Published online before print April 23, 2007, doi: 10.1161/HYPERTENSIONAHA.107.086835
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(Hypertension. 2007;49:1455.)
© 2007 American Heart Association, Inc.
Original Articles |
Hypoadiponectinemia as a Predictor for the Development of Hypertension
A 5-Year Prospective Study
From the Department of Medicine (W-S.C., B.M.Y.C., A.W.K.T., A.X., N.M.S.W., C.H.Y.F., L.H.Y.O., K.C.B.T., K.S.L.L.), the Research Centre of Heart, Brain, Hormone, and Healthy Aging (B.M.Y.C., A.X., K.C.B.T., K.S.L.L.), the Clinical Biochemistry Unit (S.T., E.D.J.), and the Department of Community Medicine (T-H.L.), University of Hong Kong, Queen Mary Hospital, Hong Kong, People’s Republic of China. Current address: Department of Medicine (E.D.J.), University of Melbourne, Western Hospital, Footscray, Australia.
Correspondence to Karen S.L. Lam, Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong, People’s Republic of China. E-mail ksllam{at}hkucc.hku.hk
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Abstract |
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Low circulating levels of adiponectin, an adipokine with insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, are found in hypertensive patients. Adiponectin replenishment ameliorated hypertension in adiponectin-deficient mice or obese, hypertensive mice with hypoadiponectinemia, suggesting an etiologic role of adiponectin in hypertension. We aimed to determine, in this 5-year prospective study, whether hypoadiponectinemia could predict the development of hypertension in a nondiabetic Chinese cohort. A total of 577 subjects (249 men and 328 women) were recruited from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study and prospectively followed up for 5 years. The relationship of serum adiponectin with the development of hypertension (sitting blood pressure
140/90 mm Hg) was investigated in a nested case–control study consisting of 70 subjects who had developed hypertension on follow-up and 140 age- and sex-matched control subjects who were normotensive both at baseline and at year 5. At baseline, serum adiponectin level in the lowest sex-specific tertile was more likely to be associated with hypertension (P=0.003 versus the highest tertile, after adjusting for age, body mass index, fasting insulin, and high-sensitivity C-reactive protein). At year 5, baseline serum adiponectin was a significant independent predictor of incident hypertension in the nested case–control study (P=0.015; age adjusted), together with mean arterial pressure (P<0.001), high-sensitivity C-reactive protein (P=0.018), and body mass index (P=0.004). Normotensive subjects with baseline serum adiponectin levels in the lowest sex-specific tertile had an increased risk of becoming hypertensive (adjusted odds ratio: 2.76; 95% CIs: 1.06 to 7.16; P=0.037 versus highest tertile). Our data suggest that hypoadiponectinaemia may be involved in the pathogenesis of hypertension in humans.
Key Words: adiponectin • hypertension • Chinese • prediction • C-reactive protein
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Introduction |
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Obesity is an important risk factor for cardiovascular disease1 and is often associated with high blood pressure and various metabolic abnormalities, such as dyslipidemia, elevated plasma glucose, and insulin resistance.2 Recent studies suggest that perturbations in the secretion of fat-derived hormones and cytokines, such as adiponectin, tumor necrosis factor-
, and interleukin-6, play an important role in linking obesity with these cardiometabolic risk factors, in part through their effects on insulin sensitivity.3 The circulating levels of adiponectin, a fat-derived hormone with insulin sensitizing,4 anti-inflammatory, and antiatherogenic properties,5 are reduced in subjects with obesity, type 2 diabetes,6 hypertension,7 and coronary artery disease.8 Hypoadiponectinemia has also been shown to be an independent risk factor for hypertension in cross-sectional studies9,10 and predicts the development of type 2 diabetes11 and myocardial infarction12 in prospective studies. An effect of adiponectin on vasoreactivity was suggested by the presence of impaired endothelium-dependent vasodilatation in mice deficient in adiponectin, which also developed hypertension on an atherogenic diet13 or a high-salt diet.14 In a more recent study, adiponectin replenishment could ameliorate the hypertension in adiponectin knockout mice on a high-salt diet and in KKay mice with obesity-related hypertension.14 Although the data from the above animal studies would suggest an etiologic role of hypoadiponectinemia in hypertension, there has been no prospective study addressing the relationship between circulating adiponectin levels and the development of hypertension in humans. We, therefore, investigated, in this 5-year prospective study, the relationship between serum adiponectin levels and the subsequent development of hypertension in a cohort of normotensive, nondiabetic Chinese subjects.
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Subjects and Methods |
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Subjects were recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study. Briefly, between 1995 and 1996, 2875 unrelated subjects, aged 25 to 74 years, were randomly recruited to participate in a population-based study to assess the prevalence of cardiovascular risk factors in our Southern Chinese population.15 Among these, 644 nondiabetic subjects (322 with impaired glucose tolerance [IGT] and 322 sex- and age-matched subjects with normal glucose tolerance) were subsequently invited to participate in a longitudinal study to examine the importance of IGT as a risk factor of diabetes and hypertension in Southern Chinese. Only the 577 subjects with available baseline blood samples for adiponectin measurement were included in the present study. The subjects returned at 2 and 5 years to repeat the baseline assessments, which included a 75-g oral glucose tolerance test, body weight, height, body mass index (BMI), waist circumference (WC), and resting blood pressure, measured or calculated as described in our published reports on glycemic progression.16–18 Between visits, subjects were under the care of their own primary care physicians. Blood pressure (BP) was measured using a mercury sphygmomanometer (Baumanometer, WA Baum) according to a standardized protocol15–18 and was taken as the mean of 2 readings measured 2 to 3 minutes apart on the right arm (with the forearm resting on the desk) after the subjects had been seated for
10 minutes. Systolic and diastolic (Korotkoff phase V) BP readings were recorded to the nearest 2 mm Hg. Standard-sized cuffs (12- to 14-cm wide) were used. The research nurses were given training by an experienced physician. Hypertension was defined as sitting BP 140/90 mm Hg or on regular antihypertensive drugs.19 Subjects were classified as having normal glucose tolerance, IGT, impaired fasting glucose (IFG) or diabetes mellitus according to the World Health Organization 1998 diagnostic criteria.20 For the nested case–control study, case subjects were normotensive subjects at baseline who had developed hypertension by year 5. For each case, 2 control subjects, matched for sex and age (to the nearest 10 years), were selected from among those normotensive subjects who had remained normotensive at year 5. The study was approved by the Ethics Committee of the University of Hong Kong, and all of the participants gave written informed consent.
Biochemical Measurements
Plasma insulin, high sensitivity C-reactive protein (hsCRP), total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured as described previously.16,18 The homeostasis model assessment of insulin resistance (HOMA-IR), a simple assessment of insulin sensitivity, was calculated using the following formula: fasting plasma glucose (mmol/L)xfasting insulin (microunits/mL)/22.5. Serum adiponectin level was determined with an in-house ELISA assay established in our laboratory.18,21
Statistical Analysis
Statistical analysis was performed using SPSS 12.0 (SPSS). Continuous variables are presented as means and SDs or medians with interquartile ranges. Data with skewed distributions were logarithmically transformed to obtain near normality before analysis. Comparisons of variables between case and control subjects were performed using 1-way ANOVA or 
2 tests as appropriate. Adiponectin levels were adjusted for age and sex in all of the analyses because the levels were higher in women and increased with age. Sex-specific adiponectin tertiles were calculated according to the baseline adiponectin levels of the entire cohort (n=577). Logistic regression analysis was used in calculating the odds ratios (OR) for the development of hypertension at year 5 in subjects with low baseline adiponectin levels (first and second tertiles), compared with those in the highest tertile (reference group). To determine the baseline parameter(s) independently associated with hypertension at baseline and year 5, stepwise logistic regression analyses, after Bonferroni correction for multiple testing, were used to examine the association of baseline adiponectin and other biologically relevant parameters with hypertension. P<0.05 was considered significant. Data are mean±SD unless otherwise stated.
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Results |
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At baseline, 440 of the 577 subjects were normotensive. The baseline clinical characteristics of the cohort are summarized in Table 1. Compared with the normotensive group, subjects with hypertension (n=137) were older (P<0.001), had higher BMI (P<0.001), had higher prevalence of IGT/IFG (P=0.001), and consisted of more men (P=0.032). Fasting serum adiponectin was significantly lower in the hypertensive subjects (P<0.001). In a stepwise logistic regression model that included age, BMI, fasting insulin, hsCRP, and adiponectin in sex-specific tertiles, only age (OR: 1.11; 95% CIs: 1.09 to 1.14; P<0.001), BMI (OR: 1.25; 95% CI: 1.17 to 1.34; P<0.001), and adiponectin (P=0.012) were independently associated with hypertension at baseline. Subjects with serum adiponectin in the lowest sex-specific tertile had an adjusted OR of 2.62 (95% CI: 1.39 to 4.97) of being hypertensive at baseline compared with subjects with serum adiponectin in tertile 3 (P=0.003). For those with serum adiponectin in tertile 2, the adjusted OR was 1.70 (95% CI: 0.94 to 3.09; P=0.08) versus subjects in tertile 3. Similar findings were obtained if WC was included in the model instead of BMI.
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Table 2 summarizes the relationship between sex-specific adiponectin tertiles and various baseline characteristics, including its positive relationship with age (P<0.001). Subjects with baseline adiponectin levels in the lowest tertile had a significantly higher adverse risk factor profile than those in the highest tertile, with higher BMI, WC, systolic BP (SBP), mean arterial BP (MAP), fasting glucose, prevalence of IGT/IFG, TG, fasting insulin, and insulin resistance index (as assessed by HOMA-IR), as well as hsCRP (P<0.05 for all parameters). They also had a lower high-density lipoprotein cholesterol level (P<0.001). When only the serum adiponectin levels of the 440 normotensive subjects were analyzed, no significant relationship of serum adiponectin tertiles with SBP, diastolic BP, or MAP could be demonstrated.
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Of the 577 subjects, 507 attended the 5-year follow-up. Baseline adiponectin, age and sex adjusted, correlated positively with year-5 WC, BMI, BP (SBP, diastolic BP, and MAP, after excluding 93 subjects on antihypertensive drugs), fasting glucose, fasting insulin, HOMA-IR, TG, and hsCRP (P<0.005) and negatively with year-5 high-density lipoprotein cholesterol level (P<0.001). Of the 440 subjects who were normotensive at baseline, 389 (88%) had returned for follow-up. Among these 389 subjects, 70 (18%) were found to have developed hypertension. There were no significant difference in baseline clinical or biochemical parameters between the attendees and those who did not attend the follow-up. Baseline adiponectin was 5.4 µg/mL (range: 3.4 to 7.3µg/mL) in men and 6.5 µg/mL (range: 4.8 to 8.8 µg/mL) in women for the 389 attendees versus 4.9 µg/mL (range: 2.9 to 8.1 µg/mL) in men and 5.9 µg/mL (range: 4.1 to 10.9 µg/mL) in women for the 51 nonattendees (P=0.617, sex and age adjusted). The baseline characteristics of the 70 case subjects, who became hypertensive after the baseline assessment, were compared in a nested case–control study with those of 140 sex- and age-matched control subjects, who were normotensive at baseline and also at year 5. Among the matched cohort (n=210), there were no significant changes in various obesity and metabolic parameters (including serum adiponectin) after 5 years, except for fasting glucose (0.1±0.6 versus –0.1±0.5 mmol/L in control subjects; P<0.05). The baseline clinical and biochemical characteristics of the case and control subjects are summarized in Table 3. Case subjects with incident hypertension had a more adverse cardiovascular risk profile at baseline, with higher BMI, WC, SBP, diastolic BP, MAP, fasting insulin, TG, HOMA-IR, and hsCRP, when compared with control subjects. In addition, case subjects had significantly lower adiponectin levels (P=0.005; Table 3). Relationships between baseline adiponectin and various baseline parameters were similar to those for the entire cohort of 577 subjects except that, with a much smaller sample size, the P values were less significant for some parameters (data not shown). Subjects with adiponectin in the lowest sex-specific tertile (tertile 1) had a greater risk of incident hypertension compared with those with adiponectin in the highest tertile or tertile 3 (P=0.003; Table 4, Model 1). No significant difference was found between tertile 2 and tertile 3 or when tertile 2 was compared with tertile 1, even when age-adjusted (OR: 0.75; 95% CI: 0.38 to 1.48; versus tertile 1). Stepwise logistic regression analysis (Table 4, Model 2) showed that the significant independent predictors for the development of hypertension at year 5 included age- and sex-adjusted adiponectin level (P=0.015), together with MAP (P<0.001), hsCRP (P=0.018), and BMI (P=0.004) at baseline, in a model including also age, fasting insulin, and TG. Normotensive subjects with baseline adiponectin in the lowest sex-specific tertile had a 2.76-fold risk of developing hypertension at year 5 compared with those with adiponectin in the highest tertile (OR: 2.76; 95% CI: 1.06 to 7.16; P=0.037) adjusted for MAP, BMI, hsCRP, age, fasting insulin, and TG. With every unit increase in MAP, BMI, and hsCRP, the associated risk of incident hypertension was 1.14-, 1.18-, and 1.48-fold, respectively. HOMA-IR, when included instead of fasting insulin in the stepwise logistic regression model, was not significantly associated with hypertension development. Replacing BMI with WC did not affect the overall conclusion.
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Discussion |
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Dysregulation in the secretion of several adipokines, including leptin, adiponectin, and angiotensinogen, has been implicated in the pathogenic mechanisms linking obesity to hypertension.22 In this study, we have confirmed the independent association between hypoadiponectinemia and hypertension, reported in previous cross-sectional studies.10,11 Because the reduction in serum adiponectin level in the hypertensive subjects was only modest in the cross-sectional study, and the inverse relationship between serum adiponectin and BP could not be demonstrated in normotensive subjects, more supporting data for a cause–effect relationship were sought in the long-term nested case–control study. We were able to demonstrate, for the first time, that hypoadiponectinemia also predicted the development of hypertension on long-term follow-up in the normotensive subjects, independent of the effects of known risk factors of hypertension, including sex, age, and BMI, although baseline MAP remained the most significant predictor in this cohort. Our data are in line with the findings in adiponectin-deficient mice and suggest that, in humans, as in animals, hypoadiponectinemia may play an etiologic role in the development of hypertension.
Hypoadiponectinemia can predispose to hypertension via multiple mechanisms. The insulin-sensitizing effect of exogenous adiponectin has been well demonstrated in mice lacking endogenous adiponectin.23 Furthermore, these mice, when fed an atherogenic diet, developed obesity, insulin resistance, hyperglycemia, and hypertension.13 In humans, hypoadiponectinemia also precedes a reduction in whole-body insulin sensitivity.4 Although it remains controversial whether insulin resistance can lead to hypertension, hyperinsulinemia, occurring in response to insulin resistance, has been shown in rodents to cause sympathetic activation in different tissues, including the kidney.22,24 The emergence of hypertension in the absence of coexisting insulin resistance in the adiponectin knockout mice maintained on a high-salt diet14 suggests that hypoadiponectinemia can also predispose to hypertension via other pathways. Elevated free fatty acid levels in obese subjects appear to participate in obesity-related hypertension, via sympathoactivation.22 Because adiponectin can reduce circulating fatty acid levels via enhanced fatty acid oxidation and reduced fatty acid synthesis,25 hypoadiponectinemia may increase the risk of hypertension in obese subjects through its adverse effects on fatty acid metabolism.
More importantly, it has been increasingly recognized that, in addition to its metabolic effects, adiponectin also acts directly on the vascular system to exert its vasoprotective functions.5 We and others have demonstrated that hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation in humans,26,27 as in mice with adiponectin deficiency.13 The adiponectin receptors adipR1 and adipR2 are expressed on human aortic endothelial cells, and adiponectin can increase the production of NO from cultured endothelial cells.27 Adiponectin stimulates the activity of endothelial NO synthase in vitro via phosphatidylinositol 3-kinase–dependent pathways involving, in part, the phosphorylation of endothelial NO synthase at Ser1179 by AMP-activated protein kinase.28 These findings are supported by the observation of reduced mRNA levels of endothelial NO synthase and prostaglandin I2 synthase in the aorta of salt-fed adiponectin-deficient mice and the correction of these mRNA changes, accompanied by a lowering of BP, by adiponectin therapy.14 The direct action of adiponectin on the endothelium, enhancing NO production,28 would suggest its potential role in improving BP and atherogenesis, and provide one explanation for the enhanced risk of hypertension in subjects with hypoadiponectinemia.
Low-grade chronic inflammation, reflected by elevated inflammatory markers, such as hsCRP, is associated with SBP, pulse pressure, and hypertension.29 On the other hand, whether hsCRP can independently predict the development of hypertension remains controversial, and both positive30 and negative31 findings have been reported. Hypertension may activate vascular inflammation through the imposition of an oscillatory shear regimen.32 In patients with hypertension and/or obesity, increased angiotensin II can also induce the release of proinflammatory cytokines from arterial smooth muscle cells32 and the production of vascular reactive oxidative species, resulting in the quenching of NO, endothelial dysfunction, further inflammation, and upregulation of the proinflammatory vasoconstrictor endothelin-1. We have reported previously an inverse relationship between changes in hsCRP and endothelium-dependent vasodilation in diabetic patients, in keeping with an adverse effect of inflammation on vasoreactivity and the potentiation of hypertension.33 In this study, hsCRP was also found to be an independent predictor for the development of hypertension, in accordance with the observation in the US Health Professionals Study.30 Adiponectin has been shown to possess anti-inflammatory and antioxidative properties.34 In cultured endothelial cells, adiponectin dose-dependently suppresses the production25 and action of tumor necrosis factor-35 and superoxide formation34 and inhibits endothelial signaling of nuclear factor 
B, a key transcription factor involved in the regulation of various adhesion molecules and proinflammatory genes, such as MCP-1.35 The inverse relationship between serum adiponectin and hsCRP,27 also seen in this study, suggests that hypoadiponectinemia may predispose to vascular dysfunction in the presence of inflammatory and oxidative injuries and, hence, accelerate the progression to hypertension.
In conclusion, hypoadiponectinemia was shown to predict the development of hypertension in this 5-year prospective study of a nondiabetic cohort of Southern Chinese, independent of the effect of age, baseline obesity parameters, MAP, insulin resistance, and hsCRP, an index of low-grade systemic inflammation.
Perspectives
The findings of this prospective study would support a role of hypoadiponectinemia in the pathogenesis of human hypertension. The current study is limited by the relatively small number of incident cases of hypertension. The fact that this study is based on survey data not obtained through a random sample may have also introduced a sample bias. Furthermore, the study population included an overrepresentation of subjects with glucose dysregulation (IGT/IFG). Our findings may not be directly applicable to the general population, although we did not find a significant association between glucose dysregulation and incident hypertension. On the other hand, these data have provided new insight into the mechanisms underlying the development of hypertension and suggest that subjects with low adiponectin levels in the lowest tertile of this population had 
3 times the 5-year risk of hypertension compared with those with high adiponectin levels in the top tertile. The findings of the current study need to be confirmed in larger population-based studies involving subjects with a wider age range and longer durations of follow-up to investigate the potential application of serum adiponectin as a biomarker to identify subjects at risk of hypertension in the general population for intensive preventive measures. Further research, using adiponectin-deficient mice, is also warranted to determine whether adiponectin contributes to the hypotensive effects of drugs that increase adiponectin, such as thiazolidinediones36 and angiotensin receptor blockers.37
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Acknowledgments |
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Sources of Funding
K.S.L.L. was supported by grants from the Hong Kong Research Grant Council (HKU7426/03M) and the Strategic Theme Research Fund on Healthy Aging, the University of Hong Kong.
Disclosures
None.
Received January 3, 2007; first decision January 18, 2007; accepted February 28, 2007.
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