http://informahealthcare.com/ceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, 2015; 37(3): 218–222 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2014.939276
Association of cardiometabolic risk profile with prehypertension accompany hyperhomocysteinaemia Huili Chen, Yuemin Sun, Xuechun Wang, Quan Si, Wei Yao, and Zheng Wan Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
Abstract
Keywords
Background: Study suggested that elevated homocysteine showed a multiplicative effect on cardiovascular diseases in hypertensive subjects. It was reported that elevated homocysteine level was independently associated with increased arterial stiffness in prehypertensives. It remains unclear whether prehypertensives combined with elevated homocysteine have adverse cardiovascular risk factors. We aimed to compare cardiometabolic risk profile between prehypertensives with hyperhomocysteinaemia and those without either condition. Methods: Plasma total homocysteine and risk profile were determined among 874 Chinese nonhypertension individuals in Tianjin. They were subdivided into four groups: prehypertension with hyperhomocysteinaemia (10 mmol/L), prehypertension with normal homocysteine (510 mmol/L), normotension with hyperhomocysteinaemia, normotension with normol homocysteine, respectively. Results: In 874 participants, 22.5% of them were male, mean age was 56.8 years. In multiple comparisons, after adjustment for age, gender, smoking, alcohol, exercise, education prehypertensives had higher body mass index (BMI) and high sensitive C reactive protein (hs-CRP) than normotensives (p50.05, respectively); Only prehypertensive subjects with hyperhomocysteinaemia had higher triglyceride and serum uric acid compared to normotensive subjects, and lower HDL cholesterol than normotensives with normal homocysteine (p50.05, respectively). However, the significance of higher hs-CRP, uric acid and lower HDL cholesterol were abolished when further adjustment was made for BMI. Conclusion: The combination of prehypertension and hyperhomocusteinaemia increases the likelihood of having adverse cardiometabolic risk profile. Strict lipid management and weigh control may be needed in prehypertensives with elevated homocysteine.
Hyperhomocysteinaemia, prehypertension, risk factor
Introduction Hypertension was a leading risk factor for cardiovascular disease and premature death globally. Prehypertension (120– 139/80–89 mmHg), seemly as a precursor of hypertension, was associated with many cardiovascular events (1). It was associated with 1.32-fold increase in coronary heart disease incidence, and 1.34-fold in cardiovascular diseases (CVD) in a national sample in China (2). A recent meta-analysis involving 518 520 subjects showed that the relative risk for stroke was 1.55 [95% CI, 1.35–1.79] in prehypertension compared with normotension (3). Meanwhile, individuals with prehypertension have high likelihood of progression to hypertension (4–7). Elevated homocysteine has been shown as a potent independent risk factor for coronary artery disease and stroke (8,9). More importantly, increased homocysteine concentration showed more than multiplicative effect on CVD risk in hypertensive subjects (10). Towfighi et al. (11)
History Received 26 September 2013 Revised 30 May 2014 Accepted 17 June 2014 Published online 18 July 2014
also established that individuals with a combination of elevated total homocysteine (10 mmol/L) and hypertension were substantially more likely to have prevalent stroke compared with individuals without either condition (men: OR 2.02, 95% CI 6.36, 22.73; women: OR 17.34, 95% CI 10.49,28.64). However, literature about the interaction of homocysteine with prehypertension is scarce. A limited study showing elevated homocysteine level was independently associated with increased arterial stiffness in prehypertensives, irrespective of confounding factors (12) was available. It remains unclear whether the combination of prehypertension and elevated homocysteine synergistically increases the likelihood of having cardiometabolic profile. We aimed to compare risk factor profile between prehypertensives with hyperhomocysteinaemia and those without either condition, so as to identify high-risk individuals and provide with possible indicators for the prevention of CVD.
Methods Correspondence: Yuemin Sun, Department of Cardiology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China. Tel: +86 13902190646. Fax: +86 022 60362427. E-mail: zyysunyueminzr@ 126.com
Study population The study subjects were participants of an ongoing community-based study which aimed to estimate rate of
DOI: 10.3109/10641963.2014.939276
prehypertension progression to hypertension in Tianjin, China. In the current Study, a total of 1069 eligible subjects (ages 40–70 years) enrolled during August 2010–July 2012; and final analysis included 874 participants with complete data. All participants were free of hypertension, self-reported CVD, and Vitamin B or folate supplement. The prevalence of self-reported diabetes mellitus was 8.6% (75/874) in the process of enrollment, and 46.7% diabetic subjects received treatment with metformin, glibenclamide, or both. Another six diabetes patients who had received insulin therapy for glucose control were not suitable to the oral glucose tolerance test (OGTT) and apart from the study. The prevalence of selfreported dyslipidemia was 30.5% in 874 subjects, and all of them were out of lipid-lowering therapy. All participants signed an informed consent in compliance with the Declaration of Helsinki. Anthropometry and blood pressure Researchers went to the communities to screen local residents for non-hypertensive individuals aged 40–70 years. Candidate non-hypertensive people were then invited to study centers for a formal screening visit. During the screening visit, every participant finished standard questionnaires to collect information on current smoking (at least one cigarette per d), alcohol consumption (2 times per week), and exercise (3 times per week), education level (illiterate or primary, Elementary, senior or higher level), medical and medication histories. Height and weight were measured using automatic instruments with participants wearing light clothing and no shoes. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters squared). Blood pressure levels were measured using mercury sphygmomanometer on the right arm of subjects in a relaxed, sitting position by trained research staff. Triplicate measurements were taken, with at least 2 min between readings. Means of replicate readings were used for analyses. Prehypertension was defined as a SBP of 120–139 mmHg or a DBP of 80–89 mmHg, and normotension was SBP lower 120 mmHg and DBP lower 80 mmHg, according to the Joint National Committee (JNC)-7 guidelines (1). Biochemical and plasma homocysteine measurements Venous blood was drawn from the forearm of each participant in the fasting status and two hours after OGTT (without medication). Fasting serum and plasma were separated from blood cells in the field within 30 minutes and kept frozen at 70 C. Plasma homocysteine was measured by an enzymecycling method using a Hitachi 7180 Automatic Analyzer (Hitachi, Japan). Serum uric acid, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and fasting and postprandial blood glucose were also measured on the same analyzer. High-sensitivity CRP was assayed by a particle-enhanced immunoturbidimetric method (Roche Diagnostics, Roche/Hitachi Analyzer, Tokyo, Japan). Hyperhomocysteinaemia was defined as plasma total homocysteine 10 mmol/L, according to the Chinese guideline for management of hypertension (13). Diabetes mellitus was defined as fasting serum glucose level of 7.0 mmol/L (125 mg/dL) or higher or two hours postprandial serum
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glucose level of 11.1 mmol/L (200 mg/dL) or higher. Dyslipidemia was defined as triglyceride greater than 2.26 mmol/L (200 mg/dL) or total cholesterol greater than 6.22 mmol/L (240 mg/dL). Statistical analyses Data are expressed as mean (95% confidence interval) or geometric mean (95% confidence interval) for continuous variables and as percentages (%) for categorical variables. Among the variables, serum triglyceride and hs-CRP, homocysteine concentrations were log-transformed for analysis to correct for skewed distributions. Multiple comparisons among the four groups: prehypertension with hyperhomocysteinaemia, prehypertension with normal homocysteine, and normotension with hyperhomocysteinaemia, normotension with normal homocysteine were calculated with ANOVA. Intergroup differences were calculated by the Bonferroni test. All comparisons were conducted in crude model and multi-adjusted model including covariates age, sex, smoking, alcohol, exercise, education, and BMI. The interaction effect of prehypertension and hyperhomocysteinaemia was added. Data analyses were performed using SAS, in which p values of 50.05 were considered statistically significant.
Results All study subjects were divided into four groups: prehypertension with hyperhomocysteinaemia, prehypertension with normal homocysteine, normotension with hyperhomocysteinaemia, and normotension with normal homocysteine, respectively (Tables 1 and 2). The general characteristics of whole subjects are showed in Table 1. Comparative analyses of among the four groups showed that prehypertensives with hyperhomocysteinaemia were older and were more often male, drinking, high education, less exercise, and had a higher prevalences of diabetes mellitus, dyslipdemia (Table 1). The comparison of cardiovascular risk factors among four groups are shown in Table 2. In the crude model, prehypertensives had higher BMI than normotensives, regardless of homocysteine level (p50.05, respectively). Prehypertensive subjects, who combined with hyperhomocysteinaemia, had higher uric acid compared to other three groups (p50.05, respectively), higher triglyceride in contrast to normotensives with hyperhomocysteinemia or not (p50.05, both), and lower HDL cholesterol than normotensive groups with normal homocysteine (p50.05). Prehypertensive groups also had elevated OGTT 2-hour glucose compared to normotensives with hyperhomocysteinaemia (p50.05, both) (Table 2). In multi-adjusted model, after adjusting for age, gender, smoking, alcohol, exercise, education, prehypertensives still had higher BMI than normotensives. Only prehypertensive subjects, who combined with hyperhomocysteinaemia, had higher uric acid, higher triglyceride than normotensives with hyperhomocysteinemia or not, and lower HDL cholesterol compared to normotensive groups with normal homocysteine after adjustment for forementioned covariates. There was no significant interaction effect of prehypertesnion and hyperhomocysteinaemia on triglycerides (p ¼ 0.760), uric acid (p ¼ 0.853), and HDL cholesterol (p ¼ 0.167). In addition,
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Table 1. General characteristics of study people by blood pressure and homocysteine.
Characteristics
The whole subjects
Prehypertnsion with normal homocysteine
Prehypertension with hyperhomocysteinaemia
Normotension with normal homocysteine
Normotension with hyperhomocysteine
N 874 356 147 245 126 Age (year) 56.8 (56.4, 57.2) 58.4 (57.7, 59.1)z*y 55.5 (54.5, 56.5) 56.6 (55.8, 57.4)y 54.1 (53.0, 55.1) Gender (male) 223 (22.5%) 137 (38.5%)z*y 30 (20.4%) 43 (17.6%) 13 (10.3%) Current smoking (n, %) 121 (13.8%) 59 (16.6%) 20 (13.6%) 30 (12.2%) 12 (9.5%) Current drinking (n, %) 187 (22.2%) 98 (28.1%)*y 33 (23.6%)* 35 (14.8%) 21 (17.9%) Exercise (n, %) 206 (23.6%) 68 (19.1%)*y 30 (20.4%) 70 (28.6%) 38 (30.2%) High education (n, %) 205 (23.5%) 99 (27.8%)zy 19 (12.9%)* 61 (24.9%) 26 (20.6%) SBP (mmHg) 120.6 (119.9, 120.3) 128.1 (127.5, 128.8)*y 127.6 (126.6, 128.6)*y 110.6 (109.8, 111.4) 110.9 (109.9, 112.0) DBP (mmHg) 75.8 (75.3, 76.2) 79.5 (79.0, 80.0)*y 79.4 (78.6, 80.2)*y 70.7 (70.1, 71.4) 70.7 (69.9, 71.7) Homocysteineô (mmol/L) 11.8 (11.4, 12.1) 14.8 (14.3, 15.3)zy 7.1 (6.7, 7.5) 14.3 (13.8, 15.2)zy 7.3 (6.8, 7.7) Dyslipidemia (n, %) 302 (34.6%) 138 (38.8%)* 50 (34.0%) 75 (30.6%) 39 (31.0%) Diabetes mellitus (n, %) 101 (11.6%) 48 (13.5%)*y 29 (19.7%)*y 15 (6.1%) 9 (7.1%)
p Value 50.001 50.001 0.193 0.001 0.011 0.001 50.001 50.001 50.001 0.157 50.001
Values are mean (95% CI) and number (percentage). SBP – systolic blood pressure, DBP – diastolic blood pressure. *Different from normotension with hyperhomocysteinaemia, p50.05. yDifferent from normotension with normal homocysteine, p50.05. zDifferent from prehypertension with normal homocysteine, p50.05. ôGeometric mean (95% CI).
Table 2. Cardiovascular risk factors of study people by blood pressure and homocysteine.
Characteristics
Prehypertension with hyperhomocysteinaemia 356
Prehypertension with normal homocysteine 147
Normotension with hyperhomocysteine 245
Normotension with normal homocysteine
p Value
N Crude model Body mass index (kg/m2) Uric acid (mmol/L) Total cholesterol (mmol/L) Triglycerideô (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Fasting serum glocose (mmol/L) OGTT 2 h glucose (mmol/L) hs-CPRô (mg/L)
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24.9 309.2 5.60 1.55 1.41 3.45 5.67 7.54 1.31
(24.6, 25.2)*y (301.7, 316.6)z*y (5.49, 5.71) (1.46, 1.64)*y (1.37, 1.45)y (3.35, 3.54) (5.50, 5.83) (7.19, 7.89)* (1.16, 1.47)
25.3 (24.8, 25.8)*y 285.7 (274.1, 297.3) 5.46 (5.29, 5.63) 1.41 (1.29, 1.54) 1.47 (1.41, 1.54) 3.30 (3.15, 3.45) 5.77 (5.50, 6.03) 8.04 (7.50, 8.59)* 1.41(1.18, 1.70)
23.2 278.8 5.40 1.25 1.47 3.33 5.35 6.79 1.35
(22.8, 23.6) (269.8, 287.8) (5.26, 5.52) (1.17, 1.34) (1.42, 1.52) (3.21, 3.44) (5.15, 5.56) (6.36, 7.21) (1.17, 1.56)
23.5 265.2 5.50 1.22 1.80 3.34 5.25 7.00 1.14
(22.9, 24.0) (252.7, 277.8) (5.31, 5.68) (1.11, 1.34) (1.51, 1.64) (3.18, 3.50) (4.96, 5.53) (6.41, 7.51) (0.94, 1.40)
50.001 50.001 0.120 50.001 0.003 0.261 0.007 0.002 0.448
Multi-adjusted modex Body mass index (kg/m2) Uric acid (mmol/L) Total cholesterol (mmol/L) Triglycerideô (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Fasting serum glucose (mmol/L) OGTT 2 h glucose (mmol/L) hs-CPRô (mg/L)
25.3 317.6 5.48 1.64 1.35 3.35 5.77 7.78 1.94
(24.9, 25.7)*y (308.7, 326.5)*y (5.34, 5.62) (1.53, 1.76)*y (1.30, 1.40)y (3.23, 3.47) (5.57, 5.99) (7.346, 8.23) (1.70, 2.21)y
25.5 307.4 5.34 1.50 1.38 3.23 5.96 8.53 2.06
(24.9, 26.1)*y (295.1, 319.8) (5.15, 5.53) (1.36, 1.66) (1.31, 1.45) (3.06, 3.40) (5.67, 6.28) (7.90, 9.15)* (1.71, 2.47)y
23.5 301.0 5.25 1.30 1.40 3.24 5.57 7.17 1.69
(23.0, 23.9) (290.9, 311.1) (5.09, 5.41) (1.20, 1.41) (1.34, 1.45) (3.10, 3.38) (5.32, 5.81) (6.66, 7.68) (1.46, 1.96)
23.6 292.2 5.37 1.28 1.48 3.28 5.49 7.50 1.41
(23.0, 24.3) (278.9, 305.4) (5.16, 5.58) (1.15, 1.43) (1.42, 1.56) (3.10, 3.47) (5.16, 5.81) (6.83, 8.17) (1.16, 1.72)
50.001 0.002 0.075 50.001 0.022 0.448 0.058 0.002 0.006
Multi-adjusted mode# Uric acid (mmol/L) Total cholesterol (mmol/L) Triglycerideô (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Fasting serum glucose (mmol/L) OGTT 2 h glucose (mmol/L) hs-CPRô (mg/L)
311.9 5.47 1.56 1.39 3.33 5.67 7.59 1.73
(303.2, 320.7) (5.33, 5.61) (1.46, 1.68)*y (1.35, 1.44) (3.20, 3.45) (5.47, 5.90) (7.14, 8.04) (1.52, 1.96)
300.7 5.33 1.42 1.43 3.20 5.87 8.30 1.80
(288.7, 312.8) (5.13, 5.52) (1.29, 1.57) (1.37, 1.50) (3.03, 3.38) (5.57, 6.17) (7.68, 8.92)* (1.51, 2.14)
305.4 5.26 1.35 1.36 3.26 5.64 7.32 1.85
(295.6, 315.3) (5.10, 5.42) (1.25, 1.46) (1.31, 1.42) (3.12, 3.40) (5.39, 5.88) (6.82, 7.83) (1.60, 2.13)
295.7 5.38 1.32 1.46 3.30 5.54 7.62 1.52
(282.9, 308.6) (5.17, 5.59) (1.19, 1.46) (1.38, 1.53) (3.11, 3.48) (5.22, 5.86) (6.95, 8.28) (1.26, 1.82)
0.094 0.126 0.003 0.087 0.573 0.389 0.052 0.255
Value are mean (95% CI). HDL-cholesterol – high-density lipoprotein-cholesterol; LDL-cholesterol – low-density lipoprotein-cholesterol; OGTT 2 h glucose – oral glucose tolerance test 2 hours serum glucose; hs-CRP – high-sensitivity C-reactive protein. *Different from normotension with hyperhomocysteinaemia, p50.05. yDifferent from normotension with normal homocysteine, p50.05. zDifferent from prehypertension with normal homocysteine, p50.05. ôGeometric mean (95% CI). xAdjust for age, sex, smoking, alcohol intake, exercise, education status. #Adjust for age, sex, smoking, alcohol intake, exercise, education status, and BMI.
DOI: 10.3109/10641963.2014.939276
hs-CRP was higher in prehypertensives than that in normotensives with normal homocysteine after adjusting the forementioned factors (p50.05, both). However, after further introduction of BMI as continuous variable in multi-adjusted model, the significance of high uric acid and low HDL cholesterol in prehypertensives with elevated homocysteine compared to normotensives was abolished (p40.05, respectively), only the significance of triglycerides was unchanged. The significance of hs-CRP in prehypertesnsives was also abolished when adjusted for BMI (p40.05, both). Postprandial serum glucose was higher in prehypertensives with normal homocysteine than that in normotensives with hyperhomocysteinaemia independence of all covariates (p50.05). In three models, total cholesterol, LDL cholesterol, fasting serum glucose were null in multiple comparisons of four groups, as shown in Table 2.
Discussion In the study, we compared CVD risk factors among four groups divided by blood pressure and homocysteine. Our findings suggested that (a) prehypertenion subtype with elevated homocysteine exposed elevated triglycerides independence of age, gender, smoking, drinking, exercise, and BMI; and elevated uric acid, reduced HDL cholesterol independence of forementioned covariates, but not including BMI; (b) prehypertensives exhibited increasing BMI and elevated hs-CPR, but the latter was related to increasing BMI; (c) it was prehypertensive patients with normal homocysteine who had higher postprandial serum glucose, rather than prehypertensives with elevated homocysteine, which might indicate that homocysteine was inversely associated with insulin resistance (14); (d) it was prehypertensives with hyperhomocysteinaemia who had adverse cardiovascular risk factors, instead of prehypertensives with normal homocysteine. Our results stressed that the combination of two risk factors prehypertension and elevated homocysteine synergistically increased the likelihood of having cardiometabolic profile, although it was associated with increasing BMI to a certain degree. In our study, BMI was significantly higher in prehypertensives compared to normotensives. Our results were consistent with previous study that obesity was a risk factor in prehypertension (15). A meta-analysis (16) regarding risk factors of prehypertension showed that higher BMI was prevalent in different regions and ethnics, such as Greece, Africans, Indians, and increasing BMI categories was positively associated with prehypertension in communitydwellings Japanese (15). It has also been observed that prehypertension seems to be associated with a low-grade inflammation state (17). The ATTICA Study reported that compared to normotensives, prehypertensive men and women had 31% higher C-reactive protein (18), and subsequently confirmed that C-reactive protein predicted the progression of hypertension in follow-up (19). Our study showed that prehypertensive subjects exhibited higher hs-CRP level compared to normotensives; however, the difference was not statistically significant after adjustment for the measure of obesity. Previous study established that obesity was a major potential confounder of
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the association between CRP and BP (20). The association between CRP and hypertension was attenuated or no longer statistically significant by controlling for obesity (20). Obesity was a potent risk factor for elevated BP (15,21), and also correlated with elevated markers of inflammation (22). Our data analysis proved that obesity affected the correlation between CRP and prehypertension, and the onset of a lowgrade proinflammatory state in prehypertension was mainly associated with increasing BMI. Higher levels of serum triglycerides and lower levels of HDL cholesterol have been associated with elevated risk for vascular events (23). The survey in Singapore established that triglyceride was increasing in prehypertensives compared to normotensives in three different ethnics (Chinese, Malays, Indians); and high triglyceride (41.7 mmol/L) was positively associated with prevalence of prehypertension in Malays (24). It was also reported that HDL cholesterol was lower in male adults with prehypertension compared with normotension (15). In our study, only subjects with prehypertension and hyperhomocysteinaemia showed significantly higher triglyceride and lower HDL cholesterol level than did those with normotension. The significant difference of triglyceride was independent of BMI, while the difference for HDL cholesterol was no longer significant after adjustment for BMI. It was associated with the findings that obesity affected metabolism of HDL cholesterol (25). These data indicated that prehypertension was prone to be in cahoots with dyslipidemia characteristics by high triglyceride and low HDL cholesterol. This disorder was obvious in prehypertensives with elevated homocysteine level in our study, although low HDL cholesterol was mainly associated with overweight. In addition, slightly higher serum uric acid also was observed in prehypertensives with hyperhomocysteinaemia, while the significance was abolished after adjustment for BMI. Similarly, obesity was closely associated with serum uric acid (26). Epidemiologic evidence indicated elevated uric acid consistently predicted the development of hypertension (27,28) and was associated with increased risk of cardiovascular events (29). It is the coexistence of prehypertension and elevated homocysteine that increases the likelihood of elevated uric acid, triglycerides, low HDL cholesterol, instead of the interaction effect of both. Recently, Esteghamati and his colleagues found metabolic abnormalities to be more prevalent in subjects with higher serum homocysteine levels (30). A close correlation between homocysteine and metabolic syndrome components was showed in their research (30). In our study, abnormal metabolic profile is more prevalent in prehypertensives with elevated homocysteine. In conclusion, present study showed that prehypertension subtype with hyperhomocysteinawmia manifested adverse cardiometabolic risk factors, such as elevated triglycerides independence of confounding factors, and high hs-CRP, uric acid, low HDL cholesterol that were closely related to increasing BMI. Early identification for individuals with prehypertension and elevated homocysteine level; and strict lipid management, weight control or folic acid supplement may play a positive role in prevention for CVD (23,31). There also were limits in our study. First, our study was refined to prehypertensives aged 40–70 years, the results were not
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suitable to massive prehypertensive people. Second, the present study was a cross-section current study, hence could not estimate the risk of CVD in prehypertensive individuals with elevated homocysteine, which may need further studies.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This study was supported by the Science and Technology Fund of Tianjin Health Bureau (11KG133).
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Association of cardiometabolic risk profile with prehypertension accompany hyperhomocysteinaemia Huili Chen, Yuemin Sun, Xuechun Wang, Quan Si, Wei Yao, and Zheng Wan Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
Abstract
Keywords
Background: Study suggested that elevated homocysteine showed a multiplicative effect on cardiovascular diseases in hypertensive subjects. It was reported that elevated homocysteine level was independently associated with increased arterial stiffness in prehypertensives. It remains unclear whether prehypertensives combined with elevated homocysteine have adverse cardiovascular risk factors. We aimed to compare cardiometabolic risk profile between prehypertensives with hyperhomocysteinaemia and those without either condition. Methods: Plasma total homocysteine and risk profile were determined among 874 Chinese nonhypertension individuals in Tianjin. They were subdivided into four groups: prehypertension with hyperhomocysteinaemia (10 mmol/L), prehypertension with normal homocysteine (510 mmol/L), normotension with hyperhomocysteinaemia, normotension with normol homocysteine, respectively. Results: In 874 participants, 22.5% of them were male, mean age was 56.8 years. In multiple comparisons, after adjustment for age, gender, smoking, alcohol, exercise, education prehypertensives had higher body mass index (BMI) and high sensitive C reactive protein (hs-CRP) than normotensives (p50.05, respectively); Only prehypertensive subjects with hyperhomocysteinaemia had higher triglyceride and serum uric acid compared to normotensive subjects, and lower HDL cholesterol than normotensives with normal homocysteine (p50.05, respectively). However, the significance of higher hs-CRP, uric acid and lower HDL cholesterol were abolished when further adjustment was made for BMI. Conclusion: The combination of prehypertension and hyperhomocusteinaemia increases the likelihood of having adverse cardiometabolic risk profile. Strict lipid management and weigh control may be needed in prehypertensives with elevated homocysteine.
Hyperhomocysteinaemia, prehypertension, risk factor
Introduction Hypertension was a leading risk factor for cardiovascular disease and premature death globally. Prehypertension (120– 139/80–89 mmHg), seemly as a precursor of hypertension, was associated with many cardiovascular events (1). It was associated with 1.32-fold increase in coronary heart disease incidence, and 1.34-fold in cardiovascular diseases (CVD) in a national sample in China (2). A recent meta-analysis involving 518 520 subjects showed that the relative risk for stroke was 1.55 [95% CI, 1.35–1.79] in prehypertension compared with normotension (3). Meanwhile, individuals with prehypertension have high likelihood of progression to hypertension (4–7). Elevated homocysteine has been shown as a potent independent risk factor for coronary artery disease and stroke (8,9). More importantly, increased homocysteine concentration showed more than multiplicative effect on CVD risk in hypertensive subjects (10). Towfighi et al. (11)
History Received 26 September 2013 Revised 30 May 2014 Accepted 17 June 2014 Published online 18 July 2014
also established that individuals with a combination of elevated total homocysteine (10 mmol/L) and hypertension were substantially more likely to have prevalent stroke compared with individuals without either condition (men: OR 2.02, 95% CI 6.36, 22.73; women: OR 17.34, 95% CI 10.49,28.64). However, literature about the interaction of homocysteine with prehypertension is scarce. A limited study showing elevated homocysteine level was independently associated with increased arterial stiffness in prehypertensives, irrespective of confounding factors (12) was available. It remains unclear whether the combination of prehypertension and elevated homocysteine synergistically increases the likelihood of having cardiometabolic profile. We aimed to compare risk factor profile between prehypertensives with hyperhomocysteinaemia and those without either condition, so as to identify high-risk individuals and provide with possible indicators for the prevention of CVD.
Methods Correspondence: Yuemin Sun, Department of Cardiology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China. Tel: +86 13902190646. Fax: +86 022 60362427. E-mail: zyysunyueminzr@ 126.com
Study population The study subjects were participants of an ongoing community-based study which aimed to estimate rate of
DOI: 10.3109/10641963.2014.939276
prehypertension progression to hypertension in Tianjin, China. In the current Study, a total of 1069 eligible subjects (ages 40–70 years) enrolled during August 2010–July 2012; and final analysis included 874 participants with complete data. All participants were free of hypertension, self-reported CVD, and Vitamin B or folate supplement. The prevalence of self-reported diabetes mellitus was 8.6% (75/874) in the process of enrollment, and 46.7% diabetic subjects received treatment with metformin, glibenclamide, or both. Another six diabetes patients who had received insulin therapy for glucose control were not suitable to the oral glucose tolerance test (OGTT) and apart from the study. The prevalence of selfreported dyslipidemia was 30.5% in 874 subjects, and all of them were out of lipid-lowering therapy. All participants signed an informed consent in compliance with the Declaration of Helsinki. Anthropometry and blood pressure Researchers went to the communities to screen local residents for non-hypertensive individuals aged 40–70 years. Candidate non-hypertensive people were then invited to study centers for a formal screening visit. During the screening visit, every participant finished standard questionnaires to collect information on current smoking (at least one cigarette per d), alcohol consumption (2 times per week), and exercise (3 times per week), education level (illiterate or primary, Elementary, senior or higher level), medical and medication histories. Height and weight were measured using automatic instruments with participants wearing light clothing and no shoes. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters squared). Blood pressure levels were measured using mercury sphygmomanometer on the right arm of subjects in a relaxed, sitting position by trained research staff. Triplicate measurements were taken, with at least 2 min between readings. Means of replicate readings were used for analyses. Prehypertension was defined as a SBP of 120–139 mmHg or a DBP of 80–89 mmHg, and normotension was SBP lower 120 mmHg and DBP lower 80 mmHg, according to the Joint National Committee (JNC)-7 guidelines (1). Biochemical and plasma homocysteine measurements Venous blood was drawn from the forearm of each participant in the fasting status and two hours after OGTT (without medication). Fasting serum and plasma were separated from blood cells in the field within 30 minutes and kept frozen at 70 C. Plasma homocysteine was measured by an enzymecycling method using a Hitachi 7180 Automatic Analyzer (Hitachi, Japan). Serum uric acid, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and fasting and postprandial blood glucose were also measured on the same analyzer. High-sensitivity CRP was assayed by a particle-enhanced immunoturbidimetric method (Roche Diagnostics, Roche/Hitachi Analyzer, Tokyo, Japan). Hyperhomocysteinaemia was defined as plasma total homocysteine 10 mmol/L, according to the Chinese guideline for management of hypertension (13). Diabetes mellitus was defined as fasting serum glucose level of 7.0 mmol/L (125 mg/dL) or higher or two hours postprandial serum
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glucose level of 11.1 mmol/L (200 mg/dL) or higher. Dyslipidemia was defined as triglyceride greater than 2.26 mmol/L (200 mg/dL) or total cholesterol greater than 6.22 mmol/L (240 mg/dL). Statistical analyses Data are expressed as mean (95% confidence interval) or geometric mean (95% confidence interval) for continuous variables and as percentages (%) for categorical variables. Among the variables, serum triglyceride and hs-CRP, homocysteine concentrations were log-transformed for analysis to correct for skewed distributions. Multiple comparisons among the four groups: prehypertension with hyperhomocysteinaemia, prehypertension with normal homocysteine, and normotension with hyperhomocysteinaemia, normotension with normal homocysteine were calculated with ANOVA. Intergroup differences were calculated by the Bonferroni test. All comparisons were conducted in crude model and multi-adjusted model including covariates age, sex, smoking, alcohol, exercise, education, and BMI. The interaction effect of prehypertension and hyperhomocysteinaemia was added. Data analyses were performed using SAS, in which p values of 50.05 were considered statistically significant.
Results All study subjects were divided into four groups: prehypertension with hyperhomocysteinaemia, prehypertension with normal homocysteine, normotension with hyperhomocysteinaemia, and normotension with normal homocysteine, respectively (Tables 1 and 2). The general characteristics of whole subjects are showed in Table 1. Comparative analyses of among the four groups showed that prehypertensives with hyperhomocysteinaemia were older and were more often male, drinking, high education, less exercise, and had a higher prevalences of diabetes mellitus, dyslipdemia (Table 1). The comparison of cardiovascular risk factors among four groups are shown in Table 2. In the crude model, prehypertensives had higher BMI than normotensives, regardless of homocysteine level (p50.05, respectively). Prehypertensive subjects, who combined with hyperhomocysteinaemia, had higher uric acid compared to other three groups (p50.05, respectively), higher triglyceride in contrast to normotensives with hyperhomocysteinemia or not (p50.05, both), and lower HDL cholesterol than normotensive groups with normal homocysteine (p50.05). Prehypertensive groups also had elevated OGTT 2-hour glucose compared to normotensives with hyperhomocysteinaemia (p50.05, both) (Table 2). In multi-adjusted model, after adjusting for age, gender, smoking, alcohol, exercise, education, prehypertensives still had higher BMI than normotensives. Only prehypertensive subjects, who combined with hyperhomocysteinaemia, had higher uric acid, higher triglyceride than normotensives with hyperhomocysteinemia or not, and lower HDL cholesterol compared to normotensive groups with normal homocysteine after adjustment for forementioned covariates. There was no significant interaction effect of prehypertesnion and hyperhomocysteinaemia on triglycerides (p ¼ 0.760), uric acid (p ¼ 0.853), and HDL cholesterol (p ¼ 0.167). In addition,
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Table 1. General characteristics of study people by blood pressure and homocysteine.
Characteristics
The whole subjects
Prehypertnsion with normal homocysteine
Prehypertension with hyperhomocysteinaemia
Normotension with normal homocysteine
Normotension with hyperhomocysteine
N 874 356 147 245 126 Age (year) 56.8 (56.4, 57.2) 58.4 (57.7, 59.1)z*y 55.5 (54.5, 56.5) 56.6 (55.8, 57.4)y 54.1 (53.0, 55.1) Gender (male) 223 (22.5%) 137 (38.5%)z*y 30 (20.4%) 43 (17.6%) 13 (10.3%) Current smoking (n, %) 121 (13.8%) 59 (16.6%) 20 (13.6%) 30 (12.2%) 12 (9.5%) Current drinking (n, %) 187 (22.2%) 98 (28.1%)*y 33 (23.6%)* 35 (14.8%) 21 (17.9%) Exercise (n, %) 206 (23.6%) 68 (19.1%)*y 30 (20.4%) 70 (28.6%) 38 (30.2%) High education (n, %) 205 (23.5%) 99 (27.8%)zy 19 (12.9%)* 61 (24.9%) 26 (20.6%) SBP (mmHg) 120.6 (119.9, 120.3) 128.1 (127.5, 128.8)*y 127.6 (126.6, 128.6)*y 110.6 (109.8, 111.4) 110.9 (109.9, 112.0) DBP (mmHg) 75.8 (75.3, 76.2) 79.5 (79.0, 80.0)*y 79.4 (78.6, 80.2)*y 70.7 (70.1, 71.4) 70.7 (69.9, 71.7) Homocysteineô (mmol/L) 11.8 (11.4, 12.1) 14.8 (14.3, 15.3)zy 7.1 (6.7, 7.5) 14.3 (13.8, 15.2)zy 7.3 (6.8, 7.7) Dyslipidemia (n, %) 302 (34.6%) 138 (38.8%)* 50 (34.0%) 75 (30.6%) 39 (31.0%) Diabetes mellitus (n, %) 101 (11.6%) 48 (13.5%)*y 29 (19.7%)*y 15 (6.1%) 9 (7.1%)
p Value 50.001 50.001 0.193 0.001 0.011 0.001 50.001 50.001 50.001 0.157 50.001
Values are mean (95% CI) and number (percentage). SBP – systolic blood pressure, DBP – diastolic blood pressure. *Different from normotension with hyperhomocysteinaemia, p50.05. yDifferent from normotension with normal homocysteine, p50.05. zDifferent from prehypertension with normal homocysteine, p50.05. ôGeometric mean (95% CI).
Table 2. Cardiovascular risk factors of study people by blood pressure and homocysteine.
Characteristics
Prehypertension with hyperhomocysteinaemia 356
Prehypertension with normal homocysteine 147
Normotension with hyperhomocysteine 245
Normotension with normal homocysteine
p Value
N Crude model Body mass index (kg/m2) Uric acid (mmol/L) Total cholesterol (mmol/L) Triglycerideô (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Fasting serum glocose (mmol/L) OGTT 2 h glucose (mmol/L) hs-CPRô (mg/L)
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24.9 309.2 5.60 1.55 1.41 3.45 5.67 7.54 1.31
(24.6, 25.2)*y (301.7, 316.6)z*y (5.49, 5.71) (1.46, 1.64)*y (1.37, 1.45)y (3.35, 3.54) (5.50, 5.83) (7.19, 7.89)* (1.16, 1.47)
25.3 (24.8, 25.8)*y 285.7 (274.1, 297.3) 5.46 (5.29, 5.63) 1.41 (1.29, 1.54) 1.47 (1.41, 1.54) 3.30 (3.15, 3.45) 5.77 (5.50, 6.03) 8.04 (7.50, 8.59)* 1.41(1.18, 1.70)
23.2 278.8 5.40 1.25 1.47 3.33 5.35 6.79 1.35
(22.8, 23.6) (269.8, 287.8) (5.26, 5.52) (1.17, 1.34) (1.42, 1.52) (3.21, 3.44) (5.15, 5.56) (6.36, 7.21) (1.17, 1.56)
23.5 265.2 5.50 1.22 1.80 3.34 5.25 7.00 1.14
(22.9, 24.0) (252.7, 277.8) (5.31, 5.68) (1.11, 1.34) (1.51, 1.64) (3.18, 3.50) (4.96, 5.53) (6.41, 7.51) (0.94, 1.40)
50.001 50.001 0.120 50.001 0.003 0.261 0.007 0.002 0.448
Multi-adjusted modex Body mass index (kg/m2) Uric acid (mmol/L) Total cholesterol (mmol/L) Triglycerideô (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Fasting serum glucose (mmol/L) OGTT 2 h glucose (mmol/L) hs-CPRô (mg/L)
25.3 317.6 5.48 1.64 1.35 3.35 5.77 7.78 1.94
(24.9, 25.7)*y (308.7, 326.5)*y (5.34, 5.62) (1.53, 1.76)*y (1.30, 1.40)y (3.23, 3.47) (5.57, 5.99) (7.346, 8.23) (1.70, 2.21)y
25.5 307.4 5.34 1.50 1.38 3.23 5.96 8.53 2.06
(24.9, 26.1)*y (295.1, 319.8) (5.15, 5.53) (1.36, 1.66) (1.31, 1.45) (3.06, 3.40) (5.67, 6.28) (7.90, 9.15)* (1.71, 2.47)y
23.5 301.0 5.25 1.30 1.40 3.24 5.57 7.17 1.69
(23.0, 23.9) (290.9, 311.1) (5.09, 5.41) (1.20, 1.41) (1.34, 1.45) (3.10, 3.38) (5.32, 5.81) (6.66, 7.68) (1.46, 1.96)
23.6 292.2 5.37 1.28 1.48 3.28 5.49 7.50 1.41
(23.0, 24.3) (278.9, 305.4) (5.16, 5.58) (1.15, 1.43) (1.42, 1.56) (3.10, 3.47) (5.16, 5.81) (6.83, 8.17) (1.16, 1.72)
50.001 0.002 0.075 50.001 0.022 0.448 0.058 0.002 0.006
Multi-adjusted mode# Uric acid (mmol/L) Total cholesterol (mmol/L) Triglycerideô (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Fasting serum glucose (mmol/L) OGTT 2 h glucose (mmol/L) hs-CPRô (mg/L)
311.9 5.47 1.56 1.39 3.33 5.67 7.59 1.73
(303.2, 320.7) (5.33, 5.61) (1.46, 1.68)*y (1.35, 1.44) (3.20, 3.45) (5.47, 5.90) (7.14, 8.04) (1.52, 1.96)
300.7 5.33 1.42 1.43 3.20 5.87 8.30 1.80
(288.7, 312.8) (5.13, 5.52) (1.29, 1.57) (1.37, 1.50) (3.03, 3.38) (5.57, 6.17) (7.68, 8.92)* (1.51, 2.14)
305.4 5.26 1.35 1.36 3.26 5.64 7.32 1.85
(295.6, 315.3) (5.10, 5.42) (1.25, 1.46) (1.31, 1.42) (3.12, 3.40) (5.39, 5.88) (6.82, 7.83) (1.60, 2.13)
295.7 5.38 1.32 1.46 3.30 5.54 7.62 1.52
(282.9, 308.6) (5.17, 5.59) (1.19, 1.46) (1.38, 1.53) (3.11, 3.48) (5.22, 5.86) (6.95, 8.28) (1.26, 1.82)
0.094 0.126 0.003 0.087 0.573 0.389 0.052 0.255
Value are mean (95% CI). HDL-cholesterol – high-density lipoprotein-cholesterol; LDL-cholesterol – low-density lipoprotein-cholesterol; OGTT 2 h glucose – oral glucose tolerance test 2 hours serum glucose; hs-CRP – high-sensitivity C-reactive protein. *Different from normotension with hyperhomocysteinaemia, p50.05. yDifferent from normotension with normal homocysteine, p50.05. zDifferent from prehypertension with normal homocysteine, p50.05. ôGeometric mean (95% CI). xAdjust for age, sex, smoking, alcohol intake, exercise, education status. #Adjust for age, sex, smoking, alcohol intake, exercise, education status, and BMI.
DOI: 10.3109/10641963.2014.939276
hs-CRP was higher in prehypertensives than that in normotensives with normal homocysteine after adjusting the forementioned factors (p50.05, both). However, after further introduction of BMI as continuous variable in multi-adjusted model, the significance of high uric acid and low HDL cholesterol in prehypertensives with elevated homocysteine compared to normotensives was abolished (p40.05, respectively), only the significance of triglycerides was unchanged. The significance of hs-CRP in prehypertesnsives was also abolished when adjusted for BMI (p40.05, both). Postprandial serum glucose was higher in prehypertensives with normal homocysteine than that in normotensives with hyperhomocysteinaemia independence of all covariates (p50.05). In three models, total cholesterol, LDL cholesterol, fasting serum glucose were null in multiple comparisons of four groups, as shown in Table 2.
Discussion In the study, we compared CVD risk factors among four groups divided by blood pressure and homocysteine. Our findings suggested that (a) prehypertenion subtype with elevated homocysteine exposed elevated triglycerides independence of age, gender, smoking, drinking, exercise, and BMI; and elevated uric acid, reduced HDL cholesterol independence of forementioned covariates, but not including BMI; (b) prehypertensives exhibited increasing BMI and elevated hs-CPR, but the latter was related to increasing BMI; (c) it was prehypertensive patients with normal homocysteine who had higher postprandial serum glucose, rather than prehypertensives with elevated homocysteine, which might indicate that homocysteine was inversely associated with insulin resistance (14); (d) it was prehypertensives with hyperhomocysteinaemia who had adverse cardiovascular risk factors, instead of prehypertensives with normal homocysteine. Our results stressed that the combination of two risk factors prehypertension and elevated homocysteine synergistically increased the likelihood of having cardiometabolic profile, although it was associated with increasing BMI to a certain degree. In our study, BMI was significantly higher in prehypertensives compared to normotensives. Our results were consistent with previous study that obesity was a risk factor in prehypertension (15). A meta-analysis (16) regarding risk factors of prehypertension showed that higher BMI was prevalent in different regions and ethnics, such as Greece, Africans, Indians, and increasing BMI categories was positively associated with prehypertension in communitydwellings Japanese (15). It has also been observed that prehypertension seems to be associated with a low-grade inflammation state (17). The ATTICA Study reported that compared to normotensives, prehypertensive men and women had 31% higher C-reactive protein (18), and subsequently confirmed that C-reactive protein predicted the progression of hypertension in follow-up (19). Our study showed that prehypertensive subjects exhibited higher hs-CRP level compared to normotensives; however, the difference was not statistically significant after adjustment for the measure of obesity. Previous study established that obesity was a major potential confounder of
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the association between CRP and BP (20). The association between CRP and hypertension was attenuated or no longer statistically significant by controlling for obesity (20). Obesity was a potent risk factor for elevated BP (15,21), and also correlated with elevated markers of inflammation (22). Our data analysis proved that obesity affected the correlation between CRP and prehypertension, and the onset of a lowgrade proinflammatory state in prehypertension was mainly associated with increasing BMI. Higher levels of serum triglycerides and lower levels of HDL cholesterol have been associated with elevated risk for vascular events (23). The survey in Singapore established that triglyceride was increasing in prehypertensives compared to normotensives in three different ethnics (Chinese, Malays, Indians); and high triglyceride (41.7 mmol/L) was positively associated with prevalence of prehypertension in Malays (24). It was also reported that HDL cholesterol was lower in male adults with prehypertension compared with normotension (15). In our study, only subjects with prehypertension and hyperhomocysteinaemia showed significantly higher triglyceride and lower HDL cholesterol level than did those with normotension. The significant difference of triglyceride was independent of BMI, while the difference for HDL cholesterol was no longer significant after adjustment for BMI. It was associated with the findings that obesity affected metabolism of HDL cholesterol (25). These data indicated that prehypertension was prone to be in cahoots with dyslipidemia characteristics by high triglyceride and low HDL cholesterol. This disorder was obvious in prehypertensives with elevated homocysteine level in our study, although low HDL cholesterol was mainly associated with overweight. In addition, slightly higher serum uric acid also was observed in prehypertensives with hyperhomocysteinaemia, while the significance was abolished after adjustment for BMI. Similarly, obesity was closely associated with serum uric acid (26). Epidemiologic evidence indicated elevated uric acid consistently predicted the development of hypertension (27,28) and was associated with increased risk of cardiovascular events (29). It is the coexistence of prehypertension and elevated homocysteine that increases the likelihood of elevated uric acid, triglycerides, low HDL cholesterol, instead of the interaction effect of both. Recently, Esteghamati and his colleagues found metabolic abnormalities to be more prevalent in subjects with higher serum homocysteine levels (30). A close correlation between homocysteine and metabolic syndrome components was showed in their research (30). In our study, abnormal metabolic profile is more prevalent in prehypertensives with elevated homocysteine. In conclusion, present study showed that prehypertension subtype with hyperhomocysteinawmia manifested adverse cardiometabolic risk factors, such as elevated triglycerides independence of confounding factors, and high hs-CRP, uric acid, low HDL cholesterol that were closely related to increasing BMI. Early identification for individuals with prehypertension and elevated homocysteine level; and strict lipid management, weight control or folic acid supplement may play a positive role in prevention for CVD (23,31). There also were limits in our study. First, our study was refined to prehypertensives aged 40–70 years, the results were not
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suitable to massive prehypertensive people. Second, the present study was a cross-section current study, hence could not estimate the risk of CVD in prehypertensive individuals with elevated homocysteine, which may need further studies.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This study was supported by the Science and Technology Fund of Tianjin Health Bureau (11KG133).
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