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Clinical Infectious Diseases
RESEARCH ARTICLE
DOI: 10.1093/cid/ciac946 1
Tuberculosis and the Risk of Ischemic Heart Disease: A
Nationwide Cohort Study
Han Rim Lee, MD1, Jung Eun Yoo, MD, PhD2, Hayoung Choi, MD, PhD3, Kyungdo Han,
PhD4, Young-Hyo Lim, MD, PhD5, Hyun Lee, MD, PhD6*, Dong Wook Shin, MD, PhD,
MBA
1
,7*
1 Department of Family Medicine & Supportive Care Center, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2 Department of
Family Medicine, Healthcare System Gangnam Center Seoul National University Hospital,
Seoul, Republic of Korea; 3 Division of Pulmonary, Allergy, and Critical Care Medicine,
Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym
University College of Medicine, Seoul, Republic of Korea; 4 Department of Statistics and
Actuarial Science, Soongsil University, Seoul, Republic of Korea; 5 Division of Cardiology,
Department of Internal Medicine, Hanyang Medical Center, Hanyang University College of
Medicine, Seoul, Republic of Korea; 6 Division of Pulmonary Medicine and Allergy, Department
————————————————————————————————————————
*These authors contributed equally as co-corresponding authors.
*Co-Corresponding authors: Dong Wook Shin, MD, DrPH, MBA Department of Family
Medicine/Supportive Care Center, Samsung Medical Center, Sungkyunkwan University School of
Medicine Department of Clinical Research Design & Evaluation/ Department of Digital Health, Samsung
Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University 81 Irwon-
Ro, Gangnam-gu, Seoul 06351, Republic of Korea Tel: 82-2-3410-5252; Fax: 82-2-3410-0388; E-
mail: dwshin.md@gmail.com
and
Hyun Lee, MD, PhD Division of Pulmonary Medicine and Allergy, Department of Internal Medicine,
Hanyang Medical Center, Hanyang University College of Medicine, Seoul, Republic of Korea 222-1
Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea Tel: 02-2290-8350; Fax: 02-2292-1477;
E-mail: namuhanayeyo@naver.com
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of
America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article
is published and distributed under the terms of the Oxford University Press, Standard Journals Publication
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DOI: 10.1093/cid/ciac946 2
of Internal Medicine, Hanyang Medical Center, Hanyang University College of Medicine, Seoul,
Republic of Korea; 7 Department of Clinical Research Design & Evaluation, Samsung Advanced
Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul,
Republic of Korea
Background: Little is known about the risk of ischemic heart disease (IHD) in tuberculosis (TB)
survivors.
Methods: We performed a population-based retrospective cohort study using the Korean
National Health Insurance Service database. TB survivors (n = 60,602) and their 1:1 age- and
sex-matched controls (n = 60,602) were enrolled. Eligible participants were followed up from 1
year after their TB diagnosis to the date of an IHD event, date of death, or the end of the study
period (December 31, 2018), whichever came first. The risk of IHD was estimated using a Cox
proportional hazards regression, and stratified analyses were performed for related factors.
Among IHD events, we additionally analyzed for myocardial infarction (MI).
Results: During a median of 3.9 years of follow-up, 2.7% of TB survivors (1,633/60,602) and
2.0% of the matched controls (1,228/60,602) developed IHD, and 0.6% of TB patients
(341/60,602) and 0.4% of the matched controls (223/60,602) developed MI. The overall risk of
developing IHD and MI was higher in TB patients (adjusted hazard [aHR] 1.21, 95% CI 1.12–
1.32 for IHD and aHR 1.48, 95% CI 1.23–1.78 for MI) than in the matched controls. Stratified
analyses showed that TB survivors have an increased risk of IHD and MI regardless of income,
place of residence, smoking status, alcohol consumption, physical activity, body mass index, and
Charlson comorbidity index.
Conclusions: TB survivors have a higher risk of IHD than matched controls. Strategies are
needed to reduce the burden of IHD in TB survivors.
Keywords: Tuberculosis, Ischemic heart disease, Myocardial infarction, Retrospective cohort
INTRODUCTION
Tuberculosis (TB) is a major public health concern worldwide. Approximately 10 million people
were estimated to be infected with Mycobacterium tuberculosis, and 1.5 million TB-related
deaths were reported in 2020.[1] As the survival rate after TB treatment increases, there is a
growing need to consider how to manage the long-term health of TB survivors.[2-15] If the End
TB Strategy’s goal of 95% reduction in TB mortality by 2035 is achieved,[16] we predict that
long-term management of TB survivors will be of increasing importance.
Recently, it has been shown that TB-induced inflammation does not end after treatment for
active TB but can persist, causing chronic inflammation in TB survivors.[17, 18] Therefore, in
addition to pulmonary sequelae,[6, 7, 9, 10] TB is also associated with chronic, non-pulmonary
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DOI: 10.1093/cid/ciac946 3
diseases such as ischemic stroke, chronic kidney disease, and diabetes mellitus.[4, 5, 8, 12] In
addition, the long-term mortality of TB survivors is higher than that in the general population.[3,
11]
Ischemic heart disease (IHD) is a major component of cardiovascular disease, which is a
common cause of morbidity and mortality.[19] IHD comprises a large spectrum of clinical
conditions, including chronic coronary syndrome (e.g., stable angina), acute coronary syndrome
(e.g., unstable angina), and myocardial infarction (MI) with and without ST elevation. The global
health burden of IHD has risen steadily since 1990, reaching 197 million cases and 9.14 million
deaths in 2019.[20] MI is a leading cause of mortality despite significant progress in its
management.[21] Because MI causes irreversible damage to cardiomyocytes and can have
serious complications, it causes a heavy global burden. The known risk factors of IHD include
smoking, diabetes mellitus, dyslipidemia, and hypertension,[22, 23] and inflammation caused by
infectious pathogens has been linked to atherosclerosis, which is also a major mechanism in
IHD.[24]
Among infectious conditions, previous studies have shown that TB survivors are more
susceptible to developing IHD than controls.[13-15] However, those results had limited value
because some of those studies didn’t consider potential confounding factors such as smoking
status, alcohol consumption, body mass index, and socioeconomic status,[13, 15] and other
studies evaluated only a small number of subjects.[14, 15] Accordingly, studies that
comprehensively evaluate potential biases are needed to confirm the risk of IHD in TB survivors
In this study, we compare the risk of IHD between TB survivors and matched controls drawn
from a large nationally representative database in Korea.
METHODS
Data source and study setting
We used data from the Korean National Health Insurance Service (KNHIS), a mandatory
universal public health insurance system that covers approximately 97% of the Korean
population and provides medical aid to the 3% of the population in the lowest income bracket.
The KNHIS also provides biennial national cardiovascular health screenings for all Koreans aged
40 and older and all employees regardless of age.[25] The KNHIS database contains
demographic data (e.g., age, sex, income, place of residence, and type of eligibility), claims data
(general information on specifications, consultation statements, diagnostic codes from the
International Classification of Disease 10th revision (ICD-10), and prescription records), health
check-up data, and death information about all enrolled Koreans.[25] During health screenings,
KNHIS study participants complete self-administered questionnaires about lifestyle factors (e.g.,
alcohol consumption, smoking, and physical activity) and medical and family history and
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DOI: 10.1093/cid/ciac946 4
undergo anthropometric measurements (blood pressure, body weight, and height) and laboratory
tests (blood glucose, lipid profile, serum creatinine).
This study was approved by the Institutional Review Board (IRB) of Hanyang University
Hospital (IRB No. HYUH 2022-06-026). The review board waived written informed consent
because the data are public and anonymized under confidentiality guidelines.
Study population
TB survivors were defined by the following criteria: 1) patients with two or more healthcare uses
(outpatient visits, emergency department visits, or hospitalizations) with the ICD-10 codes
associated with active TB (A15–A19, U88.0–U88.1) and specific insurance codes (V206, V246,
and V000) and 2) patients who were prescribed two or more anti-TB drugs (isoniazid, rifampin,
ethambutol, pyrazinamide, cycloserine, and para-aminosalicylate) for at least 90 days.[26] In
Korea, the specific insurance codes for active TB are automatically applied to patients after a
diagnosis of active TB, independent of the ICD-10 codes. Once patients receive the specific
insurance codes for TB, they receive additional insurance coverage during TB treatment to
reduce the burden of TB on the nation. Thus, the validity of the specific KNHIS codes for active
TB is strictly reviewed by the health insurance review and assessment service.
We collected data for 231,984 people who were diagnosed with TB between 2010 and 2017.
After excluding 26,928 patients with multidrug-resistant TB (ICD-10 U88.0–U88.1, n=1,088) or
those who were treated incompletely (treatment duration <156 days, n=25,950) (110 cases met
both criteria), data for 205,056 TB survivors were available.
Among them, 95,294 had undergone a health screening within 2 years before their TB diagnosis.
We excluded patients with missing data (n=854), those who died within 1 year after their TB
diagnosis (n=1,456), those who were younger than 20 years (n=87), those who had previously
been diagnosed with IHD (ICD-10 I20-25) (n=21,701), or those who were diagnosed with IHD
within 1 year of TB diagnosis (n=647) to avoid the effects of a temporal relationship and
minimize the possibility of reverse causality.[27, 28]
We obtained an initial control pool of ≈1 million who were matched approximately 1:5 to the
205,056 TB survivors. We used birth year and sex to match the TB cases diagnosed in each year
with controls who were alive until the end of that year. The matched controls were assigned an
index date equivalent to the date of TB diagnosis for the matched TB survivors. Among the
controls, 418,880 had received a health screening within 2 years before the index date, and they
were sorted using the same exclusion criteria applied to the TB cases (i.e., no missing data, IHD
before the index date, and death or IHD within 1 year after the index date). Then 1:1 age and sex
matching with the TB survivors was made for the final analyses. In that way, 60,602 TB
survivors and 60,602 matched controls were included in the present study (Figure 1).
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Study outcomes and follow up
The primary endpoint of this study was IHD newly diagnosed during the follow-up period. IHD
was defined as a hospitalization record with ICD-10 codes I20–25. We further analyzed for MI,
which was defined as a hospitalization record with ICD-10 codes I21 and I22.[29] Because we
wanted to evaluate the long-term risk of IHD in TB survivors, the study population was followed
up from 1 year after the index date to the date of IHD development, date of death, or the end of
the study period (December 31, 2018), whichever came first.
Covariates
Information on participants’ lifestyles was obtained from the health screening program
questionnaires. Smoking status was categorized as never, former, and current smokers. Alcohol
consumption was classified as non-, mild to moderate (<30g of alcohol/day), and heavy (≥30g of
alcohol/day) by assessing the amount of alcohol consumed per occasion and the frequency of
alcohol intake per week. Regular physical activity was defined as ≥30 minutes of moderate
physical activity at least 5 times per week or ≥20 minutes of vigorous physical activity at least 3
times per week as reported for the week preceding the assessment.[30] We also considered
socioeconomic position as a potential covariate, including place of residence and income level.
Body mass index (BMI) was calculated as participants’ body weight (kg) divided by the square
of their height (m2) and was categorized as low (< 18.5), normal (18.5–22.9), overweight (23–
24.9), and obese (≥ 25) according to the Asia-Pacific BMI criteria established by the World
Health Organization.[31] The Charlson comorbidity index (CCI) was used to assess the overall
comorbidity load.[32] The competing risk of mortality was assessed based on participant death
during follow-up.
Statistical analyses
Descriptive statistics are presented as numbers (percentages) for categorical variables and means
± standard deviations for continuous variables. We compared the two groups using the χ2 test for
categorical variables, as appropriate, and t-tests for continuous variables. The incidence rates of
IHD were estimated as the number of events per 1,000 person-years. A cumulative incidence plot
was used to compare the incidence of IHD between TB survivors and matched controls, and we
used a log-rank test to evaluate significant differences between the groups.
The association between TB survivors and the incidence of IHD was estimated using Cox
proportional hazards regressions with crude and multivariable-adjusted models. Model 1 was not
adjusted, and Model 2 was adjusted for age, sex, BMI, smoking status, alcohol consumption,
regular physical activity, income, and place of residence. Model 3 was further adjusted for the
participants’ CCI score. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.
To consider competing mortality risk, further analyses were performed using the Fine and Grey
model.[33] Stratified analyses were performed by sex, age, smoking status, alcohol consumption,
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DOI: 10.1093/cid/ciac946 6
regular physical activity, BMI, and CCI score. Forest plots for the HRs and 95% CIs of the
subgroups were calculated.
We additionally estimated the incidence rates of MI in both the TB survivors and matched
controls and used a log-rank test to evaluate differences in cumulative incidence between the
groups. The HRs and 95% CIs for MI were calculated by a Cox proportional hazards regression,
and the stratified analyses were also performed for related factors. All statistical analyses were
performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA), and a P-value < 0.05 was
considered statistically significant.
RESULTS
Baseline characteristics of the study population
Table 1 shows the baseline characteristics of the study participants. Their mean age was 52.4
years, and about 42.3% of them were female. TB survivors were more likely to live in an urban
area and had lower incomes than the matched controls (P <0.001 for both). Compared with
matched controls, more TB survivors were current smokers (29.3% vs. 22.7%) and heavy
drinkers (10.3% vs. 7.3%), and they had a lower BMI (P <0.001 for all). TB survivors were
likely to have a higher CCI score than the controls. Comorbidities including diabetes,
dyslipidemia, ischemic stroke and congestive heart failure were higher in TB survivors than in
the control group. In contrast, the opposite was true for hypertension (P < 0.001 for all).The
mean follow-up durations for IHD after 1 year of lag time were 3.77 years for TB survivors and
3.85 years for the matched controls, and the mean follow-up durations for MI after 1 year of lag
time were 3.81 years for TB survivors and 3.89 years for the matched controls.
Risk of IHD in TB patients compared with the matched controls
During follow-up, 2.7% of TB survivors (1,633/60,602) and 2.0% of the matched controls
(1,228/60,602) developed IHD, with incidence rates of 7.16 and 5.26 per 1,000 person-years,
respectively, and 0.6% of TB survivors (341/60,602) and 0.4% of the matched controls
(223/60,602) developed MI, with incidence rates of 1.48 and 0.95 per 1,000 person-years,
respectively (Table 2). TB survivors were thus found to have a higher risk of heart disease
(adjusted HR [aHR] 1.21, 95% CI 1.12–1.32 for IHD and aHR 1.48, 95% CI 1.23–1.78 for MI)
than the matched controls. There were no significant differences from the original results in the
analyses using the Fine and Gray competing risk model (subdistribution HR 1.19, 95% CI 1.10–
1.29 for IHD and subdistribution HR 1.45, 95% CI 1.21–1.73 for MI).
The Kaplan-Meier curves present the cumulative incidence of IHD and MI in TB patients
compared with the matched controls (Figure 2 and Figure 3, respectively). The incidence of
IHD and MI correlated positively with TB (log-rank P<0.001).
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Stratified analyses
Figures 4 and 5 show the results from stratified analyses regarding the risk of IHD and MI
among TB survivors compared with the matched controls. No significant interaction was found
for any of the variables (P for interactions >0.05). Compared with the matched controls, TB
survivors showed a higher risk of IHD across all subgroups except for the youngest age group.
TB survivors also showed a higher risk of MI regardless of sex, income level, place of residence,
smoking status, and CCI scores (Figure 5).
DISCUSSION
This large-scale, population-based, cohort study compared the risk of IHD between TB survivors
and matched controls. We found that TB survivors had 21% increased risk of IHD and 48%
increased risk of MI compared with matched controls after adjusting for demographic
characteristics, health-behavioral factors, and comorbidities. Therefore, these findings support an
independent association between TB and IHD. Our study has advantages over the previous
studies in that we considered important confounders (e.g., BMI, smoking status, and alcohol
consumption) that were not considered thoroughly in the previous studies.[13, 15] In addition,
our consistent results across various stratified analyses of a large nationally representative
sample support the association between TB and an increased risk of IHD development.
Previous studies showed a consistently higher risk of IHD development in TB survivors
(Supplementary Table 1). Blondal et al. showed a strong association (standardized mortality
ratio (SMR) 1.80, 95% CI 1.21–2.57 in males and SMR 3.94, 95% CI 1.28–9.20 in females)
between TB infection and death from IHD.[34] Two cohort studies from Taiwan also showed an
increased risk of IHD development compared with control group (HR 1.40, 95% CI 1.14–1.72 in
Chung et al. and HR 1.21, 95% CI 1.08–1.36 in Sheu et al.).[13, 15] A recent US study similarly
reported that TB is associated with the development of acute MI after adjusting for potential
confounding variables (HR 1.98, 95% CI 1.30–3.00 in the all active TB group and HR 2.43, 95%
CI 1.50–4.10 in the pulmonary TB group).[14]
The mechanisms behind this association are not known completely, but a possible mechanism
has been proposed.[35] The hypothesis is that chronic inflammation derived from TB infection
might accelerate atherosclerosis, which is known to increase the risk of coronary heart
disease.[36] In contrast to the old idea that TB-associated inflammation disappears after TB
treatment, it is now understood that chronic inflammation can persist in tissues long after the
clearance of M. tuberculosis.[37] Therefore, just as other chronic inflammatory diseases, such as
systemic lupus,[38] rheumatoid arthritis,[39] and inflammatory bowel disease,[40] are associated
with cardiovascular disease, the chronic inflammation associated with TB infection could cause
atherosclerosis and thereby induce the development of IHD, including MI. Furthermore,
accumulating evidence that the risk of ischemic stroke, which is also caused by atherosclerosis,
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is increased in TB survivors supports the link between TB and IHD.[4] The increased risk of
IHD in post-TB survivors can be also mediated by post-TB lung disease; for example, chronic
obstructive pulmonary disease and bronchiectasis, which are common sequela of TB, are well
known risk factors for IHD.[41, 42] Studies have suggested that some conditions of these
diseases (e.g., exacerbations, hypoxemia, systemic inflammation, decondition, or arterial
stiffness) can contribute to the development of IHD.[41, 42]
The clinical implications of our finding that TB survivors have higher-than-average risk of IHD
emphasize the importance of surveillance for IHD in TB survivors. IHD surveillance in TB
survivors would be also helpful to identify risk factors for IHD such as active smoking and heavy
alcohol consumption; since these are also important risk factors for developing TB, TB survivors
are naturally more likely to report smoking or alcohol consumption than non-TB subjects. A
previous study demonstrated that 15.2% of TB mortality were attributable to smoking.[46]
Smoking is also a well known risk factor of cardiovascular disease such as IHD.[28] However,
the prevalence of smoking in TB patients is much higher than in the general population.[47, 48]
Considering the increased risk of IHD in TB survivors, our findings highlight the need to control
tobacco use in TB survivors, especially in countries with intermediate to high TB burden.
Furthermore, as statins reduce systemic inflammation in addition to their role in cardiovascular
disease prevention,[49] statin use in TB survivors at high risk for IHD could be another strategy
for controlling chronic inflammation after TB infection and reduce the risk of IHD
development.[50]
This study has some limitations to be acknowledged. First, because we used a database of
insurance claims data, undetected or misclassified TB diagnoses are a possibility. However,
since the TB notification information system was established in Korea in 2000, all TB patients
have been required to register electronically since 2001,[51] so we suggest that the definition of
TB in this study is highly reliable. Second, due to the inherent limitations of claims data, the
severity of TB (e.g., TB extent in pulmonary imaging [e.g., the presence of cavitary lesions or
bilateral disease] or degree of bacterial smear and culture) and the presence of permanent
pulmonary sequelae, which can affect the development of IHD, could not be measured. Third,
there is a possibility of reverse causality. To minimize the possible effects of reverse causality,
we excluded patients diagnosed with IHD or MI before or within 1 year after their TB diagnosis.
CONCLUSION
In this nationwide population-based cohort study, we found that TB survivors had a higher risk
of IHD (including MI) than the general population. Physicians should be aware of the risk of
IHD in patients with TB and provide adequate preventive management. Further studies are
needed to clarify the exact mechanisms underlying this association and to verify whether TB
control strategies can reduce the risk of IHD.
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Acknowledgement: This study was performed using a database from the National Health
Insurance System, but the results do not necessarily represent the opinion of the National Health
Insurance Corporation.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by
the Ministry of Science, Information and Communications Technologies (MSIT) (NRF-
2020R1F1A1070468).
Funding: This work was supported by the National Research Foundation of Korea (NRF) grant
funded by the Ministry of Science, Information and Communications Technologies (MSIT)
(NRF-2020R1F1A1070468).
Competing Interests: The authors have declared that no competing interests exist.
References
1. World Health Organization. Global tuberculosis report 2021. Geneva: World Health Organization,
2021.
2. Byrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Tuberculosis and chronic respiratory
disease: a systematic review. Int J Infect Dis 2015; 32:138-46.
3. Choi H, Han K, Jung JH, et al. Long-term mortality of tuberculosis survivors in Korea: a
population-based longitudinal study. Clin Infect Dis 2022.
4. Lee HR, Yoo JE, Choi H, et al. Tuberculosis and Risk of Ischemic Stroke: A Nationwide Cohort
Study. Stroke 2022:101161STROKEAHA122039484.
5. Allwood BW, Byrne A, Meghji J, Rachow A, van der Zalm MM, Schoch OD. Post-Tuberculosis
Lung Disease: Clinical Review of an Under-Recognised Global Challenge. Respiration 2021;
100:751-63.
6. Cabrera-Sanchez J, Cuba V, Vega V, Van der Stuyft P, Otero L. Lung cancer occurrence after an
episode of tuberculosis: a systematic review and meta-analysis. Eur Respir Rev 2022; 31.
7. Choi H, Ryu J, Kim Y, et al. Incidence of bronchiectasis concerning tuberculosis epidemiology
and other ecological factors: A Korean National Cohort Study. ERJ Open Res 2020; 6.
8. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics.
Lancet Infect Dis 2009; 9:737-46.
9. Hsu D, Irfan M, Jabeen K, et al. Post tuberculosis treatment infectious complications. Int J Infect
Dis 2020; 92S:S41-S5.
10. Nightingale R, Chinoko B, Lesosky M, et al. Respiratory symptoms and lung function in patients
treated for pulmonary tuberculosis in Malawi: a prospective cohort study. Thorax 2022; 77:1131-9.
11. Romanowski K, Baumann B, Basham CA, Ahmad Khan F, Fox GJ, Johnston JC. Long-term all-
cause mortality in people treated for tuberculosis: a systematic review and meta-analysis. Lancet
Infect Dis 2019; 19:1129-37.
12. Shen TC, Huang KY, Chao CH, et al. The risk of chronic kidney disease in tuberculosis: a
population-based cohort study. QJM 2015; 108:397-403.
13. Chung WS, Lin CL, Hung CT, et al. Tuberculosis increases the subsequent risk of acute coronary
syndrome: a nationwide population-based cohort study. Int J Tuberc Lung Dis 2014; 18:79-83.
ACCEPTED MANUSCRIPT
Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac946/6905454 by medlibrary@hanyang.ac.kr user on 29 December 2022
DOI: 10.1093/cid/ciac946 10
14. Huaman MA, Kryscio RJ, Fichtenbaum CJ, et al. Tuberculosis and risk of acute myocardial
infarction: a propensity score-matched analysis. Epidemiol Infect 2017; 145:1363-7.
15. Sheu JJ, Chiou HY, Kang JH, Chen YH, Lin HC. Tuberculosis and the risk of ischemic stroke: a 3-
year follow-up study. Stroke 2010; 41:244-9.
16. World Health Organization. The End TB Strategy: Global Strategy and Targets for Tuberculosis
Prevention, Care and Control After 2015. Geneva 2015.
17. Dorhoi A, Kaufmann SH. Perspectives on host adaptation in response to Mycobacterium
tuberculosis: modulation of inflammation. Semin Immunol 2014; 26:533-42.
18. Kaufmann SH, Dorhoi A. Inflammation in tuberculosis: interactions, imbalances and interventions.
Curr Opin Immunol 2013; 25:441-9.
19. Johnson NB, Hayes LD, Brown K, et al. CDC National Health Report: leading causes of morbidity
and mortality and associated behavioral risk and protective factors--United States, 2005-2013.
MMWR Suppl 2014; 63:3-27.
20. Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk
Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol 2020; 76:2982-3021.
21. Roth GA, Johnson C, Abajobir A, et al. Global, Regional, and National Burden of Cardiovascular
Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 2017; 70:1-25.
22. Glovaci D, Fan W, Wong ND. Epidemiology of Diabetes Mellitus and Cardiovascular Disease.
Curr Cardiol Rep 2019; 21:21.
23. Jee Y, Jung KJ, Lee S, Back JH, Jee SH, Cho SI. Smoking and atherosclerotic cardiovascular
disease risk in young men: the Korean Life Course Health Study. BMJ Open 2019; 9:e024453.
24. Pothineni NVK, Subramany S, Kuriakose K, et al. Infections, atherosclerosis, and coronary heart
disease. Eur Heart J 2017; 38:3195-201.
25. Shin DW, J. C, J.H. P, B. C. National General Health Screening Program in Korea: History,
current status, and future direction. Precision and Future Medicine 2022; 6:9-31.
26. Lee CH, Kim K, Hyun MK, Jang EJ, Lee NR, Yim JJ. Use of inhaled corticosteroids and the risk
of tuberculosis. Thorax 2013; 68:1105-13.
27. Strelitz J, Ahern AL, Long GH, et al. Moderate weight change following diabetes diagnosis and 10
year incidence of cardiovascular disease and mortality. Diabetologia 2019; 62:1391-402.
28. Jeong SM, Jeon KH, Shin DW, et al. Smoking cessation, but not reduction, reduces cardiovascular
disease incidence. Eur Heart J 2021; 42:4141-53.
29. Choi EK. Cardiovascular Research Using the Korean National Health Information Database.
Korean Circ J 2020; 50:754-72.
30. Anton SD, Duncan GE, Limacher MC, Martin AD, Perri MG. How much walking is needed to
improve cardiorespiratory fitness? An examination of the 2008 Physical Activity Guidelines for
Americans. Res Q Exerc Sport 2011; 82:365-70.
31. Pan WH, Yeh WT. How to define obesity? Evidence-based multiple action points for public
awareness, screening, and treatment: an extension of Asian-Pacific recommendations. Asia Pac J
Clin Nutr 2008; 17:370-4.
32. Khan NF, Perera R, Harper S, Rose PW. Adaptation and validation of the Charlson Index for
Read/OXMIS coded databases. BMC Fam Pract 2010; 11:1.
33. Fine JP, RJ G. A proportional hazards model for the subdistribution of a competing risk. Journal of
the American Statistical Association 1999; 94:496–509.
ACCEPTED MANUSCRIPT
Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac946/6905454 by medlibrary@hanyang.ac.kr user on 29 December 2022
DOI: 10.1093/cid/ciac946 11
34. Blondal K, Rahu K, Altraja A, Viiklepp P, Rahu M. Overall and cause-specific mortality among
patients with tuberculosis and multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2013;
17:961-8.
35. Huaman MA, Henson D, Ticona E, Sterling TR, Garvy BA. Tuberculosis and Cardiovascular
Disease: Linking the Epidemics. Trop Dis Travel Med Vaccines 2015; 1.
36. Shoenfeld Y, Sherer Y, Harats D. Atherosclerosis as an infectious, inflammatory and autoimmune
disease. Trends in Immunology 2001; 22:293-5.
37. Muefong CN, Sutherland JS. Neutrophils in Tuberculosis-Associated Inflammation and Lung
Pathology. Front Immunol 2020; 11:962.
38. Bessant R, Hingorani A, Patel L, MacGregor A, Isenberg DA, Rahman A. Risk of coronary heart
disease and stroke in a large British cohort of patients with systemic lupus erythematosus.
Rheumatology (Oxford) 2004; 43:924-9.
39. Jagpal A, Navarro-Millan I. Cardiovascular co-morbidity in patients with rheumatoid arthritis: a
narrative review of risk factors, cardiovascular risk assessment and treatment. BMC Rheumatol
2018; 2:10.
40. Nevulis MG, Baker C, Lebovics E, Frishman WH. Overview of Link Between Inflammatory
Bowel Disease and Cardiovascular Disease. Cardiol Rev 2018; 26:287-93.
41. Navaratnam V, Millett ER, Hurst JR, et al. Bronchiectasis and the risk of cardiovascular disease: a
population-based study. Thorax 2017; 72:161-6.
42. Rabe KF, Hurst JR, Suissa S. Cardiovascular disease and COPD: dangerous liaisons? Eur Respir
Rev 2018; 27.
43. World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient
care 2017.
44. Joint Committee for the Revision of Korean Guidelines for Tuberculosis Korea Centers for Disease
Control and Prevention. Korean Guidelines For Tuberculosis, 4th Edition 2020.
45. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines:
Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016; 63:e147-e95.
46. Amere GA, Nayak P, Salindri AD, Narayan KMV, Magee MJ. Contribution of Smoking to
Tuberculosis Incidence and Mortality in High-Tuberculosis-Burden Countries. Am J Epidemiol
2018; 187:1846-55.
47. Ramin B, Kam D, Feleke B, Jacob B, Jha P. Smoking, HIV and non-fatal tuberculosis in an urban
African population. Int J Tuberc Lung Dis 2008; 12:695-7.
48. Brunet L, Pai M, Davids V, et al. High prevalence of smoking among patients with suspected
tuberculosis in South Africa. Eur Respir J 2011; 38:139-46.
49. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic
mechanisms. Nat Rev Drug Discov 2005; 4:977-87.
50. Chidambaram V, Ruelas Castillo J, Kumar A, et al. The association of atherosclerotic
cardiovascular disease and statin use with inflammation and treatment outcomes in tuberculosis.
Sci Rep 2021; 11:15283.
51. Cho KS. Tuberculosis control in the Republic of Korea. Epidemiol Health 2018; 40:e2018036.
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Table 1. Baseline characteristics of the study participants
Study population
N = 121,204
TB survivors
N = 60,602
Matched controls
N = 60,602
N (%)
N (%)
N (%)
p-value*
Age, yr†
20-29
8,400 (6.9)
4,200 (6.9)
4,200 (6.9)
30-39
17,306 (14.3)
8,653 (14.3)
8,653 (14.3)
40-49
26,546 (21.9)
13,273 (21.9)
13,273 (21.9)
50-59
29,116 (24.0)
14,558 (24.0)
14,558 (24.0)
60-69
21,094 (17.4)
10,547 (17.4)
10,547 (17.4)
70-79
16,216 (13.4)
8,108 (13.4)
8,108 (13.4)
≥80
2,526 (2.1)
1,263 (2.1)
1,263 (2.1)
Sex†
Male
69,938 (57.7)
34,969 (57.7)
34,969 (57.7)
Female
51,266 (42.3)
25,633 (42.3)
25,633 (42.3)
Place of residence
<.001
Urban
54,114 (44.6)
27,724 (45.7)
26,390 (43.5)
Rural
67,090 (55.4)
32,878 (54.3)
34,212 (56.5)
Income level, lowest 20%
<.001
No
99,535 (82.1)
49,442 (81.6)
50,093 (82.7)
Yes
21,669 (17.9)
11,160 (18.4)
10,509 (17.3)
Smoking status
<.001
Never
69,575 (57.4)
33,639 (55.5)
35,936 (59.3)
Ex-smoker
20,072 (16.6)
9,186 (15.2)
10,886 (18.0)
Current
31,557 (26.0)
17,777 (29.3)
13,780 (22.7)
Alcohol consumption
<.001
None
63,170 (52.1)
31,819 (52.5)
31,351 (51.7)
Mild
47,390 (39.1)
22,541 (37.2)
24,849 (41.0)
Heavy
10,644 (8.8)
6,242 (10.3)
4,402 (7.3)
Regular physical activity
<.001
No
98,558 (81.3)
50,360 (83.1)
50,093 (82.7)
Yes
22,646 (18.7)
10,242 (16.9)
10,509 (17.3)
Body mass index, kg/m2
<.001
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<18.5
8,800 (7.2)
6,586 (10.9)
2,214 (3.6)
18.5-22.9
56,704 (46.8)
33,220 (54.8)
23,484 (38.8)
23-24.9
26,652 (22.0)
11,506 (19.0)
15,146 (25.0)
≥25
29,048 (24.0)
9,290 (15.3)
19,758 (32.6)
Charlson comorbidity index score
<.001
0-2
94,702 (78.1)
42,225 (69.7)
52,477 (86.6)
≥3
26,502 (21.9)
18,377 (30.3)
8,125 (13.4)
Comorbidities
Diabetes
15,905 (13.1)
9,523 (15.7)
6,382 (10.5)
<.001
Hypertension
26,415 (21.8)
12,659 (20.9)
13,756 (22.7)
<.001
Dyslipidemia
25,874 (21.4)
14,036 (23.2)
11,838 (19.5)
<.001
Ischemic stroke
518 (0.4)
330 (0.5)
188 (0.3)
<.001
Congestive heart failure
931 (0.8)
645 (1.1)
286 (0.5)
<.001
Data are presented as number (percentage) for categorical variables and mean ± standard deviation for numerical
variables.
N, number; TB, pulmonary tuberculosis
*P values were calculated by t-test for continuous variables and chi-square test for categorical variables.
† Matched for age, sex, and year of index date.
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Table 2. Hazard ratios and 95% confidence intervals for the incidence of ischemic heart disease and myocardial
infarction in TB survivors compared with the matched controls
Subjects
(N)
Events
(n)
Duration
(person-years)
Incidence rate
(per 1,000 person -years)
HR (95% CI)
SHR (95% CI)
Model 1
Model 2
Model 3
Competing risk model
Ischemic heart disease
Matched controls
60,602
1,228
233279.9
5.26
1 (Ref.)
1 (Ref.)
1(Ref.)
1(Ref.)
TB survivors
60,602
1,633
228241.5
7.16
1.36 (1.26,
1.47)
1.44 (1.33, 1.55)
1.21 (1.12, 1.32)
1.19 (1.10, 1.29)
Myocardial infarction
Matched controls
60,602
223
235623.7
0.95
1 (Ref.)
1 (Ref.)
1(Ref.)
1(Ref.)
TB survivors
60,602
341
230973.9
1.48
1.56 (1.32,
1.85)
1.69 (1.42, 2.02)
1.48 (1.23, 1.78)
1.45 (1.21, 1.73)
HR, hazard ratio; SHR, subdistribution hazard ratio; CI, confidence interval; TB, tuberculosis,
Model 1: Non-adjusted
Model 2: adjusted for smoking, alcohol consumption, regular physical activity, body mass index, income, and place of residence
Model 3: adjusted for smoking, alcohol consumption, regular physical activity, body mass index, income, place of residence, and Charlson comorbidity index
Competing risk model: Fine and Gray model was used for competing risk analyses taking death as the competing event and variables in Model 3 were adjusted.
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FIGURE LEGENDS
Figure 1. Selection scheme for the study population
TB, tuberculosis
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Figure 2. Kaplan-Meier curves for the risk of ischemic heart disease in tuberculosis survivors
and comparison participants
Figure 3. Kaplan-Meier curves for the risk of myocardial infarction in tuberculosis survivors and
comparison participants
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Figure 4. Subgroup analyses for the incidence of ischemic heart disease in tuberculosis survivors
and the matched controls
Adjusted for age, sex, smoking, alcohol consumption, regular physical activity, body mass index, income, place of
residence, and Charlson comorbidity index
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Figure 5. Subgroup analyses for the incidence of myocardial infarction in tuberculosis survivors
and the matched controls
Adjusted for age, sex, smoking, alcohol consumption, regular physical activity, body mass index, income, place of
residence, and Charlson comorbidity index
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