Chronic Obstructive Pulmonary Disease and Risk of Sudden Cardiac Death

JACC: CLINICAL ELECTROPHYSIOLOGY

VOL. 1, NO. 5, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2405-500X/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacep.2015.06.005

Chronic Obstructive Pulmonary Disease and Risk of Sudden Cardiac Death Kumar Narayanan, MD,* Kyndaron Reinier, PHD,* Audrey Uy-Evanado, MD,* Carmen Teodorescu, MD, PHD,* Lin Zhang, MD,* Harpriya Chugh, BS,* Gregory A. Nichols, PHD,y Karen Gunson, MD,z Jonathan Jui, MD, MPH,x Sumeet S. Chugh, MD*

ABSTRACT OBJECTIVES The purpose of this study was to determine whether chronic obstructive pulmonary disease (COPD) is associated with sudden cardiac death (SCD) in the community. BACKGROUND COPD is linked to cardiovascular mortality; an association with SCD has not been systematically investigated in the general population. METHODS In the Oregon Sudden Unexpected Death Study (approximately 1 million population), adult SCD case subjects were compared with geographic control subjects with coronary artery disease. Detailed clinical and electrocardiographic risk marker information was obtained from medical records. The association of COPD with SCD in the overall population and in a propensity score–matched dataset was assessed with logistic models. RESULTS SCD case subjects (n ¼ 728; age 69.9  13.7 years) were more likely than control subjects (n ¼ 548; age 67.2  11.3 years) to have left ventricular ejection fraction #35% (27.5% vs. 12.0%; p < 0.0001), COPD (30.8% vs. 12.8%, p < 0.0001), diabetes mellitus (47.7% vs. 31.8%; p < 0.0001), use short-acting beta-2 agonist agents (SBAs) (22.3% vs. 12.6%; p < 0.0001), and less likely to use beta-blockers (60.6% vs. 66.4%; p ¼ 0.03). In multivariable analysis, COPD was significantly associated with SCD (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.4 to 3.5; p < 0.001). There was no significant interaction between COPD and medications, but an interaction was identified between SBAs and beta-blockers (p ¼ 0.04); SBAs were strongly associated with SCD in subjects not taking beta-blockers (OR: 3.3; 95% CI: 1.4 to 7.7; p ¼ 0.005) but not in those taking beta-blockers (OR: 1.3; 95% CI: 0.7 to 2.3; p ¼ 0.39). The COPD-SCD association was maintained in a propensity score–matched analysis. CONCLUSIONS COPD is associated with SCD risk in the community independent of medications, electrocardiographic risk markers, and left ventricular ejection fraction. Among other mechanisms, pro-arrhythmogenic right ventricular remodeling and systemic inflammation warrant further investigation. (J Am Coll Cardiol EP 2015;1:381–7) © 2015 by the American College of Cardiology Foundation.

C

hronic

disease

sizeable proportion of morbidity and mortality in

(COPD) is a major health problem that glob-

obstructive

pulmonary

the COPD population (4), and studies have reported

ally contributes to substantial morbidity

that COPD is an independent risk factor for cardiovas-

and mortality (1). As a chronic condition, is associated

cular mortality (5,6). Indeed, it has been suggested

with a large number of hospitalizations (2) and im-

that the burden imposed by cardiovascular pathology

poses a major financial burden on the health care sys-

in COPD patients may in fact be greater than that

tem (3). Cardiovascular disease accounts for a

directly related to COPD itself (4). The absolute value

Listen to this manuscript’s audio summary by JACC: Clinical Electrophysiology

From *The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California; yCenter for Health Research, Kaiser Permanente,

Editor-in-Chief

Portland, Oregon; zDepartment of Pathology, Oregon Health and Science University, Portland, Oregon; and the xDepartment of

Dr. David J. Wilber.

Emergency Medicine, Oregon Health and Science University, Portland, Oregon. This study was funded in part by National Heart, Lung, and Blood Institute grants R01HL105170 and R01HL122492 to Dr. Chugh. Dr. Nichols has received grant funding from Merck, Novartis, Boehringer-Ingelheim, and AstraZeneca. Dr. Chugh holds the Pauline and Harold Price Chair in Cardiac Electrophysiology Research at the Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received May 19, 2015; accepted June 17, 2015.

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COPD and Sudden Death

ABBREVIATIONS

(6) and the rate of decline (7) of the forced

is defined as a sudden, pulseless collapse of a likely

AND ACRONYMS

expiratory volume in the first second has

cardiac cause, occurring rapidly after symptom onset

been linked to risk of coronary artery disease

when witnessed or within 24 h of the subject being last

(CAD).

seen in the usual state of health if unwitnessed. Cases

CAD = coronary artery disease CI = confidence interval COPD = chronic obstructive pulmonary disease

ECG = electrocardiogram EMS = emergency medical services

ICD = implantable cardioverter-defibrillator

LVEF = left ventricular ejection

Of all manifestations of cardiovascular

of trauma, drowning, drug abuse, known terminal

disease, sudden cardiac death (SCD) is the

illness, or malignancy not in remission and extrac-

most lethal, with <10% survival on average

ardiac causes (such as pulmonary embolism) are

(8). Whether COPD is linked to SCD is

excluded. In parallel, control subjects with known

important both from a mechanistic risk

CAD are recruited from the same geographic area.

perspective and from the point of view of

Since the majority of SCD cases are found to have sig-

primary prevention of SCD, since COPD

nificant CAD (13), the control group enables the iden-

is often encountered as a comorbidity. Al-

tification of risk markers that are specific to SCD. The

fraction

though some studies have suggested that

control consists of subjects transported by the region’s

MI = myocardial infarction

COPD may be a risk factor for SCD (9), robust

EMS for symptoms of acute coronary ischemia, those

OR = odds ratio

population-based data are scarce. It is also

undergoing angiography at one of the participating

important to consider this question in the

hospitals, patients with CAD seen in a clinic, or mem-

context of associated medications such as

bers of a health maintenance organization who have

short-acting beta-2 agonists (SBAs) that may

CAD. CAD is defined as at least 50% stenosis in a cor-

be independently proarrhythmic (10). Fur-

onary artery, history of myocardial infarction (MI),

thermore, because

in-

or coronary revascularization. The present study was

creases with age, cardiovascular risk factors

a community-based case-control analysis. Adult SCD

and CAD often coexist, and these need to be

case subjects (2002 to 2013) who had physician records

accounted for as well. One of the difficulties in

and pre-arrest left ventricular ejection fraction (LVEF)

studying SCD in the community is that pre-arrest

information available were compared with CAD con-

clinical details are often sparse, and information is

trol subjects from the same geographic region over the

mostly limited to that gathered by emergency medical

same time period. No further specific matching was

services (EMS). Through the Oregon Sudden Unex-

performed between case and control subjects.

OSA = obstructive sleep apnea QTc = corrected QT interval RV = right ventricle SBA = short-acting beta-2 agonist

SCD = sudden cardiac death

COPD

prevalence

pected Death Study (Oregon-SUDS), a prospective, population-based study of SCD in the Portland, Oregon, metropolitan area, we have established a mechanism to

systematically obtain

lifetime

clinical

history for all SCD victims. We therefore performed a comprehensive evaluation of the association between COPD and SCD in the community.

COPD AND OTHER CLINICAL INFORMATION. Detailed

demographic information and a lifetime clinical history for all case subjects were obtained from medical records (prior and unrelated to the SCD event). COPD was defined as a documented physician diagnosis of COPD in the medical records. Patients using home oxygen were excluded on the basis of the a priori definition of SCD for this study. Infor-

SEE PAGE 388

mation on medications, including SBAs, long-acting beta-2 agonists, and beta blocker use, was obtained

METHODS STUDY

POPULATION. The

from physician records. The LVEF was obtained from Oregon-SUDS

is

an

ongoing, community-based study of SCD using prospective multiple-source case ascertainment. Detailed methods have been published previously (11,12). Briefly, cases of out-of-hospital-cardiac arrest are ascertained from the Portland metropolitan area (catchment population of approximately 1 million) by

the echocardiogram, left ventricular angiogram, or multigated acquisition scan performed closest but unrelated to the SCD event. Similarly, electrocardiographic (ECG) parameters, including the corrected QT interval (QTc, by the Bazett formula) and heart rate, were measured from archived ECGs closest and unrelated to SCD.

use of multiple sources, namely, first responders

STATISTICAL

(Portland fire department and local ambulance ser-

pressed as number and percentage) were compared

ANALYSIS. Categorical

variables

(ex-

vice), the county medical examiner’s office, and the

with the chi-square or Fisher exact test, and contin-

emergency departments of participating local hospi-

uous variables (expressed as mean and standard de-

tals. Detailed information on circumstances, clinical

viation) were compared with the Student t test or

history, and autopsy data (where available) is gath-

Mann-Whitney U test. Odds ratios (ORs) for the as-

ered, and SCD cases of cardiac pathogenesis are iden-

sociation of COPD and SBA use with SCD were ob-

tified through a 3-physician adjudication process. SCD

tained by use of multivariable logistic regression,

Narayanan et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 5, 2015 OCTOBER 2015:381–7

with adjustment for LVEF and clinical and ECG markers significant in univariate analysis. We as-

T A B L E 1 Demographic and Clinical Characteristics of Cases and Control Subjects

sessed for possible interaction between COPD and medications (SBA, beta-blocker use), as well as between SBA and beta-blockers. Stratified analysis was

383

COPD and Sudden Death

Age, yrs

Case Subjects (n ¼ 728)

Control Subjects (n ¼ 548)

p Value

69.9  13.7

67.2  11.3

<0.0001

Male

475 (65.2)

359 (66.4)

0.68

performed in case significant interaction was detec-

BMI, kg/m2

30.5  9.3

29.8  6.5

0.12

ted. A logistic model with a dummy variable for COPD

Smoking status 389 (68.8)

283 (71.5)

and SBA use was employed to evaluate the potential

Current/former smoker

183 (31.3)

118 (28.3)

We further performed sensitivity analysis using pro-

Diabetes mellitus

347 (47.7)

174 (31.8)

pensity score matching. The propensity matching

Hypertension

576 (79.1)

419 (76.6)

0.28

168.0  45.0

171.0  51.5

0.36

224 (30.8)

70 (12.8)

<0.0001

71 (9.8)

50 (9.1)

additive risk of presence of both COPD and SBA use.

was performed with PROC LOGISTIC (SAS version

Nonsmoker

0.38

Cholesterol, mg/dl COPD

<0.0001

9.3 SAS Institute, Cary, North Carolina) and a macro

Asthma

for 1-to-1 case-control propensity score matching,

Obstructive sleep apnea

105 (14.4)

69 (12.6)

according to methods described by Parsons (14).

Short-acting beta-2 agonist

162 (22.3)

69 (12.6)

<0.0001

First, we calculated each subject’s propensity score

Long-acting beta-2 agonist

44 (6.0)

20 (3.6)

0.052

in a logistic regression model with COPD as the

Beta blockers

441 (60.6)

364 (66.4)

0.03

outcome variable, using the following covariates: age,

ACEI

362 (49.7)

271 (49.5)

0.92

sex, smoking status, diabetes mellitus, hypertension, LVEF, and medications, including angiotensin-

ARB Statin

0.71 0.35

67 (9.2)

72 (13.1)

0.03

353 (48.5)

369 (67.3)

<0.0001

78.5  18.8

70.0  16.8

<0.0001

QTc, ms

463.3  45.3

434.5  36.4

<0.0001

blockers, beta-blockers, and SBAs. On the basis of the

LVEF, %

48.3  16.6

54.9  13.3

<0.0001

predicted probability of COPD (propensity score) from

LVEF #35%

200 (27.5)

66 (12.0)

<0.0001

converting enzyme inhibitors, angiotensin receptor

Heart rate, beats/min

the logistic regression model, case subjects were then matched to control subjects with the closest propensity score by use of nearest-neighbor matching using a 2-digit match to achieve matching while preserving sample size (i.e., subjects were matched if both the case and control subject had propensity

Values are mean  SD or n (%). BMI information available for 632 case subjects and 528 control subjects. Smoking status available for 565 case subjects and 396 control subjects. Cholesterol information available for 417 case subjects and 437 control subjects. Heart rate measurement available for 523 case subjects and 529 control subjects. QTc measurement available for 458 case subjects and 518 control subjects. ACEI ¼ angiotensin-converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; BMI ¼ body mass index; COPD ¼ chronic obstructive pulmonary disease; LVEF ¼ left ventricular ejection fraction; QTc ¼ corrected QT interval.

scores that were identical in the first significant digit [the tenths], with the hundredths allowed to range from 0.01 to 0.09 for a matched pair), which resulted in a dataset with 330 case and control subjects each. We also performed additional sensitivity analysis with stronger matching (3-digit matching, with propensity score tenths and hundredths required to be identical); the resultant dataset had 418 patients (209 case and control subjects respectively). The association of COPD with SCD in the propensity score– matched dataset was analyzed by binary logistic regression. A 2-tailed p value of #0.05 was considered significant. Analyses were performed with SPSS software version 21.0 (IBM Corporation Inc., Armonk, New York) and SAS software version 9.3 (SAS Institute

with similar sex distribution. Case and control subjects did not differ significantly with respect to mean body mass index, hypertension, mean cholesterol level, presence of obstructive sleep apnea (OSA), or smoking status. Case subjects were significantly more likely than control subjects to have diabetes mellitus (47.7% vs. 31.8%; p < 0.0001), LVEF #35% (27.5% vs. 12.0%; p < 0.0001), higher heart rate (78.5  18.8 beats/min vs. 70.0  16.8 beats/min; p < 0.0001), and higher QTc (463.3  45.3 ms vs. 434.5  36.4 ms; p < 0.0001). Implantable cardioverter-defibrillators (ICDs) were present only in a minority of SCD case subjects (3.6%) and control subjects (0.5%). COPD AND MEDICATIONS. COPD was significantly

Inc.).

more prevalent in case subjects than in control sub-

RESULTS

jects (30.8% vs. 12.8%; p < 0.0001) (Figure 1). The prevalence of asthma was not significantly different CHARACTERISTICS. Initial analysis was

(9.8% vs. 9.1%; p ¼ 0. 71). Case subjects were signif-

performed in 728 SCD case subjects and 548 control

icantly more likely to be taking SBAs (22.3% vs. 12.6%;

SUBJECT

subjects with CAD. Clinical and demographic charac-

p < 0.0001) (Figure 1) and were less likely to be taking

teristics of case and control subjects are outlined in

beta-blockers (60.6% vs. 66.4%; p ¼ 0.03). Only

Table 1. Case subjects were older than control subjects

a small percentage of case and control subjects

(age 69.9  13.7 years vs. 67.2  11.3 years; p < 0.0001),

were taking long-acting beta-2 agonists, which was

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COPD and Sudden Death

F I G U R E 1 Prevalence of COPD and SBA Use Among Cases and

Control Subjects

beta-blocker use (p ¼ 0.59). However, significant interaction was noted between SBAs and beta-blockers (p ¼ 0.04). Hence, subjects were stratified by betablocker status to assess the association between SBA use and SCD, by use of similar logistic models as before. A strong association was observed between SBA use and SCD status among subjects not taking beta-blockers (OR: 2.6 [95% CI: 1.3 to 5.2], p ¼ 0.006 for model 1; OR: 3.3 [95% CI: 1.4 to 7.7], p ¼ 0.005 for model 2), even after adjustment for COPD and other risk factors. However, such an association was not present among subjects taking beta-blockers (OR: 0.9 [95% CI: 0.6 to 1.4], p ¼ 0.72 for model 1; OR: 1.3 [95% CI: 0.7 to 2.3], p ¼ 0.39 for model 2). When patients with SBA use not taking beta-blockers were compared with those taking both SBA and beta-blockers, most

COPD ¼ chronic obstructive pulmonary disease; SBA ¼ shortacting beta-2 agonist.

cardiac risk factors were noted to be similar between the 2 groups, and the main difference was a significantly higher heart rate in the SBA-only group (85.7  20.6 beats/min vs. 75.8  15.0 beats/min; p < 0.0001).

again more likely to be seen in case subjects, with

In a logistic regression model that used dummy vari-

borderline significance (6.0% vs. 3.6%; p ¼ 0.052).

ables and adjustment for all other risk factors, pres-

All subjects taking beta-2 agonists were prescribed

ence of both COPD and SBA use was associated with

the medication in the inhaled form; no subject

higher odds for SCD (OR: 3.4; 95% CI: 2.0 to 5.7; p <

was taking oral beta-2 agonists. Case subjects were

0.001) than COPD alone (Figure 2).

also less likely to be on angiotensin receptor blockers (9.2% vs. 13.1%; p ¼ 0.03) and statins (48.5% vs. 67.3%;

p

<

0.0001);

however

the

proportion

taking angiotensin-converting enzyme inhibitors was similar.

COPD AND OSA. There was no evidence of significant

interaction between COPD and OSA (p ¼ 0.81). Also, presence of both COPD and OSA did not further increase the OR for SCD compared with presence of COPD alone (OR: 2.6 vs. 2.5, respectively).

COPD AND USE OF SBAs: EFFECTS ON SCD RISK. Table 2

shows the results of the multivariable logistic regression models. Model 1 was adjusted for age, diabetes mellitus, LVEF, and medications (including SBA use), whereas model 2 was adjusted for smoking and ECG markers in addition to the variables adjusted for in

EFFECT OF COPD ON SCD RISK EVALUATED BY PROPENSITY SCORE–MATCHED ANALYSIS. Analysis

was performed as described with a propensity score– matched dataset (330 case and control subjects each). COPD remained significantly associated with SCD in

model 1. COPD was significantly associated with SCD in both models (model 1 OR: 2.6 [95% confidence interval

F I G U R E 2 Odds Ratios for SCD With COPD Only Versus Both

(CI): 1.8 to 3.7]; model 2 OR: 2.2 [95% CI: 1.4 to 3.5]; both

COPD and SBA Use

p < 0.0001). No significant interaction was observed between COPD and either SBA use (p ¼ 0.19) or

T A B L E 2 Adjusted ORs for SCD

Model 1*

Model 2*

OR (95% CI)

p Value

OR (95% CI)

COPD

2.6 (1.8–3.7)

<0.0001

2.2 (1.4–3.5)

p Value

0.001

LVEF #35%

2.8 (2.0–3.8)

<0.0001

2.5 (1.5–3.5)

<0.0001

Diabetes mellitus

2.4 (1.8–3.1)

<0.0001

2.4 (1.7–3.4)

<0.0001

*Model 1 adjusted for age and use of beta blocker, short-acting beta-2 agonist, angiotensin receptor blocker, and statin (n ¼ 1,276). Model 2 adjusted for model 1 plus smoking status, heart rate, and corrected QT interval (n ¼ 740). CI ¼ confidence interval; COPD ¼ chronic obstructive pulmonary disease; LVEF ¼ left ventricular ejection fraction; SCD ¼ sudden cardiac death.

COPD ¼ chronic obstructive pulmonary disease; OR ¼ odds ratio; SBA ¼ short-acting beta-2 agonist; SCD ¼ sudden cardiac death.

Narayanan et al.

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COPD and Sudden Death

the propensity score–matched dataset (OR: 3.9; 95%

database. The study concluded that COPD was linked

CI: 2.2 to 6.7; p < 0.0001). When the propensity match

to higher SCD risk, and this was highest in those also

criteria were made stronger (3-digit matching, with

taking SBAs (9). However, that study relied on drug

propensity score tenths and hundredths required to

information to ascertain the presence of COPD and

be identical), the COPD-SCD association remained

other risk factors, unlike the present study in which

similar (OR: 3.2; 95% CI: 1.6 to 6.3).

physician researchers obtained information directly from medical records. Other studies have suggested

DISCUSSION

that COPD contributes independently to cardiovascular mortality and potentially to SCD. In the UPLIFT

In this population-based study, COPD was found to

(Understanding the Potential Long-term Impacts

be significantly associated with SCD after adjustment

on Function With Tiotropium) COPD trial, SCD con-

for LVEF and other cardiovascular risk factors. COPD

stituted 4.4% of all COPD deaths (16). VALIANT

and SBA were also each independently associated

(Valsartan in Acute Myocardial Infarction Trial)

with SCD, which suggests that the COPD-SCD risk

among patients with acute MI showed that COPD was

was unrelated to SBA use. Furthermore, the pres-

associated with higher risk of sudden death but not

ence of both COPD and SBA use had a higher OR for

MI or stroke (17). OSA has been reported to be a risk

SCD than COPD alone. Although no interaction was

factor for SCD, and it has been suggested that the

seen between COPD and use of SBAs or beta-

presence of both OSA and COPD may result in even

blocking

was

higher cardiovascular risk (18,19). In the present

observed between beta-blockers and SBAs, with

study, we did not find evidence of a significant

beta-blockers appearing to reduce SBA-related SCD

interaction between OSA and COPD; this needs

risk, likely by blunting the sympathetic activity

further focused evaluation in larger analyses.

drugs,

a

significant

interaction

caused by SBAs. This premise is supported by the

It could be argued that COPD may merely be a

fact that compared with patients taking both SBA

coexisting condition or a “marker” for the type of

and beta-blockers, patients taking SBAs only had a

person likely to have cardiac disease as well; how-

significantly higher resting heart rate but had no

ever, growing evidence suggests that there may be a

differences in the frequency of other risk factors.

true link. The exact mechanism underlying the COPD-

There was a borderline-significant association seen

SCD

between long-acting beta-agonists and SCD; howev-

several possibilities can be advanced. Abnormalities

er, only a small proportion of cases overall were

of cardiac repolarization including increased QTc and

taking long-acting beta-2 agonists. Because COPD

QT dispersion have been identified in COPD patients

often coexists with other comorbidities, we per-

and shown to be related to SCD (20,21), although in

formed a sensitivity analysis after propensity score

the present study, the COPD-SCD association was in-

matching based on COPD status. The COPD-SCD as-

dependent of QTc. A direct relation between hypox-

sociation was maintained in the results of the

emia and ventricular irritability has been suggested

propensity-matched dataset. Furthermore, severely

(22) but is likely to be operative only in a small sub-

ill patients on home oxygen therapy were excluded

set of severe cases. However, the increased work of

in our study. Taken together, these results indicate

breathing in COPD and resultant increased oxygen

that COPD was associated with SCD risk independent

demand (23) are additional stressors for a person with

of clinical/ECG risk markers and medications, which

heart disease and therefore potential contributors to

also suggests that COPD may exert deleterious ef-

risk. Another area of increasing focus has been the

fects on the heart via other mechanisms.

relationship

remains

speculative;

however,

inflammation that accompanies COPD (24). Con-

Lahousse et al. (15) recently reported an increased

sidering the proximity of the lungs to the heart, in-

SCD risk in patients with COPD in the Rotterdam

flammatory mediators generated in the lung can

study, with an OR of 1.34. They found this risk to be

potentially have adverse consequences for the heart.

higher in the early years after COPD diagnosis, as well

A milieu of chronic inflammation could aid progres-

as in those with frequent exacerbations. Similar to

sion of atherosclerosis and increase arterial stiffness

our study, they did not find a significant interaction

(25). COPD has been linked to greater coronary artery

between COPD and sympathomimetic drugs (15). The

calcium scores (26). Cytokines can recruit leukocytes,

other community-based study that directly addressed

contributing to inflammatory plaque rupture (27).

the question of whether COPD contributes to SCD risk

Inflammatory mediators can also predispose to

evaluated SCD cases from the ARREST (Amsterdam

hypercoagulability and coronary thrombosis (28).

Resuscitation Study) registry and compared these

Autonomic instability that leads to proarrhythmia

with non-SCD case subjects from a pharmacological

may play a role as well. Reduced heart rate

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COPD and Sudden Death

variability, which improved with a physical rehabili-

confounders with certainty. In community-based

tation program, has been demonstrated in COPD (29).

studies of this nature, it is challenging to obtain all

Finally, right ventricular (RV) remodeling may play a

aspects of data uniformly for all subjects. Thus, pre-

role in the proarrhythmic effects of COPD, because

cise data on measures that reflect overall status, such

pulmonary hypertension results in dilation, hyper-

as hospitalizations, were not available. We chose

trophy, and eventually, failure of the RV (30). Exer-

those subjects with LVEF information available for

cise, which can be a potential trigger for arrhythmia,

this analysis, and this could result in some bias;

also causes worsening pulmonary hypertension, with

however, it is important to account for ejection frac-

the potential to increase cardiac vulnerability in the

tion, which is the main marker presently used in risk

patient with COPD (31). RV failure can also lead to

stratification. Finally, our results would need to be

elevated levels of natriuretic peptides (32,33), which

confirmed in prospective studies and in other pop-

are known to be associated with increased risk of

ulations before they can be broadly applied.

ventricular arrhythmia (34). The

COPD-SCD

risk

association

is

especially

CONCLUSIONS

important in the context of primary prevention ICDs, since COPD may contribute to a greater comorbidity

In this population-based study, COPD was signifi-

burden, and ICD implantation may be less likely in

cantly associated with risk of SCD independent of the

such candidates (35). However, it has been demon-

LVEF, medications used, and clinical and ECG risk

strated that ICDs reduce mortality in patients with

markers. These results suggest that COPD may need

COPD (36), and the frequency of appropriate ICD

to be considered as a separate cardiovascular risk

shocks is actually higher than in non-COPD subjects

factor, and novel mechanisms of risk related to

(37). The findings of the current study suggest that

inflammation and RV remodeling need to be further

the COPD-SCD association would also need to be

explored.

considered in this decision-making process.

ACKNOWLEDGMENTS The authors acknowledge the

Finally, the interplay between COPD and associ-

important contribution of American Medical Res-

ated medications in the context of SCD risk remains of

ponse, Portland/Gresham fire departments, and the

considerable interest. Inhaled SBAs, which are often

Oregon State Medical Examiner’s office.

prescribed in COPD, may further increase risk of arrhythmia (38). Furthermore, studies of inhaled

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

beta-2 agonists in patients with asthma suggest that

Sumeet S. Chugh, The Heart Institute, Advanced Health

regular use, in contrast to use on an as-needed basis,

Sciences Pavilion Suite A3100, Cedars-Sinai Medical

is associated with worse control of asthma and an

Center, 127 S. San Vicente Boulevard, Los Angeles,

increase in mortality (39,40). On the other hand, beta-

California 90048. E-mail: [email protected].

blockers, which may reduce risk of arrhythmia, are often underprescribed in the COPD patient because of fear of worsening bronchospasm. It is noteworthy that a meta-analysis performed by Salpeter et al. (41) showed no worsening of lung function among COPD patients taking cardioselective beta-blockers. Especially for the COPD patient with concomitant heart disease, clinicians may need to consider minimizing SBA use and favor increased use of cardioselective

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: COPD is associated with SCD in the general population even after accounting for associated medications, ECG markers, and the left ventricular ejection fraction, which suggests the need to evaluate novel mecha-

beta-blockers.

nisms related to inflammation and right ventricular STUDY

LIMITATIONS. Population-based

design,

robust adjudication of SCD cases, and detailed lifetime clinical history for each subject are some of the strengths of the present study. We also chose control subjects with CAD so as to focus specifically on SCD risk beyond CAD. However, there are some limitations to consider. Although both multivariable models and propensity matching analyses were performed, owing to the observational nature of the study, we cannot exclude an influence of unmeasured

remodeling. TRANSLATIONAL OUTLOOK: Clinicians may need to consider COPD as a cardiovascular risk factor. Further prospective studies are needed to study the interplay between COPD, medications, and SCD risk, which may have implications for the use of shortacting beta-agonists and beta blockers in routine clinical practice among COPD patients.

Narayanan et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 5, 2015 OCTOBER 2015:381–7

COPD and Sudden Death

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KEY WORDS beta-2 agonist, COPD, sudden death

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