Increased Risk of Stroke, CV Event after Herpes Zoster Persists Beyond 12 Years

A study by researchers at the Brigham and Women’s Hospital (BWH) shows that having shingles, or herpes zoster (HZ), is associated with a nearly 30% greater long-term risk of a major cardiovascular (CV) event. The longitudinal study which followed more than 200 000 men and women also found that the elevated risk may persist for 12 years or longer after shingles has resolved.

“Our findings suggest there are long-term implications of shingles and highlight the importance of public health efforts for prevention,” said lead author Sharon Curhan, MD, ScM, a physician and epidemiologist in the Channing Division of Network Medicine at BWH, in a hospital announcement. As the American population ages, increasing the numbers at risk for the disease and its sequelae, Curhan adds, broadening uptake of shingles vaccination, penetration of which has been low to date, has the potential to reduce the disease burden as well as the risk of future CV complications.

The known and unknown

Known, common, and serious complications of HZ include postherpetic neuralgia and HZ ophthalmicus. Less well understood, write Churhan and colleagues in the Journal of the American Heart Association, is the long-term effect of reactivation of the varicella zoster virus (VZV) on the vasculature where VZV has been detected in both large and small vessels. The resulting inflammatory response and pathologic remodeling can augment the risk for vessel blockage, ischemia, and major CV events, they state.

To look beyond existing epidemiologic studies of HZ and risk of stroke and myocardial infarction (MI) days or weeks after the HZ event, Curhan and BWH colleagues tapped 3 large ongoing US cohorts with long-term participant follow-up for a prospective assessment of whether HZ is independently associated with higher long-term risk of stroke or coronary heart disease (CHD).

The investigators built the final study cohort with women participating in the Nurses’ Health Study (2000-2016; n=79 658), and in the Nurses’ Health Study II (2001-2017; n=93 932) and men participating in the Health Professionals Follow-up Study (2004-2016; n=31 440).

Information on HZ, stroke, and CHD was collected from participant questionnaires completed at baseline and every 2 years and was confirmed by medical record review. Curhan et al defined baseline in each cohort based on the year when information on the HZ event was available through the most recent follow-up cycle. Participants with a history of stroke or CHD before study baseline were excluded.

Cox proportional hazards regression models were used to estimate multivariable‐adjusted hazard ratios (MVHR) for stroke and for CHD according to years since HZ compared with never having HZ. The researchers also conducted stratified analyses among participants with and without potentially immunocompromising conditions, eg, cancer, rheumatoid arthritis, asthma, diabetes, or oral steroid use.

Findings

The final study cohort for analyses numbered 205 030 of which 173 617 were women and 31 440 were men. The majority was White and mean ages were 56 and 69.5 years, respectively.

There were largely no appreciable differences between participants with and without a history of HZ, the authors point out, however, participants with a history of HZ were slightly older vs those who had not had the infection and were also somewhat more likely to have any of the conditions that could compromise immunity.

During >2 million person-years of follow-up, investigators documented 3603 incident stroke and 8620 incident CHD cases. Overall, they found that a history of HZ was significantly and independently associated with higher long‐term risk of stroke and CHD.

In pooled analyses, compared with individuals with no history of HZ, the MVHRs (95% CIs) for stroke were:

• 1.05 (0.88–1.25) among those with 1 to 4 years since HZ
• 1.38 (1.10–1.74) for 5 to 8 years
• 1.28 (1.03–1.59) for 9 to 12 years
• 1.19 (0.90–1.56) for ≥13 years

For CHD, the corresponding MVHRs (95% CIs) were:

• 1.13 (1.01–1.27) for 1 to 4 years
• 1.16 (1.02–1.32) for 5 to 8 years
• 1.25 (1.07–1.46) for 9 to 12 years
• 1.00 (0.83–1.21) for ≥13 years

Findings from stratified analyses comparing association of HZ and long-term risk of stroke and CHD in participants with and without immunocompromising conditions “suggested” that that the magnitude of increased risk for stroke after ≥5 years since HZ was higher among women, but P for interaction was significant only in the NHS II; the same held true for increased risk for CHD. Among men, the investigators found no variation by immune status but note, too, that the absolute number of men with HZ was small.

The authors describe several potential mechanisms underlying the observed link between HZ and long-term risk of a major CVD event including that VZV is “the only human virus demonstrated to replicate in arteries” and to result in vasculopathy. Those vascular changes can lead to “alterations in arterial caliber and contractility, and vessel wall damage, arterial dissection, or aneurysm could trigger an ischemic or hemorrhagic CVD event.”

Varicella zoster virus is “the only human virus demonstrated to replicate in arteries” and to result in vasculopathy. Those vascular changes can lead to “alterations in arterial caliber and contractility, and vessel wall damage, arterial dissection, or aneurysm could trigger an ischemic or hemorrhagic CVD event.

In addition, VZV vasculopathy may be “chronic and protracted,” so that vascular changes could increase the risk of a cerebrovascular or CV event many years after an episode of HZ.

Their findings, the authors conclude, “underscore the importance of public health efforts for prevention.”

Study strengths, the authors write, include the longitudinal design and large independent cohorts with long follow-up and high retention. Self-report of information on HZ is noted as a limitation, including no access to records of dermatomal involvement, treatments, complications, or vaccination status.

Reference: Curhan SG, Kawai K, Yawn B, et al. Herpes zoster and long-term risk of cardiovascular disease. J Am Heart Assoc. 2022. Published online November 16, 2022. doi:10.1161/JAHA.122.027451