Analysis Strengthens Herpes Zoster Link With Stroke, MI

Patrice Wendling

July 11, 2017

SEOUL, REPUBLIC OF KOREA — Newly diagnosed herpes zoster (HZ) significantly raised the risks of stroke and MI in the first year after infection in a propensity score-matched analysis[1]. Perhaps more surprisingly, the risks were especially high in those under 40 years of age, a group that typically has fewer atherosclerosis risk factors.

Commenting to|Medscape Cardiology, study author Dr Sung-Han Kim (University of Ulsan College of Medicine, Seoul, Republic of Korea) said, "This study adds strong evidence of a causal relationship between HZ and cardiovascular diseases in terms of strength of associations, its specificity, and the temporal relationship."

He added, "Clinicians should be mindful of this important epidemiological association until further clinical studies have identified the appropriate clinical characteristics and biomarkers to differentiate patients with HZ-related stroke and myocardial infarction from other causes and until further epidemiological studies have elucidated the effect of antiviral-agent use or vaccination on cardiovascular outcomes."

Prior studies have reported similar increased risks of CV events following HZ, but uncertainty remains because they inadequately controlled for confounding factors, the authors note in a letter published in the July 11, 2017 issue of the Journal of the American College of Cardiology.

For the study, the researchers examined clinical information from 519,880 patients followed from 2003 to 2013 in the "medical checkup database," a subset of the National Health Insurance Service database covering the entire Korean population. The risk of the composite of cardiovascular events including stroke and MI was assessed in 23,233 patients diagnosed with HZ and matched to the same number of controls without HZ using propensity-score matching.

At baseline, the HZ group was more likely to be female than the non-HZ group and to have CV risk factors such as old age, hypertension, diabetes, dyslipidemia, angina, peripheral vascular disease, and rheumatoid arthritis, but they were also more likely to report less smoking, less alcohol use, more exercise, and a higher economic status.

Results of the propensity-score–matched analysis showed that HZ was associated with a 41% increased risk of composite cardiovascular events (hazard ratio [HR] 1.42; 95% CI 1.25–1.59); a 35% increase in stroke (HR 1.35; 95% CI 1.18–1.54); and a 59% increased risk of MI (HR 1.59; 95% CI 1.27–2.01).

When examined by age, the hazard ratios were highest among those 40 years or younger and gradually decreased with age.

Risks for Cardiovascular Events by Age After Herpes Zoster*
Age, y Composite CV events Stroke MI
HR (95% CI) P HR (95%CI) P HR (95% CI) P
<40 2.42 (1.26–4.66) 0.008 3.74 (1.51-9.25) 0.004 1.45 (0.54-3.90) 0.464
41–50 1.63 (1.16–2.28) 0.005 1.49 (1.00-2.22) 0.052 1.47 (0.84-2.55) 0.177
51–60 1.53 (1.21–1.94) <0.001 1.39 (1.05-1.84) 0.022 1.96 (1.28-2.99) 0.002
61–70 1.24 (1.02–1.50) 0.030 1.25 (1.01-1.54) 0.038 1.24 (0.82-1.86) 0.306
>71 1.35 (1.04–1.75) 0.024 1.24 (0.93-1.67) 0.150 1.91 (1.16-3.13) 0.011
*Propensity score-matched analysis

The risks of stroke and MI were highest in the first year after HZ infection and tended to decrease with time but were evenly distributed in the non-HZ group.

The authors suggest there are several possible biological causes of stroke and MI after HZ including varicella-zoster virus (VZV) replication adjacent to an artery, which leads to subsequent thrombosis and rupture; effects on the arteries from repeated subclinical VZV reactivation; and transaxonal migration of VZV in a centripetal direction.

Kim said further studies are needed on whether or how much zoster vaccination may reduce the risk of cardiovascular disease. In addition, it's important to find the subgroup of stroke or MI that is most associated with VZV.

"For example, we are currently trying to find evidence for the subclinical reactivation of VZV by saliva VZV DNA detection or VZV-specific T-cell responses in young patients with stroke," he said. "If we compare the MRI findings of stroke patients who have evidence of VZV reactivation with those of stroke patients without evidence of VZV reactivation, differences between the two groups, such as involvement at gray-white matter junctions, might provide clinical clues to differentially identify the VZV-related stroke subgroup."

He concluded, "When we classify VZV-related stroke type as a new category of stroke according to clinical characteristics, MRI findings, saliva VZV DNA [polymerase chain reaction] PCR, and VZV-specific T-cell response, antiviral therapy or vaccination might prevent further stroke attacks in these patients, which would change the clinical management of stroke."

The study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea. The authors report no relevant financial relationships.

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