Author + information
- Min-Chul Kim, MD,
- Sung-Cheol Yun, PhD,
- Han-Bin Lee, MD,
- Pil Hyung Lee, MD,
- Seung-Whan Lee, MD,
- Sang-Ho Choi, MD, PhD,
- Yang Soo Kim, MD, PhD,
- Jun Hee Woo, MD, PhD,
- Sung-Han Kim, MD, PhD∗ ( and )
- Sun U. Kwon, MD, PhD
- ↵∗Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
The association between herpes zoster (HZ) and the occurrence of stroke and myocardial infarction (MI) remains uncertain because confounding factors have not been adequately controlled in previous studies. If the association were established, it would have significant implications for public health, because some cases of stroke and MI caused by HZ might be potentially preventable with antiviral agents and vaccination. In the present work, we adjusted comprehensively for confounding factors, and assessed the risk of the composite of cardiovascular events including stroke and MI associated with HZ by propensity score matching.
We used the “medical check-up” database, a subset database of the National Health Insurance Service covering the entire Korean population. This cohort consisted of approximately 570,000 people who received a medical check-up that provided comprehensive social and medical information. The subjects were followed up from 2002 to 2013. They are representative of the total population of South Korea of all ages and regions of the country (1). We identified patients newly diagnosed with HZ, stroke, and MI using the relevant International Classification of Diseases-10 diagnostic codes.
We conducted a propensity score-matched analysis to evaluate the impact of HZ upon the risk of stroke and MI. A total of 519,880 persons were observed from 2003 to 2013. During the observation period, there were 23,233 (4%) cases of HZ. We constructed a propensity-matched cohort. The cohort was created by matching the HZ in the relevant year and identified non-HZ individuals on the logit of the propensity score using calipers of width equal to 0.2 of the standard deviation of the logit of the propensity score (C-statistic = 0.67). They were observed for the development of stroke and MI in subsequent years. Finally, 23,213 patients with HZ, and the same number of propensity score-matched control subjects were analyzed.
Female sex was more common in the HZ group, and risk factors of stroke and MI such as old age, hypertension, diabetes, dyslipidemia, angina pectoris, peripheral vascular disease, rheumatoid disease, and malignancy were also associated with the HZ group more frequently. However, the HZ group had medically advantageous lifestyles, such as less smoking, less intake of alcohol, more exercise, and a higher representation of the prosperous economic class. After propensity score matching, every variable was adjusted, by which the standardized differences for each became <10%.
The composite of cardiovascular events, stroke, and MI in the HZ group was higher than in the non-HZ group (Table 1). The differences of absolute incidences for stroke and MI in HZ group when compared to non-HZ group were 1.34 per 1,000 person-years (95% confidence intervals [CI]: 0.71 to 1.97) and 0.80 per 1,000 person-years (95% CI: 0.41 to 1.18), respectively. The hazard ratios for stroke were highest in the subgroup under 40 years of age, a relatively younger population with fewer risk factors for atherosclerosis, and gradually decreased with age. Regarding temporal relationship, the risks of both stroke and MI were highest in the first year after the onset of HZ and then tended to decrease with time, whereas it was evenly distributed in the non-HZ group (data not shown).
The association of varicella-zoster virus (VZV) with stroke and MI is reminiscent of previous “infection hypotheses” such as the association between chlamydia infection and atherosclerosis, which was eventually rejected by the WIZARD (Weekly Intervention With Zithromax for Atherosclerosis and Its Related Disorders) study demonstrating that antibiotics against C. pneumoniae failed to improve outcomes in coronary artery diseases (2). This skeptical position with regard to the association of chlamydia with atherosclerosis should not be directly applied to the association of VZV with stroke and MI. VZV is the only virus for which there is clear evidence of viral DNA and antigen in areas of ischemia or infarction in cerebral arteries (3). Moreover, the diagnosis of HZ such as the presence of VZV in the saliva of patients with HZ is more direct than that of chlamydia infection, which was largely based on serology. There are several possible biological causes of stroke and MI after HZ: 1) VZV replication adjacent to an artery, which leads to inflammation of the artery and subsequent thrombosis and rupture; 2) repeated subclinical reactivation of VZV and a subsequent effect on the arteries; 3) transaxonal migration of VZV in a centripetal direction; 4) increased sympathetic tone, blood pressure, and adverse emotional reactions; and 5) the altered immunological status caused by VZV reactivation and subsequent vulnerability to cerebrovascular events.
In conclusion, we have demonstrated that HZ significantly increases the risk of stroke and MI even after rigorously adjusting possible confounding factors in a large population cohort. In propensity score-matched analysis, HZ raised the risks of the composite of cardiovascular events, stroke, and MI by 41%, 35%, and 59%, respectively. The risks were especially high in the relatively young who have fewer risk factors for atherosclerosis. Furthermore, there was a substantial temporal link between HZ and the occurrence of stroke and MI.
Please note: This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI15C1763). This study was based on the National Health Insurance Service database of South Korea (NHS-REQ0000002692). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Min-Chul Kim and Sung-Cheol Yun contributed equally to this work.
- 2017 American College of Cardiology Foundation
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