Nilsson et al.

Respiratory Research (2020) 21:162

https://doi.org/10.1186/s12931-020-01430-z

RESEARCH Open Access

Cardiac biomarkers of prognostic

importance in chronic obstructive
pulmonary disease
Ulf Nilsson1* , Nicholas L. Mills2,3, David A. McAllister4, Helena Backman5, Caroline Stridsman6, Linnea Hedman5,
Eva Rönmark5, Takeshi Fujisawa2, Anders Blomberg1 and Anne Lindberg1

Abstract
Ischemic heart disease is common in COPD and associated with worse prognosis. This study aimed to investigate
the presence and prognostic impact of biomarkers of myocardial injury and ischemia among individuals with COPD
and normal lung function, respectively.
Methods: In 2002–04, all individuals with airway obstruction (FEV1/VC < 0.70, n = 993) were identified from
population-based cohorts, together with age and sex-matched non-obstructive referents. At re-examination in 2005,
spirometry, Minnesota-coded ECG and analyses of high-sensitivity cardiac troponin I (hs-cTnI) were performed in
individuals with COPD (n = 601) and those with normal lung function (n = 755). Deaths were recorded until
December 31st, 2010.
Results: Hs-cTnI concentrations were above the risk stratification threshold of ≥5 ng/L in 31.1 and 24.9% of those
with COPD and normal lung function, respectively. Ischemic ECG abnormalities were present in 14.8 and 13.4%,
while 7.7 and 6.6% had both elevated hs-cTnI concentrations and ischemic ECG abnormalities. The 5-year
cumulative mortality was higher in those with COPD than those with normal lung function (13.6% vs. 7.7%, p <
0.001). Among individuals with COPD, elevated hs-cTnI both independently and in combination with ischemic ECG
abnormalities were associated with an increased risk for death (adjusted hazard ratio [HR]; 95% confidence interval
[CI] 2.72; 1.46–5.07 and 4.54; 2.25–9.13, respectively). Similar associations were observed also among individuals with
COPD without reported ischemic heart disease.
Conclusions: In this study, elevated hs-cTnI concentrations in combination with myocardial ischemia on the
electrocardiogram were associated with a more than four-fold increased risk for death in a population-based COPD-
cohort, independent of disease severity.
Keywords: COPD, Multimorbidity, Myocardial ischemia, Troponin, Electrocardiography, Mortality

* Correspondence: ulf.nilsson@umu.se
1
Department of Public Health and Clinical Medicine, Section of Medicine,
Umeå University Hospital, B41, 90185 Umeå, Sweden
Full list of author information is available at the end of the article

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Nilsson et al. Respiratory Research (2020) 21:162 Page 2 of 10

Background population in this study (n = 993) was identified after re-

Chronic Obstructive Pulmonary Disease (COPD) is a examination including spirometry of four previously re-
common but under-diagnosed disease [1, 2]. In COPD, cruited population-based cohorts in 2002–04 (n = 4200),
there is an increased risk for concomitant cardiovascular together with n = 993 non-obstructive referents matched
disease [3] and cardiovascular comorbidity is associated by age and sex. The study population has since 2005
with increased mortality [4]. Still, patients with COPD been invited to annual examinations. The original age
may be less likely to receive cardiovascular preventative and sex-matching at recruitment was not maintained
therapies [5], albeit most guidelines for diagnosis and during the annual follow-ups. This paper includes data
treatment of COPD [6] include recommendations re- from 2005, when complete data on 12-lead ECG and
garding evaluation of cardiovascular risk factors and the blood samples were collected from 1356 participants, in
presence of cardiovascular disease. However, no bio- addition to spirometry and structured interviews (n =
marker has been shown to identify subclinical cardiovas- 601 COPD, n = 755 with normal lung function). Mortal-
cular disease in a representative population-based cohort ity data from the Swedish Tax Agency were obtained
of individuals with COPD, even though ischemic abnor- from the date of examination until 31st December 2010
malities on electrocardiogram (ECG) are suggested to be and causes of death were collected from the Swedish
associated with worse prognosis [7]. National Board of Health and Welfare.
Cardiac troponins are specific markers of myocardial
injury and are used universally for the diagnosis of myo- Definitions
cardial infarction [8]. High-sensitivity cardiac troponin I Smoking habits and prevalence of comorbidities were
(hs-cTnI) assays have limits of detection 10 to 100-fold categorized based on interview data [7]. Blood samples
lower than contemporary assays and can detect troponin were stored at − 20 °C and were thawed and analysed in
in the majority of healthy individuals [9]. Hence, these 2017. Analyses were performed with the ARCHITECT
assays may identify patients with subclinical cardiac dis- STAT high-sensitivity cardiac troponin I (hs-cTnI) assay
ease [10], using risk stratification thresholds well below (Abbott Laboratories, Abbott Park, IL) at the BHF Bio-
those used to diagnose myocardial infarction [11, 12]. marker Lab in the University of Edinburgh, with a lower
Recently published data suggest that a risk stratification limit of detection of 1.2 ng/L, an upper reference limit of
threshold of < 5 ng/L can identify patients with chest 34 ng/L in men and 16 ng/L in women and a coefficient
pain at low risk of having cardiac events [11] and, fur- of variation < 10% at 4.7 ng/L [12].
ther, is able stratify patients with stable COPD and con- Standard 12-lead ECGs were recorded and classified ac-
comitant cardiovascular risk factors into low and high- cording to the Minnesota code [18] by two independent
risk groups [13]. Increased troponin levels are also asso- encoders. Myocardial ischemic abnormalities defined by
ciated with poor prognosis in patients with acute exacer- Minnesota coding were grouped together [7], hereafter re-
bations of COPD [14, 15]. One recent study, including ferred to as “ischemic ECG abnormalities” (I-ECG).
stable patients with mainly moderate and severe COPD, Individuals with COPD and normal lung function were
also showed a correlation between hs-cTnI ≥6 ng/L and categorized, with respect to the cardiac biomarkers, into
poor prognosis [16]. However, this has rarely been evalu- the following groups: no cardiac biomarkers (hs-cTnI <
ated in population-based COPD-studies. Based on these 5 ng/L and no ischemic ECG abnormalities), hs-cTnI >
observations, we hypothesise that hs-cTnI concentra- 5 ng/L alone, ischemic ECG abnormalities alone, and
tions reflect subclinical heart disease and may help to both hs-cTnI > 5 ng/L and ischemic ECG abnormalities
guide prognosis among individuals with COPD in the (Fig. 1 a-b).
population. If this hypothesis is confirmed, hs-cTnI test- The fixed ratio criterion was used to define airway ob-
ing could be used more widely to identify individuals struction corresponding to COPD. The spirometry in-
with COPD at increased risk. cluded measurement of FEV1 (forced expiratory volume
The aim of this study was to evaluate hs-cTnI concen- 1 s), FVC (forced vital capacity) and SVC (slow vital cap-
trations among individuals with COPD and individuals acity) and was conducted according to the 1994 ATS
with normal lung function to determine the prognostic guidelines [19]. The highest of FVC and SVC was used
value of hs-cTnI. A secondary aim was to include ische- to define VC (vital capacity). If FEV1/VC was < 0.70 or
mic ECG abnormalities in the risk assessment. FEV1 < 80% of predicted, post-bronchodilator spirometry
was performed after the inhalation of Ventoline discus®
Methods 4 × 0.2 mg. COPD was spirometrically defined as FEV1/
Study design and study population VC < 0.70 using the highest values extracted from all of
The study design of the Obstructive Lung Disease in the acceptable spirometry curves for each of the parame-
Northern Sweden (OLIN) COPD study has previously ters [20, 21]. FEV1 reversibility was not assessed or a
been described in detail [7, 17]. In summary, the COPD part of the estimation of airway obstruction, however,
Nilsson et al. Respiratory Research (2020) 21:162 Page 3 of 10

a b

c d

Fig. 1 Prevalence of and mortality by cardiac biomarker categories based on hs-cTnI and/or ischemic ECG abnormalities (I-ECG). The prevalence
of cardiac biomarker categories is illustrated by Venn diagrams in individuals with a COPD (n = 601) and b normal lung function (NLF) (n = 755),
respectively. The cumulative mortality by cardiac biomarker category is illustrated by bar charts among individuals with c COPD and d NLF. (I-ECG
includes Major Q/QS wave, major isolated ST-T abnormality, Minor Q wave plus major ST-T and minor isolated Q wave)

FEV1 percent of predicted (highest obtained value) was years. Cardiac biomarkers were evaluated as risk factors
used to assess the severity of airflow limitation, further for death expressed as Hazard Ratios (HR) and 95%
divided into grade 1–4 according to GOLD [6], among Confidence Intervals (95% CI) in bivariate analyses and
those fulfilling the spirometric criteria for COPD by the multivariate Cox models adjusting for age, sex, smoking
fixed ratio. In the non-obstructive reference population habits, diabetes mellitus and FEV1% predicted. Kaplan
(FEV1/VC ≥0.70), those with normal lung function Meier curves and forest plots were created using Graph-
(FEV1/VC ≥0.70 and FVC > 80% of predicted) were iden- Pad Prism version 8.4 (GraphPad Software, San Diego,
tified. The OLIN reference values were used [22]. CA, USA).

Statistics
Statistical analyses were performed using SPSS version Results
25 (IBM, Armonk, NY, USA). Categorical variables were The baseline characteristics of individuals with COPD
compared using chi-square test, independent sample t- (n = 601) and those with normal lung function (n = 755)
test to compare means and Mann-Whitney U-test to are presented in Table 1. Among those with COPD,
compare medians. Survival in each of the groups was ex- 41.6, 51.1 and 7.3% were classified as GOLD grades 1, 2
amined by plotting Kaplan-Meier curves. Mortality rate and 3–4 respectively. The prevalence of reported ische-
was estimated as the number of deaths per 1000 person- mic heart disease was higher among individuals with
Nilsson et al. Respiratory Research (2020) 21:162 Page 4 of 10

Table 1 Basic characteristics of the study population, comparing individuals with COPD and normal lung function (NLF)
Category Variables COPD (n = 601) NLF (n = 755) p
Age Age, mean (SD) 67.0 (10.6) 64.5 (11.3) < 0.001
Sex Women 253 (42.1) 361 (47.8) 0.036
Smoking habits < 0.001
Never smoker 153 (25.5) 354 (46.9)
Ex-smoker 250 (41.6) 303 (40.1)
Current smoker 198 (32.9) 98 (13.0)
BMI groups 0.025
BMI < 20 20 (3.3) 12 (1.6)
BMI 20–24.9 206 (34.3) 238 (31.5)
BMI 25–29.9 279 (46.4) 347 (46.0)
BMI ≥30 96 (16.0) 158 (20.9)
Oxygen saturation Saturation percent, mean (SD) 96.2 (2.2) 97.1 (1.3) < 0.001
Hypoxemia (< 92%) 8 (1.3) 0 (0) 0.001
Exacerbations Hospital admission last 12 months1 11 (1.8) 11 (1.5) 0.589
Comorbidities Diabetes mellitus 54 (9.0) 64 (8.5) 0.742
Angina pectoris 76 (12.2) 80 (10.6) 0.240
Myocardial infarction 35 (5.8) 19 (2.5) 0.002
CABG and/or PCI 23 (3.8) 34 (4.5) 0.538
2
Ischemic heart disease 103 (17.1) 94 (12.5) 0.015
ECG Ischemic abnormalities3 89 (14.8) 101 (13.4) 0.451
4
hs-cTnI hs-cTnI, ng/L median (IQR) 3.3 (3.6) 3.2 (2.9) 0.019
hs-cTnI ≥5 ng/L, % 187 (31.1) 188 (24.9) 0.011
Lung function FEV1% of predicted value, mean (SD) 75.8 (16.4) 98.0 (10.8) < 0.001
GOLD 1 250 (41.6) n/a
GOLD 2 307 (51.1) n/a
GOLD 3–4 44 (7.3) n/a
Presented as n (%) unless otherwise stated. Significant values in bold
1
Hopsitalization due to respiratory condition
2
Including angina pectoris, myocardial infarction, coronary artery bypass grafting (CABG) and/or percutaneous coronary intervention (PCI)
3
Including Major Q/QS wave, major isolated ST-T abnormality, Minor Q wave plus major ST-T and minor isolated Q wave based on Minnesota coding
4
Mann-Whitney U test, interquartile range (IQR)

COPD (17.1%) compared to individuals with normal model confirmed that age and sex remained significantly as-
lung function (12.5%). sociated with hs-cTnI ≥5 ng/L in both COPD and NLF, to-
Troponin concentrations were above the limit of de- gether with ischemic heart disease in the COPD group and
tection in 580 (96.5%) individuals with COPD and 708 ischemic ECG abnormalities in the NLF group (see Supple-
(93.8%) individuals with normal lung function and were mentary Table 2, Additional File 1).
above the upper reference limit in 20 individuals with The prevalence of ischemic ECG abnormalities was
COPD and 24 individuals with normal lung function similar among individuals with COPD and those with
(3.3 and 3.2%, respectively). The median hs-cTnI con- normal lung function, 14.8 and 13.4% respectively
centration and proportion of individuals with hs-cTnI > (Table 1). The proportion with ischemic ECG abnor-
5 ng/L were higher in COPD than in normal lung func- malities was higher among those with hs-cTnI > 5 ng/L
tion (Table 1). than among those with hs-cTnI < 5 ng/L in both groups
In both individuals with COPD and those with normal (24.6% vs. 10.4, and 26.6% vs. 9.0% respectively; p <
lung function, hs-cTnI concentrations > 5 ng/L were associ- 0.001 for both, see Supplementary Table 1, Additional
ated with higher age, male sex, and higher proportions of File 1). Among individuals with COPD, 23.5% had hs-
diabetes mellitus and ischemic heart disease (see Supplemen- cTnI > 5 ng/L alone, 7.2% had ischemic ECG abnormal-
tary Table 1, Additional File 1). Analyses in an adjusted ities alone and 7.7% had both hs-cTnI > 5 ng/L and
Nilsson et al. Respiratory Research (2020) 21:162 Page 5 of 10

ischemic ECG abnormalities, while the corresponding corresponding analyses among subjects with normal
prevalence among those with normal lung function was lung function, ischemic ECG abnormalities alone
18.3, 6.8 and 6.6% respectively (Fig. 1 a-b). seemed to be of greater importance than cTnI > 5 ng/L
alone (Fig. 3b).
Mortality
In total, 140 individuals died during the observation Participants without reported ischemic heart disease
period; 82 with COPD and 58 with normal lung function In analyses restricted to participants without reported is-
(13.6% vs 7.7%, p < 0.001), corresponding to a mortality chemic heart disease, 72.9 and 87.5% of those with
rate of 27 and 15 per 1000 person-years respectively. In COPD and normal lung function respectively, similar
the COPD-group, 54/82 or 66% of deaths were due to associations were found for all analyses (see Supplemen-
cardiovascular disease compared with 35/58 or 60% of tary Fig. 1 and Supplementary Table 4, Additional File
the deaths in the normal lung function group. The cu- 1). Among individuals with COPD, hs-cTnI > 5 ng/L
mulative mortality was higher among those with hs-cTnI alone as well as having both hs-cTnI > 5 ng/L and ische-
> 5 ng/L than those with hs-cTnI < 5 ng/L in both mic ECG abnormalities were associated with an in-
groups (see Supplementary Table 1, Additional File 1). creased the risk for death independent of confounders
Likewise, in both groups, the cumulative mortality was and disease severity (see Supplementary Table 4, Add-
higher among those with, compared to those without, is- itional File 1).
chemic ECG abnormalities (30.3% vs. 10.7%, p < 0.001
and 17.8% vs. 6.1%, p < 0.001 respectively). Discussion
Among individuals with COPD, the cumulative mor- In this study, a history of ischemic heart disease, myo-
tality was 26.5% in those with hs-cTnI > 5 ng/L alone, cardial injury and myocardial ischemia was common and
16.3% in those with ischemic ECG abnormalities alone more frequent among individuals with COPD than
and 43.5% in those with both hs-cTnI > 5 ng/L and is- among individuals with normal lung function. As ex-
chemic ECG abnormalities. The corresponding rates in pected, mortality was higher among individuals with
those with normal lung function were 10.9, 9.8 and COPD than among those with normal lung function,
26.0% (Fig. 1 c-d). Within each of these biomarker and high-sensitivity cardiac troponin was associated with
groups, the corresponding proportions deceased due to increased mortality in both groups. An elevated hs-cTnI
cardiovascular disease were in COPD 69, 71 and 70% re- concentration with or without signs of myocardial ische-
spectively (with a proportion of 53% among those with- mia on ECG increased the risk for death three- to four-
out any of these biomarkers). The equivalent fold among individuals with COPD, independent of age,
proportions in the normal lung function group were 60, sex, smoking habits, diabetes mellitus and disease sever-
40 and 77% respectively, (56% without any of the ity. Importantly, these cardiac biomarkers were associ-
biomarkers). ated with an increased risk for death of similar
Survival by cardiac biomarker group is illustrated by magnitude also among individuals with COPD without
Kaplan Meier curves among individuals with COPD and known ischemic heart disease.
those with normal lung function, respectively (Fig. 2a-b). Even though individuals with COPD comprise a high-
Among individuals with COPD, the mortality rate risk population, ischemic heart disease is often-
amongst those without any cardiac biomarkers was 10 overlooked, but the converse is also true, as COPD is
per 1000 person-years. The corresponding mortality often undiagnosed in patients with ischemic heart dis-
rates per 1000 person-years were 52 in those with a hs- ease [23]. Most current guidelines for the diagnosis and
cTnI ≥5 ng/L alone, 31 in those with ischemic ECG ab- treatment of COPD highlight the need for greater aware-
normalities alone, and 103 in those with both hs-cTnI > ness of cardiovascular risk and comorbidities among pa-
5 ng/L and ischemic ECG abnormalities. In individuals tients with COPD, in order to initiate preventive
with normal lung function, the corresponding mortality measures and optimise outcomes. However, there are no
rates were 9, 21, 19 and 53 per 1000 person-years. specific recommendations for the approach to risk as-
Among individuals with COPD and hs-cTnI > 5 ng/L sessment of ischemic heart disease among individuals
alone and those with both hs-cTnI > 5 ng/L and ische- with COPD.
mic ECG abnormalities, the risk for death was increased In a large-scale multi-center study including > 16,000
after adjustment for potential confounders (HR 2.72, patients with COPD and cardiovascular disease or risk
95% CI 1.46–5.07; HR 4.54, 95% CI 2.25–9.13 respect- factors for cardiovascular disease, acute exacerbations of
ively) when compared to those with no cardiac bio- COPD (AECOPD) were associated with an increased
markers (Fig. 3a). The risk for death was increased, risk for new cardiovascular events, including cardiovas-
independent of disease severity assessed as FEV1% pre- cular death [24]. Cardiac troponin has over time been
dicted (see Supplementary Table 3, Additional File 1). In proven to be an independent risk factor for all-cause
Nilsson et al. Respiratory Research (2020) 21:162 Page 6 of 10

Fig. 2 (See legend on next page.)

Nilsson et al. Respiratory Research (2020) 21:162 Page 7 of 10

(See figure on previous page.)

Fig. 2 Survival among individuals with a COPD and b normal lung function, respectively, illustrated by Kaplan Meier curves by categories of cardiac
biomarkers based on hs-cTnI and ischemic ECG abnormalities (I-ECG). Due to limited sample size at the end of follow-up, one subject that deceased
after 2100 days is not included in Fig. 2 A, due to an unproportionate effect on the curve for hs-cTnI > 5 ng/L alone. This did not affect the Log Rank p-
value. (I-ECG includes Major Q/QS wave, major isolated ST-T abnormality, Minor Q wave plus major ST-T and minor isolated Q wave)

mortality during acute exacerbation of COPD [14]. demonstrated that individuals in the Emergency Depart-
Troponin, as well as NT-proBNP, a marker for chronic ment with hs-cTnI concentrations < 5 ng/L are at very
heart failure, have also been associated with an increased low risk of both short and long-term cardiac events [11].
risk for death among patients hospitalized for AECOPD Moreover, also in stable COPD patients participating in
without previously known ischemic heart disease [25]. a randomized controlled trial, the same threshold identi-
During recent years, there are a few reports based on se- fied patients at low or high risk of cardiovascular death
lected patient populations with stable COPD, indicating [13]. However, cardiovascular disease or risk factors
that troponin is increased [26] and associated with mor- were inclusion criteria in this study, and the study popu-
tality [16, 27] among COPD patients without known lation was limited to patients with moderate COPD
heart disease. In recent years, the development and clin- (FEV1 ≥ 50 and ≤ 70% of predicted) having dyspnea cor-
ical use of high-sensitivity cardiac troponin assays have responding to mMRC ≥2 and a smoking history of ≥10
permitted the detection of myocardial injury more pack-years. Still to date, this approach to risk stratifica-
widely [28]. In a recent study of 88 patients hospitalized tion has not been evaluated in a less selected group of
for AECOPD with elevated hs-cTnI, coronary angiog- individuals with COPD and, the generalizability of this
raphy detected ischemic heart disease in two-thirds, and approach to population-based COPD cohorts has not
half of these patients underwent percutaneous coronary been known.
intervention [28], supporting the assumption that, at During the observation period in the current study,
least in this setting, elevated hs-cTnI is associated with mortality was nearly three-times higher among individ-
subclinical ischemic heart disease. uals with COPD and hs-cTnI concentrations ≥5 ng/L
The diagnostic threshold for myocardial infarction and was more than four times higher in those with add-
using our high-sensitivity cTnI assay is 34 ng/L in men itional signs of ischemia on the electrocardiogram, com-
and 16 ng/L in women [13]. However, hs-cTnI is in- pared to those without these biomarkers, even after
creasingly being used to evaluate cardiovascular risk at adjusting for established cardiovascular risk factors. Fur-
concentrations well below the diagnostic threshold. The thermore, this increase in risk was independent of
optimal threshold for risk stratification continues to be COPD severity and smoking habits. Importantly, despite
debated, but the largest study performed to date, individuals with predominantly mild-moderate COPD

a b

Fig. 3 Forest plots illustrating mortality risk among individuals with a COPD and b normal lung function, respectively, by categories of cardiac
biomarkers based on hs-cTnI and ischemic ECG abnormalities (I-ECG). Multivariate Cox regression analyses of risk factors for death expressed as
HR;95% CI with “no cardiac biomarker” as reference, adjusting for age, sex, smoking habits and diabetes mellitus
Nilsson et al. Respiratory Research (2020) 21:162 Page 8 of 10

within the investigated population, abnormal cardiac However, there are some limitations that merit discus-
biomarkers were common; every fourth individual had sion. The prevalence of ischemic heart disease and dia-
hs-cTnI ≥5 ng/L, and almost one in 10 had both elevated betes mellitus was based on interview data and not on
hs-cTnI and ischemic ECG abnormalities. medical records, and we do not have data on other
Restricting our analyses to individuals with COPD known risk factors, such as blood pressure and total
without reported ischemic heart disease supported our cholesterol. Still, there is known to be fairly good agree-
hypothesis; the increased risk of death associated with ment between self-reported data and medical records on
an elevated hs-cTnI concentration alone or in combin- the comorbid conditions evaluated in the current study,
ation with ischemic ECG abnormalities persisted. Our cardiovascular disease and diabetes mellitus [37–39].
observations imply that these cardiac biomarkers may Whilst information on hypertension would also be of
identify individuals with unrecognized cardiac disease of importance, self-reported data on hypertension have a
prognostic importance. fairly low validity [40] and were thus not used. The
Both ischemic ECG abnormalities and troponin are in- blood samples were collected during epidemiological
dependently known to be risk markers for mortality, fieldwork and stored at -20 °C, but we do not anticipate
both among individuals with COPD [7, 16, 29] and in that troponin concentrations will have changed during
the general population [30, 31]. However, the impact of storage and have previously reported that hs-cTnI levels
the combination of these markers has rarely been inves- predicted long-term cardiovascular events from samples
tigated. This study shows a difference in the risk profile stored for 20 years [10]. Impaired renal function may
between individuals with COPD and NLF. Therefore, we affect troponin levels, but data on renal function were
hypothesize that I-ECG represents a past event, that in- not available in this study. Yet, in a large population-
creases long-term risk, while circulating hs-cTnI indi- based study, there were no differences in unadjusted
cates an ongoing subclinical myocardial disease that, in comparisons and, also in adjusted analyses, those with
combination with a chronic airway obstruction, nega- mild airway obstruction had similar mean glomerular fil-
tively affects the survival at a five-year perspective. Yet, tration ratio as those with normal lung function (89.1 vs.
the mechanisms behind the impact of hs-cTnI in COPD 89.6 ml/min/1.73 m2, p = 0.619), while those with moder-
are still mainly unknown [32]. Future research is re- ate/severe/very severe airway obstruction had slightly
quired to understand the relationship between these bio- lower mean value (87.6 ml/min/1.73 m2, p = 0.015) [41].
markers and coronary or structural heart disease among Our study included mainly mild to moderate COPD and
individuals with COPD. Henceforth, this may contribute we believe that adjustment for renal function would
to the development of an algorithm to identify individ- hardly affect the results. The OLIN COPD study was de-
uals with COPD in the general population at increased signed shortly after the shift of the millennium, when
risk in whom specific treatment and preventive measures the fixed ratio criterion was generally accepted to define
for cardiovascular disease could be introduced. Whilst airway obstruction in COPD. It is recognized that the
the numbers of deceased in each of the biomarker fixed ratio may overestimate COPD among elderly non-
groups in the current study were limited, still around smoker [42], and the lower limit of normal (LLN) criter-
70% of the deaths among those with COPD were cardio- ion for COPD is nowadays recommended in epidemio-
vascular, compared with 53% among those without any logical studies. Still, most clinical guidelines use the
biomarkers. Yet, death certificates are to a great extent fixed ratio criterion for COPD [6], thus the results are
based on clinical diagnosis and, thus, potential subclin- highly clinically relevant and applicable in every-day care
ical cardiovascular disease, assumed to associate with el- for COPD.
evated biomarkers under study, will therefore remain
undetected [33]. Conclusion
The strength of the current study is the large In this study, elevated hs-cTnI concentrations in com-
population-based COPD cohort identified by post- bination with signs of myocardial ischemia on the elec-
bronchodilator spirometry according to the GOLD trocardiogram were associated with a more than
guidelines [6], and with a distribution of disease severity fourfold increased risk of death in a population-based
dominated by mild to moderate COPD, as in other COPD-cohort, independent of disease severity. This in-
population-based studies [34, 35]. The cohort is thus creased risk was of similar magnitude also among those
considered representative for COPD in the population with COPD, but without known ischemic heart disease.
and under-diagnosis of COPD [2, 6] is not expected to Thus, these cardiac biomarkers may indicate the pres-
affect the results. Further strengths are the use of well- ence of undiagnosed and prognostically important car-
validated methods; a structured interview following a diovascular disease among individuals with COPD and
validated questionnaire [36] Minnesota coding of ECG should be further evaluated for screening and risk mod-
[18] and a well validated high-sensitivity cTnI assay [12]. eling at a population level.
Nilsson et al. Respiratory Research (2020) 21:162 Page 9 of 10

Supplementary information Swedish asthma and allergy foundation, grants from Norrbotten county
Supplementary information accompanies this paper at https://doi.org/10. council, grants from Nord Forsk, grants from FORMAS, grants from AstraZe-
1186/s12931-020-01430-z. neca, grants from GlaxoSmithKline, during the conduct of the study. Dr. Lind-
berg reports personal fees from Boehringer-Ingelheim, personal fees from
AstraZeneca, personal fees from Novartis, personal fees from Active Care,
Additional file 1: Supplementary Table 1. Cardiac biomarkers of
outside the submitted work.
prognostic importance in chronic obstructive pulmonary disease.
Author details
1
Abbreviations Department of Public Health and Clinical Medicine, Section of Medicine,
AEOCOPD: Acute exacerbation of chronic obstructive pulmonary disease; Umeå University Hospital, B41, 90185 Umeå, Sweden. 2BHF Centre for
CI: Confidence interval; COPD: Chronic obstructive pulmonary disease; Cardiovascular Science, University of Edinburgh, Edinburgh, UK. 3Usher
ECG: Electrocardiogram; FEV1: Forced expiratory volume in 1 s; FVC: Forced Institute of Population Health Sciences and Informatics, University of
vital capacity; HR: Hazard ratio; Hs-cTnI: High sensitive coronary troponin I; Edinburgh, Edinburgh, UK. 4Institute of Health and Wellbeing, University of
OLIN: The Obstructive Lung Disease in Northern Sweden Studies; SVC: Slow Glasgow, Glasgow, UK. 5Department of Public Health and Clinical Medicine,
vital capacity; VC: Vital capacity The OLIN unit, Section of Sustainable Health, Umeå University, Umeå,
Sweden. 6Department of Health Science, Division of Nursing, Luleå University
Acknowledgements of Technology, Luleå, Sweden.
We gratefully acknowledge work within the OLIN-studies; senior professor Bo
Lundbäck for initiating the OLIN studies and the OLIN COPD study, RN Ann- Received: 30 January 2020 Accepted: 18 June 2020
Christin Jonsson and RN Sigrid Sundberg for data collection, and Ola Bernh-
off for data management.
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