Abstract
Background
We investigated the longitudinal association of herpes zoster (HZ), commonly known as “shingles,” and long‐term risk of stroke or coronary heart disease (CHD) among participants in 3 large US cohorts, the NHS (Nurses' Health Study), NHS II (Nurses' Health Study II), and HPFS (Health Professionals Follow‐Up Study).
Methods and Results
Participants were 79 658 women in the NHS (2000–2016), 93 932 women in the NHS II (2001–2017), and 31 440 men in the HPFS (2004–2016), without prior stroke or CHD. Information on HZ, stroke, and CHD was collected on biennial questionnaires and confirmed by medical record review. Cox proportional hazards regression models were used to estimate multivariable‐adjusted hazard ratios for stroke and for CHD according to years since HZ compared with never HZ. During >2 million person‐years of follow‐up, 3603 incident stroke and 8620 incident CHD cases were documented. 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 multivariable‐adjusted hazard ratios (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 among those with 5 to 8 years since HZ, 1.28 (1.03–1.59) among those with for 9 to 12 years since HZ, and 1.19 (0.90–1.56) among those with ≥13 years since HZ. For CHD, the corresponding multivariable‐adjusted hazard ratios (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, and 1.00 (0.83–1.21) for ≥13 years.
Conclusions
HZ is associated with higher long‐term risk of a major cardiovascular event. These findings suggest there are long‐term implications of HZ and underscore the importance of prevention.
Keywords: coronary disease, follow‐up studies, herpes zoster, myocardial infarction, public health, stroke
Subject Categories: Cardiovascular Disease, Epidemiology, Risk Factors
Nonstandard Abbreviations and Acronyms
- HPFS
Health Professionals Follow‐Up Study
- HZ
herpes zoster
- MVHR
multivariable‐adjusted hazard ratio
- NHS
Nurses' Health Study
- NHS II
Nurses' Health Study II
Clinical Perspective.
What Is New?
This study demonstrates that herpes zoster is associated with an almost 30% higher long‐term risk of a major cardiovascular event.
The elevated risk of a major cardiovascular event may persist for ≥12 years following herpes zoster.
The elevated risk may be greater among those with potentially immunocompromising conditions or immunosuppressive treatments.
What Are the Clinical Implications?
These findings suggest there are long‐term cardiovascular implications of herpes zoster.
The availability of a safe and effective vaccine provides an opportunity to reduce the burden of herpes zoster and reduce the risk of subsequent cardiovascular complications.
Almost all individuals aged ≥50 years in the United States have been infected with the varicella zoster virus (VZV) and therefore are at risk for the development of herpes zoster (HZ), or “shingles.” HZ occurs in both immunocompetent and immunocompromised individuals, and the incidence increases with age, reduced cell‐mediated immunity, or immunosuppressive therapy. 1 , 2 , 3 , 4 Approximately 1 in 3 individuals will develop HZ during their lifetime, and the projected burden is expected to increase because of the demographic shift to a more aged population, increasing numbers of immunocompromised individuals, and increasing use of corticosteroids and immunosuppressive medications. 5 , 6 , 7 , 8 , 9
Several serious chronic complications of HZ can occur, most commonly postherpetic neuralgia 5 and HZ ophthalmicus, 10 but long‐term longitudinal information on HZ and risk of other adverse health outcomes is scant. VZV vasculopathy can complicate HZ and is caused by productive viral infection of the vasculature. 11 A growing body of evidence suggests VZV‐related vasculopathy plays a role in the pathogenesis of cardiovascular disorders, including stroke and coronary heart disease (CHD). 11 , 12 , 13 , 14 , 15 , 16 , 17 VZV has been detected in large and small blood vessels; and local inflammation, pathologic vascular remodeling, and chronic arterial changes can increase risk of subsequent vessel occlusion, ischemia, and a cardiovascular event. 18 , 19 HZ‐related systemic inflammation, autoimmune responses, or hemodynamic changes could also lead to a cardiovascular event. 12 , 20 , 21 Epidemiologic studies of HZ and risk of stroke and myocardial infarction (MI) demonstrate an increased risk of stroke and MI close to the HZ event 13 ; however, there is limited information on the long‐term association between HZ and cardiovascular events, particularly in the US population. Therefore, we prospectively investigated whether HZ is independently associated with higher long‐term risk of subsequent stroke or CHD in >200 000 women and men in 3 large ongoing US cohorts with long‐term follow‐up, the NHS (Nurses' Health Study), the NHS II (Nurses' Health Study II), and the HPFS (Health Professionals Follow‐Up Study). We also evaluated whether the associations differed among adults with potentially immunocompromising conditions.
METHODS
The data that support the findings of this study are available from the corresponding author on reasonable request.
Study Population
The NHS was established in 1976 when 121 700 female registered nurses, aged 30 to 55 years, were enrolled by completing a baseline questionnaire. In 1989, the NHS II was established and enrolled 116 429 female registered nurses, aged 25 to 42 years. The HPFS began in 1986 and enrolled 51 529 male health professionals, aged 40 to 75 years. Participants completed questionnaires at baseline and every 2 years on a wide range of demographic, health, diet, and lifestyle factors, including detailed information on health history and medication use. The follow‐up rates in all 3 cohorts exceed 90% of eligible person‐time. 22 , 23 For the present analyses, baseline was defined in each cohort based on the year when information on date of HZ event was first available through most recent follow‐up cycle (NHS: 2000–2016; NHS II: 2001–2017; and HPFS: 2004–2016). We excluded participants for whom the year of their HZ event was not provided and those with a history of stroke or CHD before study baseline. In total, 79 658 women in the NHS, 93 932 women in the NHS II, and 31 440 men in the HPFS were included in the analyses (total n=205 030). The Institutional Review Boards of Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health approved the study protocol. The return of the questionnaires was considered to imply informed consent.
Ascertainment of HZ (“Shingles”)
Information on history of “shingles” (HZ) and the date it occurred was collected on the 2000, 2004, 2008, and 2012 NHS questionnaires, the 2001, 2005, 2013, and 2017 NHS II questionnaires, and the 2004, 2006, and 2008 HPFS questionnaires. Participants were asked about clinician‐diagnosed “shingles” and the year of diagnosis. To confirm the validity of self‐report in our participants, we mailed a supplemental questionnaire to 99 NHS women that asked for permission to obtain medical records relating to the diagnosis of shingles, which were reviewed by a physician investigator (G.C.C.). The diagnosis of HZ was confirmed in 97%, demonstrating that self‐reported diagnosis of shingles (HZ) in this cohort of nurses is highly reliable. Notably, the participants in all 3 of our cohorts are health care professionals, and the reliability of health‐related information collected from our participants has been demonstrated for a large number of health outcomes. 22 The primary exposure for this study was categorized according to time (in years) since the participant's HZ event. Those with no history of HZ were the referent group.
Ascertainment of Stroke
Stroke was classified as total stroke, encompassing ischemic stroke and hemorrhagic stroke, confirmed by physician review of medical records according to criteria specified in the National Survey of Stroke, 24 requiring evidence of a sudden or rapid onset of neurologic deficit that persisted for >24 hours or until death. Participants who reported a nonfatal stroke on a biennial questionnaire were asked for permission to review their medical records. Deaths were reported by next of kin or postal authorities or determined by systematic searches of the National Death Index, and permission for medical records was sought. Our group previously reported that 98% of the deaths in each cohort are ascertained. 25 , 26 Cases of nonfatal stroke that were confirmed by letter/interview but lacked sufficient medical documentation were considered probable stroke. We considered both stroke confirmed by medical record review and probable stroke as cases in our analyses.
Ascertainment of CHD
CHD was defined as nonfatal or fatal MI, fatal CHD, or coronary revascularization procedure (coronary artery bypass graft or percutaneous transluminal coronary angioplasty). Participants who reported an incident event on a biennial questionnaire were asked for permission to obtain medical records, which were reviewed by physicians who were blinded to the exposure status and the specifc research question under study. Nonfatal MI was confirmed according to the World Health Organization criteria, which required typical symptoms plus diagnostic electrocardiographic findings or elevated enzyme levels. 27 Fatal CHD was identified by medical records or autopsy reports or if CHD was listed as the cause of death on the death certificate along with prior evidence of CHD. The study designated as probable fatal CHD deaths when no medical records surrounding the death were available, but CHD was the underlying cause on the death certificate or National Death Index search, or a family member provided supporting information on the diagnosis. Deaths were identified by report by the next of kin or the postal system or by searching the National Death Index using the methods described for stroke above. 25 , 26 We considered both CHD confirmed by medical record review and probable CHD as cases in our analyses, as well as self‐reported revascularization procedures. 28 , 29
Ascertainment of Covariates
In our multivariable‐adjusted analyses, we adjusted for several factors that could potentially be related to HZ and stroke or CHD, including age, race, smoking history, body mass index, waist circumference, physical activity, medical conditions strongly related to cardiovascular risk (eg, diabetes, hypertension, and elevated cholesterol), use of aspirin, thiazide or loop diuretics, statins, and antihypertensive medication, diet quality (Alternative Healthy Eating Index 2010) score, menopausal status (women), postmenopausal hormone therapy use (women), oral contraceptive use (NHS II), family history of heart disease (defined as maternal history of MI before 65 years of age or paternal history of MI before 55 years of age), and self‐reported medical conditions that potentially compromise immunity because of disease or treatment (eg, cancer other than nonmelanoma skin cancer, rheumatoid arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, asthma, diabetes, chronic obstructive pulmonary disease, and oral steroid use). Covariate information, including age, weight, physical activity, smoking status, medication use, and physician diagnosis of chronic diseases, was assessed and updated every 2 to 4 years by biennial questionnaires administered throughout follow‐up. Diet information was collected every 4 years using a validated semiquantitative food frequency questionnaire. 30 , 31 , 32 , 33 Among the women in the NHS and NHS II, information on menopausal status, postmenopausal hormone therapy, and oral contraceptive use (NHS II only) was also obtained. Self‐reported information on height and weight was used to calculate body mass index. If covariate information was missing, we carried the information forward from up to 2 previous questionnaire cycles. The validity of covariate information collected in these cohorts has been demonstrated and is described in previous publications. 22 , 28 , 34 , 35
Statistical Analysis
The short‐term (up to 1 year) relation of HZ and cardiovascular disease (CVD) outcomes has been demonstrated previously. 13 This study focuses on long‐term relations. The analyses were conducted using a prospective design, with information on HZ collected before the stroke or CHD event. We had information on the precise date of the CVD event, but the reporting of the date of HZ was less precise. To reduce the possibility that the CVD event preceded the episode of HZ, we censored participants who reported their HZ and had a stroke or CHD event within ±12 months. Thus, our study did not evaluate the short‐term relation of HZ and CVD. Person‐time was calculated for each participant based on the return date of the questionnaire to the diagnosis of stroke, CHD, death, or the end of follow‐up, whichever occurred first. Time (in years) since the HZ event was calculated based on the duration of the time interval from the reported diagnosis of HZ until the beginning of each 2‐year time period. HZ and covariate status were updated with each time period. We categorized time since HZ as never, 1 to 4 years since HZ, 5 to 8 years since HZ, 9 to 12 years since HZ, and ≥13 years since HZ. We used Cox proportional hazards models with time‐varying covariates and age as the underlying time scale, with stratification by calendar time (in 2‐year intervals), to estimate hazard ratios (MVHRs [95% CIs]) and assess the association between time since HZ and the subsequent risk of stroke or CHD event. In each cohort, separate analyses were conducted for risk of stroke, risk of CHD, and risk of a composite CVD outcome (a composite of stroke or CHD, whichever came first). We also performed pooled analyses for each outcome with the use of fixed‐effects meta‐analysis with inverse‐variance weighting. Heterogeneity was assessed with the I2 statistic, and low to moderate heterogeneity was observed (I2<40%). We conducted sensitivity analyses that restricted the CHD outcome to fatal and nonfatal MI and fatal CHD events and censored those who reported coronary revascularization procedures (coronary artery bypass graft or percutaneous transluminal coronary angioplasty) during follow‐up. We also conducted stratified analyses among those with and without potentially immunocompromising health conditions, including cancer, rheumatoid arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, asthma, diabetes, chronic obstructive pulmonary disease, or oral steroid use.
RESULTS
The total study sample included 79 658 women (mean [SD] age, 65.8 [7.1] years at baseline) in the NHS (2000–2021), 93 932 women (mean [SD] age, 46.2 [4.7] years) in the NHS II (2001–2021), and 31 440 men in the HPFS (mean [SD] age, 69.5 [8.6] years) (total n=205 030). The age‐standardized characteristics of study participants according to history of HZ at a midpoint during follow‐up in each of the cohorts are shown in Table 1 (NHS: 2008; NHS II: 2009; and HPFS: 2008). Participants with a history of HZ were slightly older than those with no history of HZ, and they were slightly more likely to have conditions that could potentially compromise immunity, including cancer, rheumatoid arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, asthma, chronic obstructive pulmonary disease, and oral steroid use. There were no other appreciable differences.
Table 1.
Age‐Standardized Characteristics of Participants in the NHS, NHS II, and HPFS at Midpoint of Follow‐Up
| Time since HZ, y | |||||
|---|---|---|---|---|---|
| Never HZ | 1–4 | 5–8 | 9–12 | ||
| Characteristic | (n=48 908) | (n=2455) | (n=2068) | (n=1302) | |
| NHS (2008) | |||||
| Age, y | 72.4 (6.7) | 73.0 (6.6) | 73.9 (6.9) | 73.9 (7.0) | |
| Race, White, % | 94.1 | 95.1 | 95.1 | 94.6 | |
| Body mass index, kg/m2 | 26.5 (5.3) | 26.2 (5.1) | 26.5 (5.5) | 26.6 (5.3) | |
| Waist circumference, cm* | 86.4 (13.1) | 86.4 (12.7) | 86.7 (13.6) | 86.8 (12.5) | |
| Physical activity, METS/wk | 18.7 (24.0) | 18.5 (23.1) | 18.1 (21.5) | 17.9 (21.8) | |
| Never smoker, % | 46.2 | 46.5 | 45.0 | 45.5 | |
| Past smoker, % | 48.2 | 48.9 | 50.4 | 50.3 | |
| Current smoker, % | 5.6 | 4.6 | 4.6 | 4.3 | |
| AHEI 2010 score | 60.0 (12.2) | 60.1 (11.2) | 60.2 (12.0) | 60.3 (12.1) | |
| History of cancer, % | 21.8 | 25.1 | 23.9 | 27.0 | |
| Rheumatoid arthritis, % | 11.2 | 13.4 | 14.0 | 13.4 | |
| Crohn's disease/ulcerative colitis, % | 2.6 | 3.5 | 3.5 | 3.6 | |
| Systemic lupus erythematosus, % | 1.0 | 1.4 | 1.8 | 1.7 | |
| Asthma, % | 13.3 | 14.4 | 16.8 | 14.7 | |
| COPD, % | 7.5 | 7.9 | 9.3 | 9.8 | |
| Oral steroid use, % | 4.6 | 6.6 | 6.4 | 6.8 | |
| Diabetes, % | 12.5 | 11.3 | 12.2 | 12.5 | |
| Hypertension, % | 63.4 | 63.6 | 64.3 | 63.2 | |
| Elevated cholesterol, % | 72.2 | 73.3 | 73.9 | 75.5 | |
| Aspirin use, ≥2 d/wk, % | 61.5 | 59.9 | 59.5 | 58.6 | |
| Antihypertensive use, % | 51.5 | 52.9 | 53.8 | 54.7 | |
| Statin use, % | 48.3 | 48.7 | 49.5 | 49.6 | |
| Thiazide or loop diuretic use, % | 28.4 | 30.3 | 31.3 | 29.8 | |
| Menopausal, yes, % | 100 | 100 | 100 | 100 | |
| Past hormone therapy use, % | 62.0 | 65.4 | 63.9 | 61.7 | |
| Current hormone therapy use, % | 11.4 | 11.7 | 12.5 | 12.4 | |
| Family history of heart disease, % | 17.8 | 18.0 | 17.8 | 17.4 | |
| Never HZ | 1–4 | 5–8 | 9–12 | ≥13 | |
|---|---|---|---|---|---|
| (n=66 127) | (n=1310) | (n=1486) | (n=1076) | (n=992) | |
| NHS II (2009) | |||||
| Age, y | 54.4 (4.6) | 55.9 (4.4) | 55.5 (4.5) | 55.8 (4.6) | 55.0 (4.8) |
| Race, White, % | 94.5 | 95.3 | 94.6 | 96.2 | 95.6 |
| Body mass index, kg/m2 | 27.5 (6.4) | 28.0 (6.4) | 28.0 (6.5) | 28.0 (6.7) | 27.9 (6.3) |
| Waist circumference, cm* | 87.2 (14.8) | 88.2 (14.8) | 88.4 (15.0) | 88.1 (15.1) | 87.9 (14.7) |
| Physical activity, METS/wk | 24.2 (29.6) | 23.0 (28.0) | 20.9 (27.7) | 22.1 (25.7) | 21.1 (25.5) |
| Never smoker, % | 65.7 | 64.7 | 64.3 | 65.0 | 62.7 |
| Past smoker, % | 28.4 | 30.6 | 29.8 | 27.8 | 29.5 |
| Current smoker, % | 5.7 | 4.7 | 5.6 | 6.9 | 7.6 |
| AHEI 2010 score | 62.6 (12.8) | 62.6 (12.7) | 62.3 (12.2) | 62.6 (12.5) | 61.3 (12.5) |
| History of cancer, % | 9.5 | 13.4 | 10.0 | 11.3 | 11.1 |
| Rheumatoid arthritis, % | 3.6 | 4.3 | 6.6 | 3.7 | 6.5 |
| Crohn's disease/ulcerative colitis, % | 2.0 | 2.8 | 3.8 | 4.0 | 2.9 |
| Systemic lupus erythematosus, % | 0.8 | 1.4 | 1.8 | 1.7 | 2.4 |
| Asthma, % | 17.7 | 21.7 | 24.0 | 23.9 | 26.3 |
| COPD, % | 2.9 | 3.4 | 4.4 | 4.6 | 4.7 |
| Oral steroid use, % | 4.5 | 9.1 | 8.8 | 7.9 | 7.9 |
| Diabetes, % | 9.7 | 9.6 | 11.7 | 10.6 | 11.7 |
| Hypertension, % | 32.5 | 33.5 | 35.4 | 35.0 | 37.0 |
| Elevated cholesterol, % | 49.0 | 52.7 | 54.4 | 55.2 | 52.1 |
| Aspirin use, ≥2 d/wk, % | 36.7 | 36.6 | 40.2 | 41.1 | 39.4 |
| Antihypertensive use, % | 24.0 | 27.0 | 27.3 | 27.6 | 27.0 |
| Current statin use, % | 24.7 | 28.7 | 29.0 | 32.9 | 27.1 |
| Thiazide or loop diuretic use, % | 14.5 | 16.6 | 17.6 | 16.9 | 17.9 |
| Menopausal, yes, % | 67.7 | 70.5 | 71.5 | 70.3 | 70.3 |
| Current hormone therapy use, % | 14.0 | 14.4 | 16.0 | 15.9 | 16.3 |
| Family history of heart disease, % | 42.0 | 42.5 | 45.0 | 48.0 | 44.5 |
| Never HZ | 1–4 | 5–8 | 9–12 | ≥13 | |
|---|---|---|---|---|---|
| (n=17 574) | (n=588) | (n=316) | (n=245) | (n=406) | |
| HPFS (2008) | |||||
| Age, y | 71.1 (7.7) | 73.2 (7.9) | 73.6 (7.8) | 73.3 (7.9) | 74.0 (8.3) |
| Race, White, % | 90.9 | 92.9 | 91.0 | 90.5 | 91.6 |
| Body mass index, kg/m2 | 26.1 (3.8) | 26.1 (3.7) | 25.7 (3.5) | 25.6 (3.5) | 25.8 (3.7) |
| Waist circumference, cm* | 100.3 (10.9) | 100.6 (10.9) | 99.7 (9.6) | 98.9 (10.2) | 99.5 (10.4) |
| Physical activity, METS/wk | 42.1 (35.5) | 42.0 (35.1) | 44.4 (38.1) | 36.6 (30.2) | 44.6 (34.0) |
| Never smoker, % | 42.1 | 40.4 | 41.6 | 44.1 | 45.4 |
| Past smoker, % | 42.6 | 46.4 | 42.0 | 44.9 | 41.5 |
| Current smoker, % | 2.5 | 1.8 | 1.5 | 2.0 | 2.7 |
| AHEI 2010 score | 62.6 (11.9) | 62.6 (11.3) | 63.1 (11.7) | 63.8 (12.7) | 62.2 (11.5) |
| History of cancer, % | 23.8 | 25.9 | 23.7 | 27.5 | 27.3 |
| Rheumatoid arthritis, % | 7.3 | 8.8 | 8.0 | 9.7 | 7.7 |
| Crohn's disease/ulcerative colitis, % | 2.1 | 2.2 | 2.9 | 4.0 | 3.0 |
| Asthma, % | 10.3 | 11.6 | 10.9 | 11.9 | 8.7 |
| COPD, % | 3.6 | 6.0 | 3.7 | 4.5 | 3.3 |
| Oral steroid use, % | 1.6 | 1.3 | 2.3 | 3.0 | 1.6 |
| Diabetes, % | 10.2 | 11.3 | 13.5 | 6.4 | 9.6 |
| Hypertension, % | 53.7 | 57.5 | 55.7 | 52.0 | 53.9 |
| Elevated cholesterol, % | 61.9 | 64.8 | 59.0 | 66.9 | 66.5 |
| Aspirin use, ≥2 d/wk, % | 66.2 | 63.6 | 65.0 | 74.7 | 65.8 |
| Antihypertensive use, % | 46.1 | 47.5 | 47.2 | 47.2 | 49.4 |
| Current statin use, % | 46.4 | 52.2 | 47.4 | 45.8 | 48.2 |
| Thiazide or loop diuretic use, % | 18.0 | 20.5 | 15.6 | 19.5 | 18.0 |
| Family history of heart disease, % | 14.0 | 14.3 | 11.2 | 14.0 | 16.1 |
Values are means (SDs) for continuous variables; percentages are given for categorical variables and are standardized to the age distribution of the study population. Values of polytomous variables may not sum to 100% because of rounding. AHEI indicates Alternative Healthy Eating Index; COPD, chronic obstructive pulmonary disease; HPFS, Health Professionals Follow‐Up Study; HZ, herpes zoster; METS, metabolic equivalents; NHS, Nurses' Health Study; and NHS II, Nurses' Health Study II.
Waist circumference assessed in 2000 (NHS), 2005 (NHS II), and 1996 (HPFS).
HZ and Long‐Term Risk of Incident Stroke
During a total of 2 471 975 person‐years of follow‐up, 2461 cases of incident stroke among women in the NHS, 537 incident strokes among women in the NHS II, and 605 incident strokes among men in the HPFS were documented and included in the analysis. History of HZ was significantly and independently associated with higher long‐term risk of incident stroke (Table 2). In pooled multivariable analyses accounting for multiple potential confounding factors, compared with individuals with no history of HZ, the MVHRs (95% CIs) for incident stroke were 1.05 (0.88–1.25) among those with 1 to 4 years since HZ, 1.38 (1.10–1.74) among those with 5 to 8 years since HZ, 1.28 (1.03–1.59) among those with 9 to 12 years since HZ, and 1.19 (0.90–1.56) among those with ≥13 years since HZ. The findings for the individual cohorts are also shown in Table 2.
Table 2.
HZ and Long‐Term Risk of Stroke in the NHS, NHS II, and HPFS
| Time since HZ, y | |||||
|---|---|---|---|---|---|
| Variable | Never | 1–4 | 5–8 | 9–12 | ≥13 |
| NHS | |||||
| Cases/person‐years | 2181/879 821 | 95/35 929 | 99/25 406 | 61/15 037 | 25/6169 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 0.98 (0.80–1.21) | 1.32 (1.08–1.62) | 1.27 (0.98–1.64) | 1.33 (0.89–1.99) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 0.96 (0.79–1.19) | 1.29 (1.05–1.58) | 1.25 (0.96–1.62) | 1.33 (0.89–1.99) |
| NHS II | |||||
| Cases/person‐years | 472/1 151 523 | 17/28 235 | 22/20 942 | 16/17 473 | 10/17 583 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.29 (0.79–2.10) | 2.23 (1.45–3.42) | 1.89 (1.15–3.13) | 1.11 (0.59–2.09) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.19 (0.73–1.94) | 2.01 (1.31–3.10) | 1.69 (1.03–2.79) | 0.97 (0.52–1.82) |
| HPFS | |||||
| Cases/person‐years | 541/251 884 | 21/5577 | 15/5594 | 9/3974 | 19/6828 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.38 (0.89–2.13) | 1.15 (0.69–1.93) | 0.93 (0.48–1.79) | 1.14 (0.72–1.81) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.39 (0.90–2.16) | 1.14 (0.68–1.91) | 0.90 (0.47–1.75) | 1.14 (0.72–1.81) |
| Pooled | |||||
| Total No. of cases | 3194 | 133 | 136 | 86 | 54 |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.05 (0.88–1.25) | 1.38 (1.10–1.74) | 1.28 (1.03–1.59) | 1.19 (0.90–1.56) |
HPFS indicates Health Professionals Follow‐Up Study; HR, hazard ratio; HZ, herpes zoster; NHS, Nurses' Health Study; and NHS II, Nurses' Health Study II.
Multivariable model adjusted for age, race, family history of heart disease (yes/no), smoking history, body mass index, waist circumference (≤70, 71–79, 80–88, and >88 cm), physical activity, diabetes, hypertension, elevated cholesterol, regular use (≥2 days/week) of aspirin, thiazide diuretics, loop diuretics, “statins,” or other cholesterol‐lowering drugs, calcium‐channel blockers, β‐blockers, angiotensin‐converting enzyme inhibitors, or “other” antihypertensive drugs, Alternative Healthy Eating Index 2010 score, menopausal status (in NHS and NHS II), oral contraceptive use (in NHS II), postmenopausal hormonal therapy use (in NHS and NHS II), history of coronary heart disease, and a report of ≥1 of the following: cancer (other than nonmelanoma skin cancer), rheumatoid arthritis, Crohn's disease/ulcerative colitis (inflammatory bowel disease), systemic lupus erythematosus, asthma, diabetes, chronic obstructive pulmonary disease, or oral steroids/corticosteroid use.
HZ and Long‐Term Risk of Incident CHD
During a total of 2 350 066 person‐years of follow‐up, 4910 cases of incident CHD (nonfatal/fatal MI, fatal CHD, or coronary revascularization procedure) among women in the NHS, 1183 cases among women in the NHS II, and 2527 cases among men in the HPFS were documented and included in the analysis. History of HZ was significantly and independently associated with higher long‐term risk of CHD (Table 3). In pooled multivariable analyses accounting for multiple potential confounding factors, compared with individuals with no history of HZ, the MVHRs (95% CIs) for incident CHD were 1.13 (1.01–1.27) among those with 1 to 4 years since HZ, 1.16 (1.02–1.32) among those with 5 to 8 years since HZ, 1.25 (1.07–1.46) among those with 9 to 12 years since HZ, and 1.00 (0.83–1.21) among those with ≥13 years since HZ. The findings for the individual cohorts are also shown in Table 3.
Table 3.
HZ and Long‐Term Risk of CHD in the NHS, NHS II, and HPFS
| Time since HZ, y | |||||
|---|---|---|---|---|---|
| Variable | Never | 1–4 | 5–8 | 9–12 | ≥13 |
| NHS | |||||
| Cases/person‐years | 4419/825 984 | 229/33 176 | 147/23 345 | 89/13 832 | 26/5704 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.20 (1.05–1.37) | 1.18 (1.00–1.39) | 1.30 (1.05–1.61) | 0.97 (0.66–1.44) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.18 (1.04–1.35) | 1.16 (1.00–1.37) | 1.29 (1.04–1.59) | 0.96 (0.65–1.42) |
| NHS II | |||||
| Cases/person‐years | 1072/1 145 251 | 34/28 003 | 31/20 797 | 27/17 244 | 19/17 272 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.11 (0.79–1.57) | 1.35 (0.94–1.93) | 1.48 (1.01–2.17) | 1.04 (0.66–1.64) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.04 (0.74–1.46) | 1.23 (0.86–1.76) | 1.30 (0.89–1.91) | 0.90 (0.57–1.41) |
| HPFS | |||||
| Cases/person‐years | 2301/202 673 | 57/4320 | 59/4286 | 43/3059 | 67/5120 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.02 (0.78–1.32) | 1.15 (0.89–1.49) | 1.17 (0.86–1.58) | 1.07 (0.84–1.37) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.01 (0.78–1.32) | 1.13 (0.87–1.47) | 1.15 (0.85–1.56) | 1.05 (0.82–1.34) |
| Pooled | |||||
| Total No. of cases | 7792 | 320 | 237 | 159 | 112 |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.13 (1.01–1.27) | 1.16 (1.02–1.32) | 1.25 (1.07–1.46) | 1.00 (0.83–1.21) |
CHD indicates coronary heart disease; HPFS, Health Professionals Follow‐Up Study; HR, hazard ratio; HZ, herpes zoster; NHS, Nurses' Health Study; and NHS II, Nurses' Health Study II.
Multivariable model adjusted for age, race, family history of heart disease (yes/no), smoking history, body mass index, waist circumference (≤70, 71–79, 80–88, and >88 cm), physical activity, diabetes, hypertension, elevated cholesterol, regular use (≥2 days/week) of aspirin, thiazide diuretics, loop diuretics, “statins,” or other cholesterol‐lowering drugs, calcium‐channel blockers, β‐blockers, angiotensin‐converting enzyme inhibitors, or “other” antihypertensive drugs, Alternative Healthy Eating Index 2010 score, menopausal status (in NHS and NHS II), oral contraceptive use (in NHS II), postmenopausal hormonal therapy use (in NHS and NHS II), history of coronary heart disease, and a report of ≥1 of the following: cancer (other than nonmelanoma skin cancer), rheumatoid arthritis, Crohn's disease/ulcerative colitis (inflammatory bowel disease), systemic lupus erythematosus, asthma, diabetes, chronic obstructive pulmonary disease, or oral steroids/corticosteroid use.
The results from sensitivity analyses that restricted the CHD outcome to fatal and nonfatal MI and fatal CHD and censored those who reported coronary revascularization procedures are shown in Table S1. In the female cohorts, the findings were similar. However, in men, compared with those with no history of HZ, we observed a statistically significant higher risk of CHD among those with a history of HZ using the more restrictive outcome definition; compared with men with no history of HZ, the MVHR (95% CI) for incident MI was 1.36 (1.02–1.81) among those with ≥5 years since HZ.
HZ and Long‐Term Risk of Incident CVD
In analyses examining HZ and risk of a composite CVD outcome (stroke or CHD, whichever came first), previous HZ was significantly and independently associated with risk of a major cardiovascular event (Table 4). In the pooled multivariable analyses, compared with individuals with no history of HZ, the MVHRs (95% CIs) for a cardiovascular event were 1.11 (1.01–1.23) among those with 1 to 4 years since HZ, 1.26 (1.13–1.41) among those with 5 to 8 years since HZ, 1.27 (1.11–1.46) among those with 9 to 12 years since HZ, and 1.08 (0.92–1.28) among those with ≥13 years since HZ. Table 4 also shows the findings for the individual cohorts.
Table 4.
HZ and Long‐Term Risk of CVD (Composite) in the NHS, NHS II, and HPFS
| Time since HZ, y | |||||
|---|---|---|---|---|---|
| Variable | Never | 1–4 | 5–8 | 9–12 | ≥13 |
| NHS | |||||
| Cases/person‐years | 5960/800 811 | 287/32 100 | 219/22 404 | 134/13 153 | 47/5379 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.12 (0.99–1.26) | 1.24 (1.08–1.42) | 1.32 (1.11–1.57) | 1.17 (0.88–1.57) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.10 (0.97–1.23) | 1.23 (1.07–1.41) | 1.31 (1.10–1.56) | 1.17 (0.87–1.57) |
| NHS II | |||||
| Cases/person‐years | 1497/1 131 343 | 52/27 538 | 53/20 424 | 40/16 888 | 26/16 840 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.25 (0.94–1.64) | 1.68 (1.27–2.21) | 1.57 (1.14–2.15) | 1.01 (0.68–1.49) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.16 (0.88–1.53) | 1.53 (1.16–2.01) | 1.39 (1.01–1.90) | 0.88 (0.59–1.29) |
| HPFS | |||||
| Cases/person‐years | 2512/198 791 | 70/4212 | 67/4154 | 44/2980 | 76/4988 |
| Age‐adjusted HR (95% CI) | 1.00 (Reference) | 1.14 (0.90–1.45) | 1.21 (0.95–1.54) | 1.10 (0.82–1.48) | 1.14 (0.90–1.43) |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.13 (0.89–1.44) | 1.19 (0.93–1.52) | 1.08 (0.80–1.46) | 1.11 (0.88–1.40) |
| Pooled | |||||
| Total No. of cases | 9969 | 409 | 339 | 218 | 149 |
| Multivariable‐adjusted HR (95% CI)* | 1.00 (Reference) | 1.11 (1.01–1.23) | 1.26 (1.13–1.41) | 1.27 (1.11–1.46) | 1.08 (0.92–1.28) |
CVD is a composite of total stroke and coronary heart disease (CHD), defined as nonfatal or fatal myocardial infarction, fatal CHD, or coronary revascularization procedure. CVD indicates cardiovascular disease; HPFS, Health Professionals Follow‐Up Study; HR, hazard ratio; HZ, herpes zoster; NHS, Nurses' Health Study; and NHS II, Nurses' Health Study II.
Multivariable model adjusted for age, race, family history of heart disease (yes/no), smoking history, body mass index, waist circumference (≤70, 71–79, 80–88, and >88 cm), physical activity, diabetes, hypertension, elevated cholesterol, regular use (≥2 days/week) of aspirin, thiazide diuretics, loop diuretics, “statins,” or other cholesterol‐lowering drugs, calcium‐channel blockers, β‐blockers, angiotensin‐converting enzyme inhibitors, or “other” antihypertensive drugs, Alternative Healthy Eating Index 2010 score, menopausal status (in NHS and NHS II), oral contraceptive use (in NHS II), postmenopausal hormonal therapy use (in NHS and NHS II), and a report of ≥1 of the following: cancer (other than nonmelanoma skin cancer), rheumatoid arthritis, Crohn's disease/ulcerative colitis (inflammatory bowel disease), systemic lupus erythematosus, asthma, diabetes, chronic obstructive pulmonary disease, or oral steroids/corticosteroid use.
Additional Analyses
We performed stratified analyses that compared the association of HZ and long‐term risk of stroke and CHD among those with and without potentially immunocompromising conditions. There was a suggestion that the magnitude of the elevated risk for stroke after ≥5 years since HZ was greater among women with potentially immunocompromising conditions; however, the P value for interaction was statistically significant only in the NHS II (P‐interaction=0.05) (Table S2). In men, we did not observe that the risk varied by immune status (P‐interaction=0.68), but the number of cases among men with a history of HZ was small. There was a suggestion that the magnitude of the risk for CHD after ≥5 years since HZ was greater among women with potentially immunocompromising conditions in the NHS II (P‐interaction=0.03) (Table S3), but there was no evidence that the risk differed by immune status in the other 2 cohorts (P‐interaction ≥0.2). Similarly, there was a suggestion that the magnitude of the risk for CVD (composite) after ≥5 years since HZ was greater among women with potentially immunocompromising conditions in the NHS II (P‐interaction=0.02) but not in the other 2 cohorts (P‐interaction ≥0.28) (Table S4).
In the male cohort, we did not have information on HZ that occurred after 2008; thus, men who had HZ after the return of the 2008 questionnaire were misclassified in the later time periods; this could have biased the results for the 1 to 4 and 5 to 8 years since HZ toward the null. When we conducted sensitivity analyses that ended follow‐up in 2010, the findings were similar.
In additional analyses that included intakes of alcohol and specific dietary factors as individual covariates, the results were not materially different (data not shown). To consider the possibility that the true effect size may differ among the cohorts, we also conducted meta‐analyses using the random effects approach. The findings were essentially unchanged.
DISCUSSION
In 3 large cohorts of women and men with up to 16 years of follow‐up, HZ was associated with higher long‐term risk of a major adverse cardiovascular event. The higher risk persisted for 12 years and possibly longer. There was a suggestion that the magnitude of the elevated risk may be greater among those with potentially immunocompromising conditions.
Several mechanisms could underlie the observed association of HZ and long‐term risk of a major CVD event. VZV is the only human virus demonstrated to replicate in arteries and lead to vasculopathy, 11 and a growing body of evidence links VZV to vascular disease. 12 , 13 VZV has been detected in large and small blood vessels and has been implicated in the pathogenesis of several VZV‐related cardiovascular disorders. 11 , 14 , 15 , 16 , 17 VZV vasculopathy develops from viral spread along nerve fibers, directly involves both intracranial and extracranial vasculature, 36 , 37 and has been confirmed by the presence of multinucleated giant cells, herpesvirus particles, VZV DNA, and VZV antigen in arteries. 18 Vascular changes associated with VZV vasculopathy, including disruption of the internal elastic lamina, intimal thickening, and reduced medial smooth muscle cells, can lead to alterations in arterial caliber and contractility, 19 and vessel wall damage, arterial dissection, or aneurysm could trigger an ischemic or hemorrhagic CVD event. 11 , 20 , 36 , 38 Notably, VZV vasculopathy may be chronic and protracted, 39 and thus vascular changes could elevate risk of a CVD event years after an episode of HZ. 11 Furthermore, systemic inflammation, autoimmune reactions, or hemodynamic perturbations related to HZ may also contribute to risk of a CVD event, irrespective of the site of dermatomal involvement. 12 , 20 , 21 VZV‐related inflammation may also lead to endothelial dysfunction accompanied by disruption of atheromatous plaques and hypercoagulability. 37
Our study expands on prior studies by demonstrating the association between HZ and long‐term risk of stroke and CHD. Elevated risk of a major cardiovascular event within days or weeks after HZ has been reported previously. 20 , 38 , 40 A comprehensive review by Wu et al summarized the findings from epidemiologic studies of HZ and risk of stroke and MI. 13 Among the 15 more recent epidemiologic studies from Asia, Europe, and the United States, there was an increased incidence of stroke or MI in individuals with a recent history of HZ; the risk appeared to be highest closest to the HZ event and decreased over time. 13 A meta‐analysis found higher odds of a major CVD event within 3 months of HZ onset, but whether the elevated risk persisted for more than a year was unclear. 41 Notably, data on long‐term risk were limited and findings were inconsistent across studies. Most studies had limited information on health and lifestyle factors related to risk of stroke or CHD, and most were based on retrospective reviews of insurance claims or other administrative databases using diagnostic codes; thus, they captured only those individuals who sought medical attention for their HZ. 41 Our study included 3 prospective cohorts with long duration of follow‐up, controlled for multiple potential confounding cardiovascular risk factors, and captured individuals whose HZ may or may not have come to medical attention, thereby providing new insight into the long‐term association of HZ and CVD.
We observed suggestive evidence of a difference in the association of HZ and risk of a major event among those with potentially immunocompromising conditions or using immunosuppressive medication in the NHS II, but not in the NHS or the HPFS. The magnitude of the elevated risk for stroke or CHD after ≥5 years since HZ was greater among NHS II women with potentially immunocompromising conditions or medication use, but there was no statistically significant evidence that the risk differed in the 2 other cohorts, so this could be a chance finding. Plausibly, reduced T‐cell immunity or other host factors could increase the risk of viral reactivation and development of vasculopathy, 42 but further study of whether the association between HZ and long‐term CVD risk is modified by factors that may influence immune status is merited.
Strengths of this study include the longitudinal design, multiple independent cohorts with large sample sizes, long follow‐up with high retention rate, and repeated assessments of exposure and covariate information. Our study also has limitations. Information on HZ was self‐reported; however, it was shown to be highly reliable in the NHS. We did not have information on dermatomal involvement, treatment course, or complications, such as HZ opthalmicus; thus, future investigations that evaluate these factors could be informative. We did not have information on the date of HZ at younger ages; therefore, we were not able to examine whether the associations differed among younger individuals. We did not have information on VZV vaccination; however, we do not expect that vaccination status substantially influenced our findings. Notably, the live attenuated VZV vaccine was first recommended for individuals aged ≥60 years by the Centers for Disease Control and Prevention in 2008, a midpoint during follow‐up in our study. In 2011, expanded recommendations included individuals aged ≥50 years, but uptake was low; in 2012, uptake was 3.9% of the eligible subjects in one study 43 and 20% in another. 44 The more recent nonlive, recombinant subunit adjuvanted vaccine was not available until after the end of follow‐up in our study. As uptake of the VZV vaccine increases, future studies that evaluate whether vaccination status influences the relation of HZ and risk of CVD would be informative. Although we had information on specific stroke subtypes, there was not sufficient power to evaluate the associations of HZ with long‐term risk of ischemic versus hemorrhagic stroke. We controlled for several repeated measurements of diet, health, and lifestyle factors, but we cannot rule out the possibility of residual and unmeasured confounding. The generalizability of these findings may be limited because participants were predominantly non‐Hispanic White individuals.
CONCLUSIONS
A history of HZ is associated with higher long‐term risk of a major cardiovascular event. These findings suggest there are long‐term implications of HZ and underscore the importance of public health efforts for prevention.
Sources of Funding
This study was supported by GlaxoSmithKline Biologicals SA Supported Studies Programme Protocol 216148. The NHS (Nurses' Health Study), NHS II (Nurses' Health Study II), and HPFS (Health Professionals Follow‐Up Study) cohorts are supported by the following National Institutes of Health grants: R01 HL35464, UM1 CA186107, R01 HL034594, R01 HL088521, U01 CA176726, and U01 CA167552.
Disclosures
Dr S. G. Curhan received an investigator‐initiated grant from GlaxoSmithKline Biologicals SA to examine the long‐term outcomes potentially associated with herpes zoster. Dr Yawn reports consulting with GlaxoSmithKline related to herpes zoster epidemiology and receipt of an investigator‐initiated grant related to herpes zoster and chronic obstructive pulmonary disease. Dr Kawai was employed by Boston Children's Hospital during the study and is now an employee of and a shareholder in Moderna, Inc. Dr G. C. Curhan is an employee of OM1, has equity in Allena Pahrmaceuticals, and receives royalties from UpToDate for being an author and Section Editor. The remaining authors have no disclosures to report.
Supporting information
Tables S1–S4
Acknowledgments
We would like to thank Elaine Coughlan‐Gifford for her programming help on this project. All authors had access to the data and participated in the preparation of the manuscript.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.122.027451
For Sources of Funding and Disclosures, see page 10.
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Supplementary Materials
Tables S1–S4