defined as hypertensive. Pulse

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pressure was calculated as the difference between SBP and DBP. Secondary forms of

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Diabetes evaluation

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hypertension were excluded by appropriate laboratory and imaging tests.

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The diagnosis of type-2 diabetes was performed according with the following criteria: 1) presence of more than one classic symptom of hyperglycemia plus either a fasting plasma glucose >7.0 mmol/l or random plasma glucose >11.1 mmol/l, 2) two or more elevated plasma glucose concentrations (fasting plasma glucose >7.0 mmol/l, random plasma glucose >11.1 mmol/l, or 2-h plasma glucose >11.1 mmol/l during oral glucose tolerance test), and 3) use of an oral hypoglycemic drug or insulin.

COPD assessment The presence of COPD was considered according to medical history and by a standard spirometry. In particular, the established criterion for COPD were a post-bronchodilator

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ACCEPTED MANUSCRIPT forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio <70%. Severity of COPD was defined according to GOLD criteria, and in this analysis we included

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only patients with GOLD 1 and 2 stage because they represent the majority of our population

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(95%).

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Laboratory determinations

All the laboratory measurements performed at the enrollment visit and during follow-

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up, were carried out after a fasting of at least 12 hours and baseline values were retained for the statistical analysis. Plasma glucose was measured by the glucose oxidase method (Glucose Analyzer, Beckman Coulter SpA,Milan, Italy). Total, low-density lipoprotein (LDL), triglyceride and high-density lipoprotein (HDL) cholesterol levels were determined by an

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enzymatic method (Roche Diagnostics GmbH, Mannheim, Germany). For the assessment of

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renal function, serum creatinine was measured by an automated technique based on the Jaffe chromogenic assay. Finally, the value of estimated glomerular filtration rate (e-GFR;

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mL/min/1.73m2) was determined by the equation proposed in the Chronic Kidney Disease

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Epidemiology (CKD-EPI) Collaboration [23].

Vascular disease assessment Carotid atherosclerosis was evaluated by calculation of intima–media thickness (IMT) as mean value of the near and far wall in both carotid arteries, measured 10–15 mm proximal to the carotid bulb in a site free of plaque. An expert examiner has performed all measurements, by a blind approach respect to the clinical and laboratory patients’ data. An IMT value >0.9 mm identified a carotid wall thickening [24]. Moreover, the resting ABI, defined as the ratio of SBP in the ankle to the SBP in the arm, was calculated to detect peripheral artery disease (PAD). The highest value of the right

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ACCEPTED MANUSCRIPT or left arm SBP was used as the denominator, and ABI was calculated for both the right and

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left legs. For this analysis we used the lower value of right and left ABI.

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Follow-up and incidence of AF

To detect AF appearance, patients underwent every 6 months, physical examination,

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standard 12-lead electrocardiogram and routine laboratory tests. As previously describe by us [14], follow-up was improved by contacting patients by phone, or by mailing a

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questionnaire to family physicians, for assessing the appearance of new symptoms or clinical events. In addition, all subjects were asked about previous hospitalizations, discharge summaries and diagnoses. AF diagnosis was made by standard electrocardiogram, hospital discharge diagnoses, and by the all-clinical documentation

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provided by the patients or presence in the general practitioner files. In addition, to

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Statistical analysis

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detect asymptomatic AF, we annually performed a 24-h ECG-Holter monitoring.

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Continuous variables are reported as mean + SD and categorical data as frequencies and percentages. Unpaired Student’s t-test was used to test differences between clinical and biological data, and the chi-square test for categorical variables. Only clinical and biochemical data registered at the baseline visit were considered for statistical analysis. If some of the variables resulted incomplete, missing values were inferred using the expectation–maximization procedure for multivariate normal data, available in SPSS program. Event rate was reported as number of events/100 patients-year. Last contact represented the date of the censor for patients without events, while for patients who underwent multiple events, survival analysis was limited to the first event.

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ACCEPTED MANUSCRIPT The relationship between CHA2DS2-VASc score (>2 versus <2) and presence/absence of COPD with the incidence rate of AF was investigated by stratified Kaplan-Meier analyses

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as well as by univariate and multiple Cox regression models (these latter built up at different

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levels of data adjustment). Tested covariates included CHA2DS2-VASc score and COPD as well as all biologically plausible risk factors for AF (age, gender, PP, BMI, smoking, hs-CRP

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and e-GFR). We considered PP, instead of SBP and DBP, because it provided a better model fitting as compared to the two other BP determinants. Similarly, we included BMI instead of

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waist circumference, because BMI-AF link was stronger than that of waist circumference. In multiple Cox models, in which we always adjusted for age and gender, we introduced all risk factors that resulted to be related with the outcome variable with P<0.10 at univariate Cox analyses. In Cox models, data were expressed as hazard ratio (HR), 95% confidence intervals

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(95% CI), and P values. The mutual effect modification of key risk factors (i.e. the effect

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modification by CHA2DS2-VASc on the COPD-study outcome link and that by COPD on the CHA2DS2-VASc -study outcome relationship) was investigated by simultaneously

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introducing CHA2DS2-VASc, COPD and their interaction term (CHA2DS2-VASc x COPD)

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into the same Cox model also adjusting for a series of potential confounders. The HRs of CHA2DS2-VASc by COPD groups as well as the HRs of COPD by CHA2DS2-VASc groups, were investigated by standard linear combination method. All comparisons were performed using the statistical package SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results Baseline demographic and clinical characteristics of patients according to value of CHA2DS2-VASc score (<2 and >2) and presence/absence of COPD are reported in Table 1. The prevalence of COPD in the whole population was 12.4%, and it was significantly higher

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ACCEPTED MANUSCRIPT in patients with CHA2DS2-VASc score >2 in comparison with lower CHA2DS2-VASc score (13.3% vs 10.5%, P=0.009). During a mean follow-up of 59.4+22.7 months, 589 cases of AF

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were documented (3.8 events/100 patients-year). The incidence of AF was significantly

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higher in patients with CHA2DS2-VASc score >2 compared to patients with CHA2DS2-VASc score <2 (13.0 vs 3.1 events/100 patients-year, P<0.0001). Of interest, patients affected by

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COPD showed a significantly higher incidence of AF when compared with patients without COPD (17.4 vs 8.4 events/100 patients-year, P<0.0001).

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Obviously, the group of patients with CHA2DS2-VASc score >2 showed higher prevalence of women, an older age, increased levels of SBP, PP, fasting glucose and hs-CRP values; in addition, they presented reduced e-GFR values compared to patients with CHA2DS2-VASc score <2. On the contrary, there was a slight but significant increase in

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HDL-cholesterol and decrease of total- and LDL-cholesterol and a lower number of smokers.

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There were no statistically significant differences for DBP and triglyceride. When we considered the study population stratified according to the presence of COPD,

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patients affected were older and showed higher prevalence of men and smokers, lower levels

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of HDL-cholesterol and higher levels of PP, triglyceride, fasting glucose and hs-CRP with lower values of e-GFR. There was no significant difference for BMI and SBP, but a significant decrease in DBP, total and LDL-cholesterol. A higher prevalence of patients in COPD group showed a CHA2DS2-VASc score >2 (71.4% vs 65.7%, P=0.009). During the follow-up period, all subjects were treated with both pharmacological and lifestyle interventions according to current guidelines, to control all CV risk factors and COPD, without any significant difference between groups.

CHA2DS2-VASc score and COPD as predictors of AF: Cox regression analyses

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ACCEPTED MANUSCRIPT In two separate Cox regression models, both CHA2DS2-VASc score (HR=4.70, 95% CI=3.63-6.08) and COPD (HR=2.04, 95% CI=1.69-2.48) significantly predicted the incidence

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of AF and this was also confirmed when the two variables were simultaneously introduced

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into the same Cox model (CHA2DS2-VASc score: HR=4.59, 95% CI=3.55-5.94; COPD: HR=1.92, 95% CI=1.58-2.33). The associations between CHA2DS2-VASc score and COPD

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with the study outcomes remained significant also in a Cox model adjusted for all biologically plausible (see Methods – Statistical Analysis) univariate predictors (with P<0.10) of AF

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(Table 2).

A significant competitive (i.e. inverse) interaction (P<0.001) between CHA2DS2-VASc score and COPD was found in a Cox model (data not shown) including these two variables

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and their interaction term (CHA2DS2-VASc score * COPD) so that the HR of AF associated to COPD was significantly higher (HR=8.45, 95% CI=5.20-13.74) in patients with CHA2DS2-

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VASc score <2 than in those with CHA2DS2-VASc score > 2 (Figure 1, upper panel). By the same token, the excess risk of AF associated to CHA2DS2-VASc score was significantly

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higher (HR=7.94, 95% CI=5.54-13.37) in patients without COPD than in those with COPD

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(HR=1.42, 95% CI=0.96-2.11) so as reported in Figure 1, bottom panel. Remarkably, such a mutual and inverse effect modification remained significant also after data adjustment for all potential confounders (Table 3). In fact, the adjusted HR of AF associated to COPD was significantly higher in patients with CHA2DS2-VASc score <2 (HR=4.82, 95% CI=2.93-7.93) than in those with CHA2DS2-VASc score >2 (HR=1.00, 95% CI=0.80-1.25) and vice versa, the excess risk of the same outcome associated to CHA2DS2-VASc score >2 was significantly higher in patients without COPD (HR=3.40, 95% CI=2.31-5.00) than in those with COPD (HR=0.70, 95% CI=0.46-1.07) (Table 3).

Discussion

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ACCEPTED MANUSCRIPT The major finding obtained in this very large observational prospective cohort study is that COPD is an independent and strong predictor of incident AF, independently of other well

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established risk factors for this arrhythmia during an average follow-up of 5.9 years. The

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present study is, to our knowledge, the first that prioritized the potential impact of COPD in the appearance of AF in patients at high CV risk. This fact has a very important clinical

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significance because COPD is independently associated with an increased burden of fatal and nonfatal CV disease [4-6]. On the other hand, AF is the most frequent arrhythmia in clinical

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practice, especially in adult and older patients [9,10,25]. It may be triggered by many clinical conditions such as age, cardiac diseases, thyroid disorders, obesity, diabetes, renal dysfunction, alcohol consumption, etc. [19,26,27]. In patients with COPD, AF may be triggered by many insults such as pulmonary and hemodynamic abnormalities with associated

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structural and functional modifications of right cardiac chambers, hypoxia and/or hypercapnia

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that can alter the electrophysiological properties of the right atrium [27-29]. The coexistence of both AF and COPD, beyond increasing thromboembolic risk, also complicates the

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treatment of both diseases, representing a new challenging clinical condition to be managed.

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Another result, clinically relevant, is that the incidence of new AF was significantly higher in patients with CHA2DS2-VASc score >2 compared to that of patients with CHA2DS2-VASc score <2, thus confirming previously published results obtained by our [14] and other groups [15,30,31] in different settings of patients. In particular, differently from other Authors, we demonstrated the prognostic significance of this score in a very large cohort of high CV risk patients without previous clinical events, while Baturova et al. obtained similar results in patients after first-ever ischemic stroke [31]. This is not surprising because, as previously hypothesized, this score for thromboembolic disease is constructed on the basis of different vascular risk factors and clinical conditions that are consistently associated with incident AF. In addition, increasing evidences support the hypothesis that AF

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ACCEPTED MANUSCRIPT may be considered a clinical manifestation in the context of CV risk profile, as a result of subclinical mild inflammation due to an increase of oxidative stress and neurohormonal

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activation [32]. These evidences have important pathophysiological implications because AF

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may be considered not only as a disturbance of cardiac rhythm, but also as the consequence of subclinical inflammatory atrium damage inducing both anatomical and functional alterations.

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A second novelty of our study is that the presence of COPD has a greater impact on AF onset in patients with CHA2DS2VASc <2, thus bringing out the evidence of a competitive

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interaction between COPD and all clinical components of CHA2DS2VASc score. Particularly, the presence of COPD increases the HR for incident AF more than eight times in patients with CHA2DS2VASc score <2, while the coexistence of a CHA2DS2VASc score >2 minimizes the prognostic significance of COPD (Figure 1, upper panel). It is plausible that in patients with a

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CHA2DS2-VASc score <2 the alterations of the right atrium predominates over left atrium

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ones, due to the increase in pulmonary pression. Since a lower CHA2DS2 VASc score identifies patients with a lower involvement of the left atrium, this could be a possible

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explanation of our finding. Of interest, similar results were observed for CHA2DS2VASc

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score >2 in patients without and with COPD (Figure 1, bottom panel). These results were reinforced by the results obtained by multiple Cox regression analysis of the mutual and inverse effect modification that remained significant also after data adjustment for all potential confounders (Table 3). Of interest, in the patients with CHA2DS2VASc score <2, COPD explains an excess risk about five times for incident AF. These findings have a hard clinical impact since it may allow to reclassify patients considered at low risk for AF on the basis of CHA2DS2-VASc score. The results of the present study allow to extend previous knowledge about the pathogenetic mechanisms underlying the appearance of AF and to focus on the relevant role of COPD in promoting this cardiac arrhythmia. On the basis of our and other [33] results, it is

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ACCEPTED MANUSCRIPT possible to hypothesize a direct involvement of right-sided cardiac chambers in the appearance of new AF, even if there are also few studies demonstrating structural and

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electrophysiological modifications of left-cardiac chambers in patients with COPD [33-35].

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Obviously, all these considerations remain speculative, requiring further animal and human demonstrations. In addition, the subclinical systemic inflammation is emerged as another

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possible pathogenetic mechanism in incident AF because increasing evidences indicate that levels of systemic markers of inflammation are associated with incident AF [36-38].

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According with this, in our population we observed significantly higher values of hs-CRP in COPD patients versus those without COPD, and in patients with CHA2DS2VASc score >2 versus those with CHA2DS2VASc score <2, even if this parameter was not retained as independent predictor in the Cox analysis. This is not surprising because our study population

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is characterized by a very high CV risk with a concomitant systemic inflammatory burden that

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Conclusions

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thus not confer a biological difference between groups.

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In conclusions, our data provide further insight into the pathogenetic mechanisms involved in the appearance of AF and in the CV morbidity and mortality in patients with COPD. Obviously, further studies are needed to both clarify the underlying pathogenetic mechanisms and to identify the most appropriate therapeutic strategy to reduce the excess of mortality in this setting of patients. Study limitations The most important limitation of this study is that we applied the CHA2DS2-VASc score –developed to assess the risk of mortality and thromboembolic events in AF patients- to stratify a cohort of high-CV risk patients. This score excludes several important AF risk

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ACCEPTED MANUSCRIPT factors, such as smoking and height, both associated with lung volumes. These factors should

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be taken into consideration in further studies.

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ACCEPTED MANUSCRIPT 26. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart

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Study. JAMA 1994; 271(11):840-844.

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27. Goudis CA. Chronic obstructive pulmonary disease and atrial fibrillation: An unknown relationship. J Cardiol 2017 Feb 7. pii: S0914-5087(17)30016-3.

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28. Roh SY, Choi JI, Lee JY, et al. Catheter ablation of atrial fibrillation in patients with chronic lung disease. Circ Arrhythm Electrophysiol 2011; 4(6):815-822.

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29. Sciacqua A, Perticone M, Tripepi G, et al. Renal disease and left atrial remodeling predict atrial fibrillation in patients with cardiovascular risk factors. Int J Cardiol 2014; 175(1):90-95.

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30. Zuo K, Sun L, Yang X, Lyu X, Li K. Correlation between cardiac rhythm, left atrial appendage flow velocity, and CHA2 DS2 -VASc score: Study based on transesophageal

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echocardiography and 2-dimensional speckle tracking [published online January 11, 2017]. Clin Cardiol [E-pus ahead of print]; http://dx.doi.org/10.1002/clc.22639.

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31. Baturova MA, Lindgren A, Carlson J, Shubik YV, Olsson SB, Platonov PG. Predictors of

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new onset atrial fibrillation during 10-year follow-up after first-ever ischemic stroke. Int J Cardiol. 2015; 199:248-252. 32. Violi F, Lip GY, Basili S. Peripheral artery disease and atrial fibrillation: a potentially dangerous combination. Intern Emerg Med 2012; 7(3):213-218. 33. Li J, Agarwal SK, Alonso A, et al. Airflow obstruction, lung function, and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2014; 129(9):971-980. 34. Smith BM, Kawut SM, Bluemke DA, et al. Pulmonary hyperinflation and left ventricular mass: the Multi-Ethnic Study of Atherosclerosis COPD Study. Circulation 2013; 127(14):1503–1511.

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ACCEPTED MANUSCRIPT 35. Smith BM, Prince MR, Hoffman EA, et al. Impaired left ventricular filling in COPD and emphysema: is it the heart or the lungs? The Multi-Ethnic Study of Atherosclerosis

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COPD Study. Chest 2013; 144(4):1143–1151.

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36. Rienstra M, Sun JX, Magnani JW, et al. White blood cell count and risk of incident atrial fibrillation (from the Framingham Heart Study). Am J Cardiol 2012;109(4):533–537.

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37. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003; 108(24):3006–3010.

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38. Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol

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2012; 60:2263-70.

Figure legends

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ACCEPTED MANUSCRIPT Figure 1. Kaplan-Meier survival estimates according to CHA2DS2-VASc score <2 vs CHA2DS2-VASc score >2 (upper panel) and to COPD- vs COPD+ status (bottom

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panel).

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The hazard ratio of atrial fibrillation (AF) associated to chronic obstructive pulmonary disease (COPD) was significantly higher (HR=8.45, 95% CI=5.20-13.74) in patients with CHA2DS2-

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VASc score <2 than in those with CHA2DS2-VASc score > 2 (upper panel). Similarly, the excess risk of AF associated to CHA2DS2-VASc score was significantly higher (HR=7.94,

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95% CI=5.54-13.37) in patients without COPD than in those with COPD (HR=1.42, 95%

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CI=0.96-2.11) (bottom panel).

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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of the study population according to CHA2DS2-VASc score and presence of COPD CHA2DS2-VASc <2

CHA2DS2-VASc >2

COPD (-)

COPD (+)

n=4322

n=1452

n=2870

3787

535

Gender, M/F

2270/2052

1146/306

1124/1746

<0.0001

1874/1913

396/139

<0.0001

Age, yrs

59.2+11.7

51.8+8.8

62.9+11.2

<0.0001

58.5+11.3

64.2+13.1

<0.0001

Body Mass Index, Kg/m2

29.1+5.0

28.8+4.6

29.5+5.1

<0.0001

29.3+4.9

29.5+5.7

0.336

Smoking, n (%)

1722 (39.8)

650 (44.8)

909 (31.7)

<0.0001

1208 (31.9)

351 (65.6)

<0.0001

Systolic Blood Pressure, mmHg

140.2+18.2

134.3+17.9

143.2+17.5

<0.0001

140.2+18.1

140.4+18.6

0.851

Diastolic Blood Pressure, mmHg

83.9+11.2

83.8+11.5

83.9+10.9

0.652

84.2+11.1

81.9+10.6

<0.0001

Pulse pressure, mm/Hg

56.3+15.2

50.5+12.4

59.3+15.7

<0.0001

56.1+15.1

58.4+16.6

0.002

Total cholesterol, mg/dl

201.1+37.3

202.8+36.4

200.2+37.8

0.032

201.8+37.3

196.2+37.3

0.001

LDL-cholesterol, mg/dl

125.5+34.7

128.6+32.9

123.9+35.5

<0.0001

126.1+34.5

121.4+36.3

0.004

HDL-cholesterol, mg/dl

48.7+13.0

47.3+12.4

49.5+13.2

<0.0001

48.9+13.1

47.4+12.3

0.012

Triglyceride, mg/dl

133.6+69.1

133.8+73.1

133.5+67.1

0.916

132.5+67.1

141.1+81.8

0.007

Fasting glucose, mg/dl

111.2+42.5

96.9+17.7

118.5+49.1

<0.0001

109.4+40.6

124.4+52.4

<0.0001

3.7+2.6

3.6+2.7

3.9+2.5

0.010

3.6+2.5

4.6+2.8

<0.0001

e-GFR, ml/min/1.73m2

93.1+31.1

104.8+28.9

87.2+30.5

<0.0001

94.5+31.4

83.7+27.1

<0.0001

CHA2DS2-VASc score >2, n(%)

2870(66.4)

-

-

-

2488 (65.7)

382 (71.4)

0.009

COPD, n(%)

535(12.4)

153 (10.5)

382 (13.3)

0.009

-

-

-

hs-CRP, mg/L

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All

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Variables

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hs-CRP= high sensitiviy C reactive protein; e-GFR= estimated- glomerular filtration rate; COPD= chronic obstructive pulmonary disease; AF= atrial fibrillation.

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ACCEPTED MANUSCRIPT Table 2. Cox regression analyses Dependent variable: AF

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Cox Model based on main effects of CHA2DS2-VASc and COPD HR, 95% CI and P values

CHA2DS2-VASc (0=<2; 1>2)

1.98 (1.48-2.65), P<0.001

COPD (0=no; 1=yes)

1.25 (1.02-1.52), P=0.028

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Variables (units of increase)

1.72 (1.58-1.88), P<0.001

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Age (10 years) Male gender BMI (1 kg/m2) Pulse Pressure (10 mmHg)

1.05 (1.04-1.07), P<0.001 0.99 (0.94-1.04), P=0.57 0.87 (0.84-0.90), P<0.001

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e-GFR (10 ml/min/1.73 m2)

1.23 (1.04-1.46), P=0.016

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Table 3. Multiple Cox Regression Analysis of the mutual effect modification of CHA2DS2-

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VASc and COPD for explaining the incidence rate of atrial fibrillation in the study cohort.

*HRs,

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Effect modification of COPD on the relationship between CHA2DS2-VASc and atrial fibrillation

95% CI and P

(CHA2DS2-VASc >2 vs <2)

Without COPD

With COPD

P for effect modification

3.40 (2.31-5.00)

0.70 (0.46-1.07)

P<0.001

P=0.10

<0.001

Effect modification of CHA2DS2-VASc on the relationship between COPD and atrial fibrillation

CHA2DS2-VASc <2

CHA2DS2-VASc >2

P for effect modification

*HRs,

95% CI and P

(COPD+ vs COPD-)

4.82 (2.93-7.93)

1.00 (0.80-1.25)

P<0.001

P=0.98

<0.001

*Adjusted for CHA2DS2-VASc and COPD as well as for age, gender, BMI, Pulse pressure and e-GFR.

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