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Geriatr Gerontol Int 2016; 16: 21–27
ORIGINAL ARTICLE: EPIDEMIOLOGY, CLINICAL PRACTICE AND HEALTH
Association between human cytomegalovirus antibody levels, and essential hypertension and functional status in elderly Koreans Su Jin Jeong, Sang Hoon Han, Chang Oh Kim, Jun Yong Choi, Young Goo Song and June Myung Kim Department of Internal Medicine, AIDS Research Institute, Yonsei University College of Medicine, Seoul, South Korea
Aim: To evaluate the relationship between human cytomegalovirus (HCMV) antibody status, and hypertension and functional status among elderly Koreans. Methods: Patients aged ≥65 years were prospectively enrolled from March 2011 to February 2012 at a 2000-bed university hospital. We collected data including CD4+ and CD8+ T-lymphocyte count, and functional status by measuring basic activities of daily living and instrumental activities of daily living for all patients. In addition, HCMV immunoglobulin G levels were analyzed using enzyme-linked fluorescent assay. Results: During the study period, 103 patients (51 men), who were admitted for treatment of infections or other diseases, were enrolled. Multivariate analysis showed that body mass index and HCMV immunoglobulin G antibody titers were independent factors associated with hypertension in elderly patients (OR 1.347, 95% CI 1.113–1.630, P = 0.002; OR 1.023, 95% CI 1.001–1.047, P = 0.042, respectively). In univariate linear correlations, HCMV antibody levels were positively correlated with systolic blood pressure levels (r = 0.303, P = 0.002), CD8+ T-lymphocyte count (r = 0.313, P = 0.001) and instrumental activities of daily living scores (r = 0.217, P = 0.028). In addition, HCMV immunoglobulin G titers were inversely associated with estimated glomerular filtration rate (r = −0.268, P = 0.006). These four variables remained independently significant in multivariate correlation analysis. Conclusion: These findings could provide insight into the important role of HCMV in the pathogenesis of essential hypertension and decreased functional status in the elderly. Geriatr Gerontol Int 2016; 16: 21–27. Keywords: antibody, cytomegalovirus, elderly patients, functional status, hypertension.
Introduction Essential hypertension is an independent risk factor for stroke, myocardial infarction, heart failure and arterial aneurysm, and is the leading cause of chronic renal failure.1 Approximately 90%–95% of hypertension cases, affecting more than 1 billion adults worldwide, are a result of essential hypertension.2 Both genetic and environmental factors are involved in the development of hypertension, but the underlying mechanism of
Accepted for publication 17 October 2014. Correspondence: Prof Chang Oh Kim MD PhD, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea. Email: [email protected]
© 2014 Japan Geriatrics Society
essential hypertension is poorly understood. The signs of essential hypertension include elevated systemic levels of inflammatory markers and activated inflammatory cells.3,4 These findings suggest that inflammation plays an important role in the pathogenesis of essential hypertension. Human cytomegalovirus (HCMV), a member of the beta herpes virus family, is a ubiquitous pathogen that infects only humans.5 Although HCMV infection is usually asymptomatic in healthy adults, it can infect organs and tissues throughout the body. HCMV can infect endothelial cells, smooth muscle cells and macrophages, which are all considered important in the pathogenesis of vascular disease.6,7 HCMV could also exacerbate inflammation in diseased vessels by altering the expression of cell adhesion molecules and by interfering with cytokine signaling.8 doi: 10.1111/ggi.12428
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Recent studies have suggested that HCMV infection is associated with a significantly increased risk for all-cause and cardiovascular disease (CVD)-related mortality.9 HCMV infection has been implicated in endothelial dysfunction10 and different CVD, such as atherosclerosis and coronary artery disease.11,12 However the clinical relationship between HCMV infection and hypertension is still unclear. In contrast, functional impairment, a common occurrence in aging, is generally measured as any difficulty that interferes with or limits function in one or more major life activities, including basic activities of daily living (ADL) and instrumental activities of daily living (IADL).13,14 Previous reports have described relationships between markers, such as C-reactive protein (CRP), interleukin-6 (IL-6) and D-dimer, and measures of functional impairment in older patients.15,16 Ferrucci et al. suggest that cytokine overproduction and maintenance of an inflammatory state over a long period of time might lead to physical degeneration in the elderly.17 The relationships between levels of HCMV immunoglobulin G (IgG) antibody and essential hypertension or functional status in the elderly have not been clearly assessed. The aim of the present study was to evaluate the relationship between HCMV, and essential hypertension and functional status among elderly Koreans.
Methods Study design and sample The study was carried out at Severance Hospital, a 2000-bed university-affiliated tertiary care referral hospital in Seoul, Korea, from March 2011 to February 2012. Patients with the following criteria were included in the study population: (i) aged older than 65 years; (ii) patients who were admitted for treatment of infections or other diseases; and (iii) patients without active inflammation. Patients who could not express their will were excluded from the study. All patients were enrolled prospectively if inclusion criteria were met. Hypertension was defined as the use of antihypertensive medications or a systolic blood pressure (BP) greater than or equal to 140 mmHg and/or a diastolic BP greater than or equal to 90 mmHg. The institutional review board of Severance Hospital approved the protocol. All participants were provided with written informed consent.
Data collection The following data were collected: age, sex, comorbid conditions, duration of hospital stay, levels of erythrocyte sedimentation rate (ESR) and CRP, source of infection, CD4+ and CD8+ T-lymphocyte count, and routine blood tests. A history of comorbid conditions, which included solid cancer, hematological malignancy, old cerebrovas22
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cular accident, cardiovascular disease, chronic heart failure, chronic renal disease, chronic liver disease, chronic lung disease, old tuberculosis and diabetes, was obtained. CVD included angina or myocardial infarction. Diabetes was defined as a fasting glucose of ≥7.0 mmol/L (126 mg/dL), non-fasting glucose of ≥11.1 mmol/L (200 mg/dL), previous diagnosis by a doctor or use of antidiabetic medications. Kidney function was assessed by estimated glomerular filtration rate (eGFR), which was calculated using the Modification of Diet in Renal Disease formula as follows: 186.3 × (serum creatinine1.154) × (age0.203) × (0.742 if female), with the serum creatinine concentration expressed as mg/dL.18 Height and bodyweight were measured on the day of admission for all participants. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. BP was measured manually by a trained operator using a mercury sphygmomanometer, and the mean of three measurements was used in the analysis. The functional status of individuals was assessed in terms of their ability to carry out important ADL and IADL without help. ADL measurement consisted of seven items, and was used to measure the ability to carry out activities, such as bathing, walking, transfer, dressing, personal grooming, eating and using the toilet.13 IADL measurement consisted of four items, and was used to measure the ability to carry out activities, such as preparing meals, managing money, managing medications and using a telephone.14 All ADL and IADL items were coded as “1” if the participant was independent, “2” if the participant needed some assistance, or “3” if the participant was completely dependent on others to carry out the activity. The ADL and IADL scale ranges were 7–21 and 4–12, respectively, where a higher number showed higher impairment for a specific task.
Measurement of HCMV antibody Blood samples were taken and stored at–20°C until analyzed. The serum was examined for HCMV. HCMV IgM and IgG levels were measured using the enzymelinked fluorescent assay (ELFA) (Biomérieux VIDAS, Lyon, France) method. The Biomérieux VIDAS HCMV IgM and IgG ELFA measurement method was quantitative and qualitative, and used solid phase receptacles coated with HCMV antigen (strain AD169) derived from cell cultures. These methods have been used in the laboratory for more than 10 years, and therefore were considered as the reference in this study. Samples with VIDAS HCMV IgG ≥6 AU/mL were classified as positive, whereas results between 4 and 6 AU/mL were classified as equivocal. The VIDAS HCMV IgG method is linear up to 400 AU/mL. A VIDAS HCMV IgM index © 2014 Japan Geriatrics Society
HCMV antibody and hypertension
>0.9 was considered positive, whereas indexes between 0.7 and 0.9 were considered equivocal.
Statistical analysis All variables are expressed as the mean ± standard deviation (SD), unless otherwise indicated. Associations among dichotomous variables were assessed using contingency tables to determine Pearson’s χ2 and linear χ2 functions. Continuous variables were compared by Student’s t-test and the Mann–Whitney U-test. Multivariate analysis was carried out using a logistic regression model to estimate the odds ratio (OR) of hypertension along with 95% confidence intervals (CI). Single linear univariate correlations (Pearson’s correlation coefficients) and stepwise multivariate regression analyses were carried out to evaluate the relationships between the value of HCMV IgG titer and other variables. Statistical power was calculated using PASS software (power analysis and sample-size package; NCSS statistical software, Kaysville, UT, USA). Statistical analyses were carried out using the Statistics Package for Social Science (SPSS 18.0 for Windows; SPSS, Chicago, IL, USA), and P-values less than 0.05 were considered statistically significant.
Results During the study period, a total of 103 patients (51 men) were enrolled, and 81 (78.6%) had hypertension. Clinical characteristics of the patients are shown in Table 1. The mean age of patients was 80.3 ± 8.2 years, and the
all-cause in-hospital mortality rate was 21.4% (22/103). Age, sex and underlying disease did not differ significantly between patients with and without hypertension. Hypertensive patients had a greater BMI (P = 0.001) and were more likely to have diabetes (P = 0.018), compared with patients without hypertension. Table 2 shows the clinical and biological data among patients according to hypertension status. The median leukocyte counts (8954 [2690–32500] vs 6395 [1710– 14600] × 103 cells/μL, P = 0.025) and the mean levels of creatinine (1.28 ± 0.94 vs 0.90 ± 0.51 mg/dL, P = 0.014) were higher in the hypertensive group than in the nonhypertensive group. In addition, the mean eGFR level was significantly lower in the hypertensive group than in the non-hypertensive group (68.85 ± 36.57 vs 83.59 ± 27.89 mL/min per 1.73 m2, P = 0.047). Table 3 shows the levels of HCMV antibody titers among patients with and without hypertension. HCMV IgG antibody titers were significantly higher in patients with hypertension than in those without hypertension (69.3 ± 38.0 vs 52.0 ± 25.2, P = 0.015). In the multivariate logistic regression model to identify risk factors for hypertension in elderly patients, the BMI and HCMV IgG antibody titer were identified (OR 1.347, 95% CI 1.113–1.630, P = 0.002; OR 1.023, 95% CI 1.001– 1.047, P = 0.042, respectively). Correlations between HCMV IgG titer and other variables are shown in Table 4. In single linear univariate correlations, HCMV antibody levels were positively correlated with systolic BP levels (r = 0.303, P = 0.002), CD8+ T lymphocyte count (r = 0.313, P = 0.001) and IADL scores (r = 0.217, P = 0.028). In addition,
Table 1 Clinical characteristics of study participants Characteristics
Patients with hypertension (n = 81)
Patients without hypertension (n = 22)
P-value
Age (years) Male, n (%) BMI Underlying diseases (yes), n (%) Solid cancer Hematological malignancy Old cerebrovascular accident Cardiovascular disease Chronic heart failure Chronic renal disease Chronic liver disease Chronic lung disease Old TB DM Mortality, n (%)
80.3 ± 7.5 38 (46.9) 22.7 ± 3.9
80.5 ± 10.5 13 (59.1) 19.4 ± 3.2
0.936† 0.311‡ 0.001†
23 (28.4) 1 (1.2) 39 (48.1) 21 (25.9) 14 (17.3) 19 (23.5) 4 (4.9) 9 (11.1) 7 (8.6) 33 (40.7) 19 (23.5)
5 (22.7) 1 (4.5) 10 (45.5) 3 (13.6) 2 (9.1) 2 (9.1) 0 (0.0) 3 (13.6) 0 (0.0) 3 (13.6) 3 (13.6)
0.596‡ 0.383‡ 0.822‡ 0.227‡ 0.512‡ 0.231‡ 0.575‡ 0.716‡ 0.341‡ 0.018‡ 0.393‡
Data are expressed as the mean ± SD or number (%). †Student t-test. ‡Pearson’s χ. BMI, body mass index; DM, diabetes mellitus; SD, standard deviation; TB, tuberculosis. © 2014 Japan Geriatrics Society
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Table 2 Clinical and biological data among patients with and without hypertension Characteristic
Patients with hypertension (n = 81)
Patients without hypertension (n = 22)
P-value
Hospital stay (days) ESR (mm/h) CRP (mg/L) Leukocyte count (×103 cells/μL) Platelet count Delta neutrophil count (%) CD4+ T-lymphocyte count (/μL) CD8+ T-lymphocyte count (/μL) CD4/CD8 T-cell ratio CD4/CD8 > 1, n (%) BUN (mg/dL) Creatinine (mg/dL) eGFR (mL/min per 1.73 m2) Albumin (g/dL) Total cholesterol (mg/dL) Functional status ADL score IADL score
42.9 ± 49.1 79.7 ± 35.7 64.1 ± 64.4 8954 (2690–32500) 279 ± 147 2.34 ± 3.30 443 ± 249 335 ± 251 1.82 ± 1.26 56 (69.1) 22.8 ± 16.6 1.28 ± 0.94 68.85 ± 36.57 2.82 ± 0.53 124.6 ± 33.2
25.6 ± 29.4 75.1 ± 26.5 42.3 ± 52.3 6395 (1710–14600) 267 ± 111 3.13 ± 5.67 366 ± 174 245 ± 188 2.02 ± 1.25 17 (77.3) 18.6 ± 13.5 0.90 ± 0.51 83.59 ± 27.89 2.89 ± 0.50 125.3 ± 49.9
0.042 0.620 0.148 0.025† 0.724 0.401 0.177 0.122 0.508 0.456 0.281 0.014 0.047 0.610 0.935
14.4 ± 5.6 9.1 ± 3.1
13.9 ± 5.9 9.0 ± 3.0
0.697 0.947
Data are expressed as the mean ± SD or median (interquartile range). †Mann–Whitney U-test. ADL, activities of daily living; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; IADL, instrumental activities of daily living; SD, standard deviation.
Table 3 Measurement of human cytomegalovirus antibody Variables
Patients with hypertension (n = 81)
Patients without hypertension (n = 22)
P-value
HCMV IgM, positive (%) HCMV IgG, positive (%) HCMV IgG titer (AU/mL)
0 (0.0) 81 (100.0) 69.3 ± 38.0
0 (0.0) 22 (100.0) 52.0 ± 25.2
1.000 1.000 0.015
HCMV, human cytomegalovirus; IgG, immunoglobulin G, IgM, immunoglobulin M.
HCMV IgG titers were inversely associated with eGFR (r = −0.268, P = 0.006). These four variables remained independently significant in multiple stepwise regression analyses. However, HCMV IgG titers were not statistically associated with other parameters of inflammation including leukocyte count, delta neutrophil count, ESR and CRP. The association between HCMV IgG titers and systolic BP is shown in Figure 1.
Discussion In the present study, we found that higher BMI and HCMV IgG titer were significant risk factors for hypertension in elderly patients. In addition, increasing HCMV IgG antibody titers were associated with increased systolic BP, CD8+ T-cell counts, decreased eGFR and greater impairments in IADL. To the best of 24
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our knowledge, the present study is the first to analyze the relationship between HCMV IgG titer and hypertension or other variables including functional status in elderly patients. We found that there is strong evidence to support HCMV as a significant cause of hypertension. There is a theoretical basis for this association, and several mechanisms can be expected. HCMV infection could lead to oxidative stress and endothelial dysfunction,7,10,19 and endothelial dysfunction and inflammation are two key mechanisms in the development and progression of hypertension.20,21 Thus, we observed how through oxidative stress and resultant inflammation, and endothelial dysfunction, HCMV infection might result in hypertension. In addition, HCMV infection triggers the proliferation of one type of T lymphocytes, CD8+ T lymphocytes, which could be involved in the development of hypertension.21,22 In the present study, mean © 2014 Japan Geriatrics Society
HCMV antibody and hypertension
Table 4 Correlation between antibody titer and clinical or biological factors Variables
Age (years) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Leukocyte count (×103 cells/μL) Delta neutrophil count (%) ESR (mm/h) CRP (mg/L) T-C (mmol/L) CD4+ T-lymphocyte count (/μL) CD8+ T-lymphocyte count (/μL) CD4/CD8 ratio Folate BUN eGFR (mL/min per 1.73 m2) Creatinine ADL IADL R2
HCMV IgG antibody (AU/mL) Multivariate‡ Univariate† β P β F −0.083 0.033 0.303 0.109 0.176 −0.133 0.098 −0.039 −0.085 −0.005 0.313 −0.221 0.224 0.130 −0.268 0.294 0.210 0.217
0.405 0.744 0.002 0.271 0.075 0.179 0.418 0.697 0.395 0.958 0.001 0.025 0.034 0.192 0.006 0.003 0.033 0.028
P
0.247
6.84
0.011§
0.265
7.69
0.007§
−0.233
6.24
0.014§
0.223 0.262
5.54
0.021§
β indicates regression coefficients. †Univariate coefficients. ‡A stepwise multivariate regression analysis was carried out. §The power calculation was performed (systolic blood pressure [BP], CD8+ T-lymphocyte count, estimated glomerular filtration rate [eGFR] and instrumental activities of daily living [IADL] were 99.92%). ADL, activities of daily living; BMI, body mass index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; T-C, total cholesterol.
CD8+ T-cell counts were higher in the hypertensive group than in the non-hypertensive group, but this difference was not statistically significant. However, we also observed significant correlations between HCMV IgG titer and CD8+ T-cell counts. Increasing titers of HCMV IgG were closely related to increasing CD8+ T-lymphocyte counts. It is also known that T lymphocytes take part in the alteration of vascular tone encountered in hypertension induced by angiotensin II, which is a potent vasoconstrictor.23 Therefore, T cells might be a link between HCMV infection and hypertension. In the present study, functional impairment represented by high IADL scores was associated with increasing HCMV IgG antibody titers in elderly patients. Functional status was measured in other studies with the Barthel Index (BI), which was originally developed to measure ADL in stroke patients. Associations between functional status by BI and prognosis in patients with infectious disease have been described previously in other studies.24,25 Torres et al. found that in elderly patients with pneumonia, a high BI, which is associated with greater functional abilities, was related to reduced 30-day and 18-month mortalities.24 In a prospective study of 244 patients with acute exacerbations of © 2014 Japan Geriatrics Society
chronic obstructive pulmonary disease and a mean age of 81.7 years, Ranieri et al. also found that body mass index, BI at discharge and comorbidities were risk factors for 6-month mortality.25 Recently, HCMV has even been linked with reduced cognitive functioning including vascular dementia26 and functional impairment.27 Several mechanisms might explain the associations between increased HCMV IgG antibody titers and disabilities in IADL in older adults. HCMV could exacerbate inflammation in diseased vessels.8 Chronic inflammation, which has negative impacts on endothelial integrity and blood flow control in the microcirculation, decreases the coordinated vasodilatory response to increase blood flow to meet the metabolic demands of skeletal muscle.28 Higher levels of inflammatory markers, linked to greater loss of muscle mass and strength,29 have been shown to be an important predictor for late-life disability.17 Additionally, previous studies have shown an association between HCMV and CVD through impaired endothelial nitric oxide synthase function, and subsequent endothelial dysfunction.11 HCMV infection stimulates rennin and angiotensin II expression in human vascular endothelial cells, thus enhancing NADPH oxidase activity, and |
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sample taken at a certain point in time could fail to reflect the natural course of the process being studied, and might not elucidate a clear cause–effect relationship. A larger and longitudinal study would be required to identify independent and strong correlations between HCMV infection and hypertension in elderly patients. An additional limitation is that gender-adjusted analyses could not be carried out because of the small sample size. However, we confirmed that the differences of sex between groups did not reach statistical significance. In conclusion, these results suggest that BMI and HCMV IgG titers could be used as predictors to identify elderly Koreans at high risk of developing hypertension. In addition, we showed a novel link between HCMV antibody titers and functional status. These findings could provide important insight into the pathogenesis of essential hypertension and functional status in the elderly.
Acknowledgments Figure 1 Relationship between human cytomegalovirus (HCMV) immunoglobulin G (IgG) titers and systolic blood pressure in elderly patients (r = 0.303; P = 0.002).
eliciting the production of reactive oxygen species (ROS).30 HCMV infections of smooth muscle cells also generate ROS through a COX-2-dependent pathway, thereby activating nuclear factor-κB.31 Nuclear factor-κB is associated with endothelial dysfunction and vascular inflammation, as well as vascular smooth muscle cell proliferation.32 In addition, the infection of smooth muscle cells with HCMV leads to the expression and secretion of growth factors,33,34 and it has also been shown that HCMV infection activated nuclear factor-κB.32 The virus is capable of enhancing leukocyte and platelet adhesion to endothelial cells by inducing cellular expression of adhesion molecules,35,36 and might cause procoagulant changes.37 Endothelial dysfunction, closely related to atherosclerotic change, could potentially lead to peripheral vascular disease, which has been shown to be an essential risk factor of low gait speed, decreased muscle strength and physical disability.38,39 Such results of epidemiology and vascular pathophysiology studies provide possible mechanistic explanations for the associations between HCMV infection and disability. There were several limitations to the present study. First, this was a cross-sectional study with a relatively small number of participants. However, this prospective study was carefully carried out, and a power calculation confirmed that small differences in the key variables could be detected in a sample of this size. In addition, this type of study is inherently limited, because a single 26
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This study was supported by the Public Welfare & Safety Research Program through the National Research Foundation of Korea (NRF), and funded by the Ministry of Education, Science and Technology (2011-0020961).
Disclosure statement No potential conflicts of interest were disclosed.
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24 Torres OH, Muoz J, Ruiz D et al. Outcome predictors of pneumonia in elderly patients: importance of functional assessment. J Am Geriatr Soc 2004; 52 (10): 1603–1609. 25 Ranieri P, Bianchetti A, Margiotta A, Virgillo A, Clini EM, Trabucchi M. Predictors of 6-month mortality in elderly patients with mild chronic obstructive pulmonary disease discharged from a medical ward after acute nonacidotic exacerbation. J Am Geriatr Soc 2008; 56 (5): 909–913. 26 Aiello AE, Haan M, Blythe L, Moore K, Gonzalez JM, Jagust W. The influence of latent viral infection on rate of cognitive decline over 4 years. J Am Geriatr Soc 2006; 54 (7): 1046–1054. 27 Aiello AE, Haan MN, Pierce CM, Simanek AM, Liang J. Persistent infection, inflammation, and functional impairment in older Latinos. J Gerontol A Biol Sci Med Sci 2008; 63 (6): 610–618. 28 Payne GW. Effect of inflammation on the aging microcirculation: impact on skeletal muscle blood flow control. Microcirculation 2006; 13 (4): 343–352. 29 Schaap LA, Pluijm SM, Deeg DJ et al. Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J Gerontol A Biol Sci Med Sci 2009; 64 (11): 1183–1189. 30 Cheng J, Ke Q, Jin Z et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog 2009; 5 (5): e1000427–e1000427. 31 Speir E, Yu ZX, Ferrans VJ, Huang ES, Epstein SE. Aspirin attenuates cytomegalovirus infectivity and gene expression mediated by cyclooxygenase-2 in coronary artery smooth muscle cells. Circ Res 1998; 83 (2): 210–216. 32 Kowalik TF, Wing B, Haskill JS, Azizkhan JC, Baldwin AS, Huang ES. Multiple mechanisms are implicated in the regulation of NF-kappa B activity during human cytomegalovirus infection. Proc Natl Acad Sci U S A 1993; 90 (3): 1107–1111. 33 Geist LJ, Monick MM, Stinski MF, Hunninghake GW. The immediate early genes of human cytomegalovirus upregulate expression of the interleukin-2 and interleukin-2 receptor genes. Am J Respir Cell Mol Biol 1991; 5 (3): 292–296. 34 Alcami J, Barzu T, Michelson S. Induction of an endothelial cell growth factor by human cytomegalovirus infection of fibroblasts. J Gen Virol 1991; 72 (11): 2765–2770. 35 O’Brien KD, Allen MD, McDonald TO et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest 1993; 92 (2): 945–951. 36 Span AH, van Dam-Mieras MC, Mullers W, Endert J, Muller AD, Bruggeman CA. The effect of virus infection on the adherence of leukocytes or platelets to endothelial cells. Eur J Clin Invest 1991; 21 (3): 331–338. 37 van Dam-Mieras MC, Muller AD, van Hinsbergh VW, Mullers WJ, Bomans PH, Bruggeman CA. The procoagulant response of cytomegalovirus infected endothelial cells. Thromb Haemost 1992; 68 (3): 364–370. 38 Kuo H, Yu Y. The relation of peripheral arterial disease to leg force, gait speed, and functional dependence among older adults. J Gerontol A Biol Sci Med Sci 2008; 63 (4): 384–390. 39 McDermott MM, Liu K, Greenland P et al. Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. JAMA 2004; 292 (4): 453–461.
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Geriatr Gerontol Int 2016; 16: 21–27
ORIGINAL ARTICLE: EPIDEMIOLOGY, CLINICAL PRACTICE AND HEALTH
Association between human cytomegalovirus antibody levels, and essential hypertension and functional status in elderly Koreans Su Jin Jeong, Sang Hoon Han, Chang Oh Kim, Jun Yong Choi, Young Goo Song and June Myung Kim Department of Internal Medicine, AIDS Research Institute, Yonsei University College of Medicine, Seoul, South Korea
Aim: To evaluate the relationship between human cytomegalovirus (HCMV) antibody status, and hypertension and functional status among elderly Koreans. Methods: Patients aged ≥65 years were prospectively enrolled from March 2011 to February 2012 at a 2000-bed university hospital. We collected data including CD4+ and CD8+ T-lymphocyte count, and functional status by measuring basic activities of daily living and instrumental activities of daily living for all patients. In addition, HCMV immunoglobulin G levels were analyzed using enzyme-linked fluorescent assay. Results: During the study period, 103 patients (51 men), who were admitted for treatment of infections or other diseases, were enrolled. Multivariate analysis showed that body mass index and HCMV immunoglobulin G antibody titers were independent factors associated with hypertension in elderly patients (OR 1.347, 95% CI 1.113–1.630, P = 0.002; OR 1.023, 95% CI 1.001–1.047, P = 0.042, respectively). In univariate linear correlations, HCMV antibody levels were positively correlated with systolic blood pressure levels (r = 0.303, P = 0.002), CD8+ T-lymphocyte count (r = 0.313, P = 0.001) and instrumental activities of daily living scores (r = 0.217, P = 0.028). In addition, HCMV immunoglobulin G titers were inversely associated with estimated glomerular filtration rate (r = −0.268, P = 0.006). These four variables remained independently significant in multivariate correlation analysis. Conclusion: These findings could provide insight into the important role of HCMV in the pathogenesis of essential hypertension and decreased functional status in the elderly. Geriatr Gerontol Int 2016; 16: 21–27. Keywords: antibody, cytomegalovirus, elderly patients, functional status, hypertension.
Introduction Essential hypertension is an independent risk factor for stroke, myocardial infarction, heart failure and arterial aneurysm, and is the leading cause of chronic renal failure.1 Approximately 90%–95% of hypertension cases, affecting more than 1 billion adults worldwide, are a result of essential hypertension.2 Both genetic and environmental factors are involved in the development of hypertension, but the underlying mechanism of
Accepted for publication 17 October 2014. Correspondence: Prof Chang Oh Kim MD PhD, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea. Email: [email protected]
© 2014 Japan Geriatrics Society
essential hypertension is poorly understood. The signs of essential hypertension include elevated systemic levels of inflammatory markers and activated inflammatory cells.3,4 These findings suggest that inflammation plays an important role in the pathogenesis of essential hypertension. Human cytomegalovirus (HCMV), a member of the beta herpes virus family, is a ubiquitous pathogen that infects only humans.5 Although HCMV infection is usually asymptomatic in healthy adults, it can infect organs and tissues throughout the body. HCMV can infect endothelial cells, smooth muscle cells and macrophages, which are all considered important in the pathogenesis of vascular disease.6,7 HCMV could also exacerbate inflammation in diseased vessels by altering the expression of cell adhesion molecules and by interfering with cytokine signaling.8 doi: 10.1111/ggi.12428
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Recent studies have suggested that HCMV infection is associated with a significantly increased risk for all-cause and cardiovascular disease (CVD)-related mortality.9 HCMV infection has been implicated in endothelial dysfunction10 and different CVD, such as atherosclerosis and coronary artery disease.11,12 However the clinical relationship between HCMV infection and hypertension is still unclear. In contrast, functional impairment, a common occurrence in aging, is generally measured as any difficulty that interferes with or limits function in one or more major life activities, including basic activities of daily living (ADL) and instrumental activities of daily living (IADL).13,14 Previous reports have described relationships between markers, such as C-reactive protein (CRP), interleukin-6 (IL-6) and D-dimer, and measures of functional impairment in older patients.15,16 Ferrucci et al. suggest that cytokine overproduction and maintenance of an inflammatory state over a long period of time might lead to physical degeneration in the elderly.17 The relationships between levels of HCMV immunoglobulin G (IgG) antibody and essential hypertension or functional status in the elderly have not been clearly assessed. The aim of the present study was to evaluate the relationship between HCMV, and essential hypertension and functional status among elderly Koreans.
Methods Study design and sample The study was carried out at Severance Hospital, a 2000-bed university-affiliated tertiary care referral hospital in Seoul, Korea, from March 2011 to February 2012. Patients with the following criteria were included in the study population: (i) aged older than 65 years; (ii) patients who were admitted for treatment of infections or other diseases; and (iii) patients without active inflammation. Patients who could not express their will were excluded from the study. All patients were enrolled prospectively if inclusion criteria were met. Hypertension was defined as the use of antihypertensive medications or a systolic blood pressure (BP) greater than or equal to 140 mmHg and/or a diastolic BP greater than or equal to 90 mmHg. The institutional review board of Severance Hospital approved the protocol. All participants were provided with written informed consent.
Data collection The following data were collected: age, sex, comorbid conditions, duration of hospital stay, levels of erythrocyte sedimentation rate (ESR) and CRP, source of infection, CD4+ and CD8+ T-lymphocyte count, and routine blood tests. A history of comorbid conditions, which included solid cancer, hematological malignancy, old cerebrovas22
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cular accident, cardiovascular disease, chronic heart failure, chronic renal disease, chronic liver disease, chronic lung disease, old tuberculosis and diabetes, was obtained. CVD included angina or myocardial infarction. Diabetes was defined as a fasting glucose of ≥7.0 mmol/L (126 mg/dL), non-fasting glucose of ≥11.1 mmol/L (200 mg/dL), previous diagnosis by a doctor or use of antidiabetic medications. Kidney function was assessed by estimated glomerular filtration rate (eGFR), which was calculated using the Modification of Diet in Renal Disease formula as follows: 186.3 × (serum creatinine1.154) × (age0.203) × (0.742 if female), with the serum creatinine concentration expressed as mg/dL.18 Height and bodyweight were measured on the day of admission for all participants. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. BP was measured manually by a trained operator using a mercury sphygmomanometer, and the mean of three measurements was used in the analysis. The functional status of individuals was assessed in terms of their ability to carry out important ADL and IADL without help. ADL measurement consisted of seven items, and was used to measure the ability to carry out activities, such as bathing, walking, transfer, dressing, personal grooming, eating and using the toilet.13 IADL measurement consisted of four items, and was used to measure the ability to carry out activities, such as preparing meals, managing money, managing medications and using a telephone.14 All ADL and IADL items were coded as “1” if the participant was independent, “2” if the participant needed some assistance, or “3” if the participant was completely dependent on others to carry out the activity. The ADL and IADL scale ranges were 7–21 and 4–12, respectively, where a higher number showed higher impairment for a specific task.
Measurement of HCMV antibody Blood samples were taken and stored at–20°C until analyzed. The serum was examined for HCMV. HCMV IgM and IgG levels were measured using the enzymelinked fluorescent assay (ELFA) (Biomérieux VIDAS, Lyon, France) method. The Biomérieux VIDAS HCMV IgM and IgG ELFA measurement method was quantitative and qualitative, and used solid phase receptacles coated with HCMV antigen (strain AD169) derived from cell cultures. These methods have been used in the laboratory for more than 10 years, and therefore were considered as the reference in this study. Samples with VIDAS HCMV IgG ≥6 AU/mL were classified as positive, whereas results between 4 and 6 AU/mL were classified as equivocal. The VIDAS HCMV IgG method is linear up to 400 AU/mL. A VIDAS HCMV IgM index © 2014 Japan Geriatrics Society
HCMV antibody and hypertension
>0.9 was considered positive, whereas indexes between 0.7 and 0.9 were considered equivocal.
Statistical analysis All variables are expressed as the mean ± standard deviation (SD), unless otherwise indicated. Associations among dichotomous variables were assessed using contingency tables to determine Pearson’s χ2 and linear χ2 functions. Continuous variables were compared by Student’s t-test and the Mann–Whitney U-test. Multivariate analysis was carried out using a logistic regression model to estimate the odds ratio (OR) of hypertension along with 95% confidence intervals (CI). Single linear univariate correlations (Pearson’s correlation coefficients) and stepwise multivariate regression analyses were carried out to evaluate the relationships between the value of HCMV IgG titer and other variables. Statistical power was calculated using PASS software (power analysis and sample-size package; NCSS statistical software, Kaysville, UT, USA). Statistical analyses were carried out using the Statistics Package for Social Science (SPSS 18.0 for Windows; SPSS, Chicago, IL, USA), and P-values less than 0.05 were considered statistically significant.
Results During the study period, a total of 103 patients (51 men) were enrolled, and 81 (78.6%) had hypertension. Clinical characteristics of the patients are shown in Table 1. The mean age of patients was 80.3 ± 8.2 years, and the
all-cause in-hospital mortality rate was 21.4% (22/103). Age, sex and underlying disease did not differ significantly between patients with and without hypertension. Hypertensive patients had a greater BMI (P = 0.001) and were more likely to have diabetes (P = 0.018), compared with patients without hypertension. Table 2 shows the clinical and biological data among patients according to hypertension status. The median leukocyte counts (8954 [2690–32500] vs 6395 [1710– 14600] × 103 cells/μL, P = 0.025) and the mean levels of creatinine (1.28 ± 0.94 vs 0.90 ± 0.51 mg/dL, P = 0.014) were higher in the hypertensive group than in the nonhypertensive group. In addition, the mean eGFR level was significantly lower in the hypertensive group than in the non-hypertensive group (68.85 ± 36.57 vs 83.59 ± 27.89 mL/min per 1.73 m2, P = 0.047). Table 3 shows the levels of HCMV antibody titers among patients with and without hypertension. HCMV IgG antibody titers were significantly higher in patients with hypertension than in those without hypertension (69.3 ± 38.0 vs 52.0 ± 25.2, P = 0.015). In the multivariate logistic regression model to identify risk factors for hypertension in elderly patients, the BMI and HCMV IgG antibody titer were identified (OR 1.347, 95% CI 1.113–1.630, P = 0.002; OR 1.023, 95% CI 1.001– 1.047, P = 0.042, respectively). Correlations between HCMV IgG titer and other variables are shown in Table 4. In single linear univariate correlations, HCMV antibody levels were positively correlated with systolic BP levels (r = 0.303, P = 0.002), CD8+ T lymphocyte count (r = 0.313, P = 0.001) and IADL scores (r = 0.217, P = 0.028). In addition,
Table 1 Clinical characteristics of study participants Characteristics
Patients with hypertension (n = 81)
Patients without hypertension (n = 22)
P-value
Age (years) Male, n (%) BMI Underlying diseases (yes), n (%) Solid cancer Hematological malignancy Old cerebrovascular accident Cardiovascular disease Chronic heart failure Chronic renal disease Chronic liver disease Chronic lung disease Old TB DM Mortality, n (%)
80.3 ± 7.5 38 (46.9) 22.7 ± 3.9
80.5 ± 10.5 13 (59.1) 19.4 ± 3.2
0.936† 0.311‡ 0.001†
23 (28.4) 1 (1.2) 39 (48.1) 21 (25.9) 14 (17.3) 19 (23.5) 4 (4.9) 9 (11.1) 7 (8.6) 33 (40.7) 19 (23.5)
5 (22.7) 1 (4.5) 10 (45.5) 3 (13.6) 2 (9.1) 2 (9.1) 0 (0.0) 3 (13.6) 0 (0.0) 3 (13.6) 3 (13.6)
0.596‡ 0.383‡ 0.822‡ 0.227‡ 0.512‡ 0.231‡ 0.575‡ 0.716‡ 0.341‡ 0.018‡ 0.393‡
Data are expressed as the mean ± SD or number (%). †Student t-test. ‡Pearson’s χ. BMI, body mass index; DM, diabetes mellitus; SD, standard deviation; TB, tuberculosis. © 2014 Japan Geriatrics Society
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Table 2 Clinical and biological data among patients with and without hypertension Characteristic
Patients with hypertension (n = 81)
Patients without hypertension (n = 22)
P-value
Hospital stay (days) ESR (mm/h) CRP (mg/L) Leukocyte count (×103 cells/μL) Platelet count Delta neutrophil count (%) CD4+ T-lymphocyte count (/μL) CD8+ T-lymphocyte count (/μL) CD4/CD8 T-cell ratio CD4/CD8 > 1, n (%) BUN (mg/dL) Creatinine (mg/dL) eGFR (mL/min per 1.73 m2) Albumin (g/dL) Total cholesterol (mg/dL) Functional status ADL score IADL score
42.9 ± 49.1 79.7 ± 35.7 64.1 ± 64.4 8954 (2690–32500) 279 ± 147 2.34 ± 3.30 443 ± 249 335 ± 251 1.82 ± 1.26 56 (69.1) 22.8 ± 16.6 1.28 ± 0.94 68.85 ± 36.57 2.82 ± 0.53 124.6 ± 33.2
25.6 ± 29.4 75.1 ± 26.5 42.3 ± 52.3 6395 (1710–14600) 267 ± 111 3.13 ± 5.67 366 ± 174 245 ± 188 2.02 ± 1.25 17 (77.3) 18.6 ± 13.5 0.90 ± 0.51 83.59 ± 27.89 2.89 ± 0.50 125.3 ± 49.9
0.042 0.620 0.148 0.025† 0.724 0.401 0.177 0.122 0.508 0.456 0.281 0.014 0.047 0.610 0.935
14.4 ± 5.6 9.1 ± 3.1
13.9 ± 5.9 9.0 ± 3.0
0.697 0.947
Data are expressed as the mean ± SD or median (interquartile range). †Mann–Whitney U-test. ADL, activities of daily living; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; IADL, instrumental activities of daily living; SD, standard deviation.
Table 3 Measurement of human cytomegalovirus antibody Variables
Patients with hypertension (n = 81)
Patients without hypertension (n = 22)
P-value
HCMV IgM, positive (%) HCMV IgG, positive (%) HCMV IgG titer (AU/mL)
0 (0.0) 81 (100.0) 69.3 ± 38.0
0 (0.0) 22 (100.0) 52.0 ± 25.2
1.000 1.000 0.015
HCMV, human cytomegalovirus; IgG, immunoglobulin G, IgM, immunoglobulin M.
HCMV IgG titers were inversely associated with eGFR (r = −0.268, P = 0.006). These four variables remained independently significant in multiple stepwise regression analyses. However, HCMV IgG titers were not statistically associated with other parameters of inflammation including leukocyte count, delta neutrophil count, ESR and CRP. The association between HCMV IgG titers and systolic BP is shown in Figure 1.
Discussion In the present study, we found that higher BMI and HCMV IgG titer were significant risk factors for hypertension in elderly patients. In addition, increasing HCMV IgG antibody titers were associated with increased systolic BP, CD8+ T-cell counts, decreased eGFR and greater impairments in IADL. To the best of 24
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our knowledge, the present study is the first to analyze the relationship between HCMV IgG titer and hypertension or other variables including functional status in elderly patients. We found that there is strong evidence to support HCMV as a significant cause of hypertension. There is a theoretical basis for this association, and several mechanisms can be expected. HCMV infection could lead to oxidative stress and endothelial dysfunction,7,10,19 and endothelial dysfunction and inflammation are two key mechanisms in the development and progression of hypertension.20,21 Thus, we observed how through oxidative stress and resultant inflammation, and endothelial dysfunction, HCMV infection might result in hypertension. In addition, HCMV infection triggers the proliferation of one type of T lymphocytes, CD8+ T lymphocytes, which could be involved in the development of hypertension.21,22 In the present study, mean © 2014 Japan Geriatrics Society
HCMV antibody and hypertension
Table 4 Correlation between antibody titer and clinical or biological factors Variables
Age (years) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Leukocyte count (×103 cells/μL) Delta neutrophil count (%) ESR (mm/h) CRP (mg/L) T-C (mmol/L) CD4+ T-lymphocyte count (/μL) CD8+ T-lymphocyte count (/μL) CD4/CD8 ratio Folate BUN eGFR (mL/min per 1.73 m2) Creatinine ADL IADL R2
HCMV IgG antibody (AU/mL) Multivariate‡ Univariate† β P β F −0.083 0.033 0.303 0.109 0.176 −0.133 0.098 −0.039 −0.085 −0.005 0.313 −0.221 0.224 0.130 −0.268 0.294 0.210 0.217
0.405 0.744 0.002 0.271 0.075 0.179 0.418 0.697 0.395 0.958 0.001 0.025 0.034 0.192 0.006 0.003 0.033 0.028
P
0.247
6.84
0.011§
0.265
7.69
0.007§
−0.233
6.24
0.014§
0.223 0.262
5.54
0.021§
β indicates regression coefficients. †Univariate coefficients. ‡A stepwise multivariate regression analysis was carried out. §The power calculation was performed (systolic blood pressure [BP], CD8+ T-lymphocyte count, estimated glomerular filtration rate [eGFR] and instrumental activities of daily living [IADL] were 99.92%). ADL, activities of daily living; BMI, body mass index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; T-C, total cholesterol.
CD8+ T-cell counts were higher in the hypertensive group than in the non-hypertensive group, but this difference was not statistically significant. However, we also observed significant correlations between HCMV IgG titer and CD8+ T-cell counts. Increasing titers of HCMV IgG were closely related to increasing CD8+ T-lymphocyte counts. It is also known that T lymphocytes take part in the alteration of vascular tone encountered in hypertension induced by angiotensin II, which is a potent vasoconstrictor.23 Therefore, T cells might be a link between HCMV infection and hypertension. In the present study, functional impairment represented by high IADL scores was associated with increasing HCMV IgG antibody titers in elderly patients. Functional status was measured in other studies with the Barthel Index (BI), which was originally developed to measure ADL in stroke patients. Associations between functional status by BI and prognosis in patients with infectious disease have been described previously in other studies.24,25 Torres et al. found that in elderly patients with pneumonia, a high BI, which is associated with greater functional abilities, was related to reduced 30-day and 18-month mortalities.24 In a prospective study of 244 patients with acute exacerbations of © 2014 Japan Geriatrics Society
chronic obstructive pulmonary disease and a mean age of 81.7 years, Ranieri et al. also found that body mass index, BI at discharge and comorbidities were risk factors for 6-month mortality.25 Recently, HCMV has even been linked with reduced cognitive functioning including vascular dementia26 and functional impairment.27 Several mechanisms might explain the associations between increased HCMV IgG antibody titers and disabilities in IADL in older adults. HCMV could exacerbate inflammation in diseased vessels.8 Chronic inflammation, which has negative impacts on endothelial integrity and blood flow control in the microcirculation, decreases the coordinated vasodilatory response to increase blood flow to meet the metabolic demands of skeletal muscle.28 Higher levels of inflammatory markers, linked to greater loss of muscle mass and strength,29 have been shown to be an important predictor for late-life disability.17 Additionally, previous studies have shown an association between HCMV and CVD through impaired endothelial nitric oxide synthase function, and subsequent endothelial dysfunction.11 HCMV infection stimulates rennin and angiotensin II expression in human vascular endothelial cells, thus enhancing NADPH oxidase activity, and |
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sample taken at a certain point in time could fail to reflect the natural course of the process being studied, and might not elucidate a clear cause–effect relationship. A larger and longitudinal study would be required to identify independent and strong correlations between HCMV infection and hypertension in elderly patients. An additional limitation is that gender-adjusted analyses could not be carried out because of the small sample size. However, we confirmed that the differences of sex between groups did not reach statistical significance. In conclusion, these results suggest that BMI and HCMV IgG titers could be used as predictors to identify elderly Koreans at high risk of developing hypertension. In addition, we showed a novel link between HCMV antibody titers and functional status. These findings could provide important insight into the pathogenesis of essential hypertension and functional status in the elderly.
Acknowledgments Figure 1 Relationship between human cytomegalovirus (HCMV) immunoglobulin G (IgG) titers and systolic blood pressure in elderly patients (r = 0.303; P = 0.002).
eliciting the production of reactive oxygen species (ROS).30 HCMV infections of smooth muscle cells also generate ROS through a COX-2-dependent pathway, thereby activating nuclear factor-κB.31 Nuclear factor-κB is associated with endothelial dysfunction and vascular inflammation, as well as vascular smooth muscle cell proliferation.32 In addition, the infection of smooth muscle cells with HCMV leads to the expression and secretion of growth factors,33,34 and it has also been shown that HCMV infection activated nuclear factor-κB.32 The virus is capable of enhancing leukocyte and platelet adhesion to endothelial cells by inducing cellular expression of adhesion molecules,35,36 and might cause procoagulant changes.37 Endothelial dysfunction, closely related to atherosclerotic change, could potentially lead to peripheral vascular disease, which has been shown to be an essential risk factor of low gait speed, decreased muscle strength and physical disability.38,39 Such results of epidemiology and vascular pathophysiology studies provide possible mechanistic explanations for the associations between HCMV infection and disability. There were several limitations to the present study. First, this was a cross-sectional study with a relatively small number of participants. However, this prospective study was carefully carried out, and a power calculation confirmed that small differences in the key variables could be detected in a sample of this size. In addition, this type of study is inherently limited, because a single 26
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This study was supported by the Public Welfare & Safety Research Program through the National Research Foundation of Korea (NRF), and funded by the Ministry of Education, Science and Technology (2011-0020961).
Disclosure statement No potential conflicts of interest were disclosed.
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