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Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2244-2249
Published online before print July 26, 2007, doi: 10.1161/ATVBAHA.107.149641
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2244.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Carotid Intima-Media Thickness in Confirmed Prehypertensive Subjects

Predictors and Progression

Romana Femia; Michaela Kozakova; Monica Nannipieri; Clicerio Gonzales-Villalpando; Michael P. Stern; Steven M. Haffner; Ele Ferrannini

From the Department of Internal Medicine and Metabolism Unit of the C.N.R. Institute of Clinical Physiology (R.F., M.K., M.N., E.F.) and Centro de Estudios en Diabetes (C.G.-V.), American British Cowdray Hospital, Mexico City, Mexico; and the Division of Clinical Epidemiology, Department of Medicine (M.P.S., S.M.H.), University of Texas Health Science Center at San Antonio, Texas, USA.

Correspondence to Ele Ferrannini, MD, Department of Internal Medicine Via Roma, 67, 56126 Pisa, Italy. E-mail ferranni{at}ifc.cnr.it


*    Abstract
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Objective— The purpose of this study was to test whether carotid intima-media thickness (IMT) is already increased in normotensive subjects who progress to hypertension (confirmed prehypertensives) independently of known determinants of vessel wall thickness.

Methods and Results— Common carotid artery (CCA) far-wall IMT was measured (B-mode ultrasound) in 1536 subjects from the population-based Mexico City Diabetes Study at baseline and 3.5 years later. In the 136 confirmed prehypertensives, CCA-IMT (720 [253] µm, median[interquartile range]) was intermediate between normotensives (615 [140] µm) and hypertensives (725 [215] µm). After multiadjusting for gender, age, BMI, blood pressure, total cholesterol, antihypertensive therapy, and diabetes, converter status was independently associated with a higher CCA-IMT (+93±14 µm). At follow-up, CCA-IMT increased by 35 [180] µm. Gender, age, blood pressure, and presence of diabetes, but not the converter status, were significant independent predictors of CCA-IMT progression. In a model adjusting for gender, age, blood pressure (level, status and treatment), diabetes status, total and HDL-cholesterol, the G variant of the 45T/G polymorphism of the adiponectin gene was associated with a hazard ratio of 1.45 (95% CI: 1.04 to 2.01) of a baseline CCA-IMT in the top quintile.

Conclusions— In confirmed prehypertensives, CCA-IMT is increased independently of blood pressure and known determinants of wall thickness, but short-term CCA-IMT progression is not accelerated.

In 136 confirmed prehypertensives CCA far-wall IMT is increased—to values intermediate between normotensives and hypertensives—independently of known determinants of wall thickness. The 45T/G polymorphism in the adiponectin gene confers independent risk; gender, age, mean BP, diabetes, but not converter status were independent predictors of a faster CCA-IMT progression.


Key Words: blood pressure • carotid arteries • diabetes mellitus • high-resolution B-mode ultrasonography


*    Introduction
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Intima-media thickness (IMT) of extracranial carotid arteries, as measured by high-resolution B-mode ultrasonography, marks advanced vascular disease in the peripheral and coronary circulation,1 predicts cardiovascular (CVD) events2,3 and response to therapy.4 Several cross-sectional studies have demonstrated the association between carotid IMT and traditional CVD risk factors.5

Hypertension is a major CVD risk factor that directly contributes to CVD, and carotid IMT is increased in hypertensive patients as compared with normotensive subjects.6–8 High blood pressure (BP) plays a direct pathogenic role in the initiation and progression of carotid wall hypertrophy as hemodynamic factors—such as local distending pressure, pulsatile load, and shear stress9–12—can induce intrinsic alterations of the arterial wall resulting in intimal/medial thickening. Previous studies have demonstrated that carotid IMT is increased already in subjects with borderline hypertension.13,14 This group of subjects is also characterized by concomitant metabolic abnormalities, such as obesity—especially visceral fat accumulation15—type 2 diabetes (DM2) or impaired glucose tolerance and dyslipidemia, which enhance CVD risk. Whether carotid IMT is increased also in normotensive subjects that will develop hypertension (ie, confirmed prehypertensives) has not been determined. Therefore, the main aim of this work was to test whether carotid IMT is increased in confirmed prehypertensives independently of known determinants of vessel wall thickness.

Low circulating levels of adiponectin, an adipose tissue-specific collagen-like factor, have been reported in association with obesity,16 DM2,17 coronary artery disease, and hypertension.18 Some studies have reported hypoadiponectinemia in subjects with high-normal BP,19 whereas others have found that only hypertensive patients with insulin resistance20 or renal dysfunction21 had lower adiponectin levels. In studies measuring carotid IMT,22,23 no significant association was detected between adiponectin levels and IMT when accounting for other relevant risk factors. Perhaps more interesting is the potential association between polymorphisms of the adiponectin gene (APM1) and carotid IMT. The only study searching for an association between the 2 most common APM1 haplotypes (45 and 276) found no association with carotid IMT.22 A secondary aim of the present study therefore was to test for the independent association of the APM1 SNP45 with prehypertension or carotid IMT at the population level.


*    Methods
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For details please see the supplemental materials, available online at http://atvb.ahajournals.org.

Study Population
The Mexico City Diabetes Study is a population-based cohort participating in a longitudinal survey of incident diabetes and CVD. Recruitment methods and inclusion/exclusion criteria have been previously described.24 Subjects whose BP was <140/90 mm Hg on both follow-up visits were classified as normotensives, those whose BP was <140/90 mm Hg at the first follow-up visit but became hypertensive at the second one were classified as converters (or confirmed prehypertensives). Hypertension was defined as a systolic BP ≥140 mm Hg or a diastolic BP ≥90 mm Hg or current antihypertensive treatment. BP was the average of at least three measurements obtained in the supine position.

B-Mode Ultrasound Examination
B-mode ultrasound examination of extracranial carotid arteries was performed using scanning, reading, and image conservation protocols identical to those used in the Cardiovascular Health Study.25 In a repeatability analysis24 with 58 randomly chosen ultrasound scans, the average percent differences between the first and second readings relative to the first reading for mean CCA IMT and mean ICA IMT measurements were 2.3% [95% confidence interval (CI): –24 to 24] and –3.7% [95% CI: –48 to 48].

DNA Analysis
DNA was available in 1116 subjects. Leukocytes were isolated from peripheral blood and DNA was extracted by standard techniques.26

Statistical Analysis
Values are given as means±SD. Serum triglycerides, fasting and 2-hour plasma glucose, fasting and 2-hour insulin, and CRP are given as median and [interquartile range] and were log-transformed for use in statistical analyses. Between-group mean differences were tested by ANOVA or the {chi}2 test, as appropriate. Two-way ANOVA was used when stratifying data for hypertension and diabetes status. Multiple regression analyses were carried out by standard methods; results are given as regression coefficient (mean±SE) and standardized regression coefficient; post hoc testing was carried out using linear contrasts. Logistic regression was performed by standard methods; results are given as hazard ratio and 95% confidence interval.


*    Results
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Between the first and second follow up, 136 normotensive subjects converted to hypertension, a crude rate of 2.4% per year. Converters were more frequent among diabetic than nondiabetic subjects (22% versus 8%, {chi}2=41.9, P<0.0001). When stratifying subjects by both hypertension and diabetes (Table 1), converters and hypertensive subjects were older, heavier and more centrally obese, smoked less, and had higher BP than normotensives. In addition, fasting and postglucose plasma glucose and insulin concentrations were higher and serum triglycerides tended to be higher. Higher CRP levels were associated with diabetes but not hypertension.


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  		Table 1. Clinical Characteristics of Study Subjects Stratified by Hypertension and Diabetes Status (ND vs D)

Both diabetes and BP status were independently associated with an increased CCA-IMT (both P<0.0001), with no interaction between them. The diabetes- and BP-adjusted increase in CCA-IMT associated with the BP converter status averaged 93±14 µm.

In univariate analysis on the whole dataset, CCA-IMT was related to gender, age, BMI, waist girth, total cholesterol, triglycerides, and fasting glucose (r’s=0.09 to 0.42, all P≤0.001), and with all BP components (r’s of 0.32, 0.15, 0.24, and 0.33 for systolic, diastolic, mean, and pulse pressure, P<0.0001 for all). In a multivariate model adjusting for gender, age, BMI, pulse pressure, total cholesterol, and antihypertensive therapy, diabetes and converter status were still independently associated with CCA-IMT (Table 2). Essentially identical results were obtained on replacing pulse pressure with systolic or diastolic BP.


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  		Table 2. Multivariate Predictors of CCA-IMT

As CCA-IMT measures were not normally distributed (and logarithmic transformation improved distribution only partially), data were also analyzed by logistic regression using the highest CCA-IMT quintile (≥800 µm, median=905 µm) as the dependent variable. The results yielded a similar set of predictors (Figure 1), with converter status still significantly associated with a CCA-IMT value in the top quintile of the population independently of BP.


Figure 1
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  		Figure 1. Multivariate logistic regression of factors predicting the probability of CCA-IMT being in the top quintile of the distribution. Hazard ratios are calculated for 1 SD of the continuous variables.

In the subjects in whom ICA-IMT measurements were available, the clinical characteristics ordered by diabetes and BP status (supplemental Table I, available online at http://atvb.ahajournals.org) were similar to those of the entire cohort. By 2-way ANOVA, BP status was associated with an increased ICA-IMT in interaction with diabetes (P=0.002). The increase in ICA-IMT associated with the converter status averaged 58±25 µm in nondiabetic subjects (P=0.02) and –10±38 µm in diabetic subjects (P=ns). In a multivariate model also adjusting for antihypertensive therapy, only age, smoking, pulse pressure, and hypertension in the diabetic were independently related to ICA-IMT (supplemental Table II).

At the 3.5-year follow up, CCA-IMT was measured again in the whole cohort and was found to have increased by 35 (180) µm, ({approx}10 µm per year). CCA-IMT progression was similar irrespective of BP status. When the hypertensive group was excluded, gender, age, mean BP, and presence of diabetes, but not the hypertension converter status, were significant independent predictors of a CCA-IMT progression falling into the top quintile (ie, >110 µm, median=185 µm; Figure 2).


Figure 2
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  		Figure 2. Multivariate logistic regression of factors predicting the probability of CCA-IMT progression falling into the top quintile of the distribution. Hazard ratios are calculated for 1 SD of the continuous variables.

In the subgroup (n=1116) in whom it was measured, the APM1 45T/G alleles were in Hardy-Weinberg equilibrium ({chi}2=0.19, P=0.9). The G allele was not associated with either diabetes or BP status but was significantly more frequent among subjects in the top quintile of CCA-IMT (>765 µm) than in the remainder of the population (23.0% versus 17.5%, {chi}2=6.95, P=0.008). In a multiple logistic model adjusting for gender, age, BP (level, status and treatment), diabetes status, total and HDL-cholesterol (ie, the model in Figure 2), the G variant was associated with a hazard ratio of 1.45 (95% CI: 1.04 to 2.01).


*    Discussion
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A preliminary issue is the definition of prehypertension. According to JNC 7,27 prehypertension is a systolic BP between 120 to 139 mm Hg or a diastolic BP between 80 to 89 mm Hg. In our study, converter status was assigned to those individuals who progressed to clinical hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) from any BP level lower than that. It is interesting to note that 88/136 converters were prehypertensive by JNC 7 criteria, whereas more than one third of them progressed from true normotension. Conversely, less than one third (88/312) JNC 7 prehypertensives converted to clinical hypertension over 3.5 years. Moreover, when they became hypertensive, one third of our converters ended up in JNC 7 stage I/II hypertension irrespective of treatment. Thus, the JNC 7 prehypertension stratum is enriched with future hypertensives, who, however, can derive from the normotensive pool and end up in severe hypertension at diagnosis.

The main findings of the present study were: (1) in confirmed prehypertensives IMT was increased in the common carotid artery in comparison with subjects who remained normotensive; (2) the association between increased IMT and the prehypertensive state persisted after accounting for the known predictors of carotid IMT, ie, sex, age, obesity, diabetes, total cholesterol levels, and BP levels themselves; (3) CCA-IMT progression was no faster in prehypertensives than normotensives when controlling for known predictors of progression; and (4) a polymorphism in adiponectin gene was independently associated with increased CCA-IMT.

With regard to the first finding, several carotid ultrasound studies have demonstrated an association between carotid IMT and BP, with 1 study estimating that IMT starts to accelerate at a systolic BP of {approx}120 mm Hg and a pulse pressure of {approx}36 mm Hg.28 However, no previous study has examined IMT in a large group of confirmed prehypertensives independently of the presence of diabetes, itself a major risk factor for arterial wall thickening.24,29 Furthermore, because BP levels per se are a major predictor of IMT, it was of special importance to find that the entire set of IMT predictors did not fully account for the observed increase in CCA-IMT in prehypertensive women and men (Table 2). Thus, in our population each decade of age was associated with an IMT increase of {approx}50 µm, in close agreement with the AXA Study,30 and each 12-mm Hg increase in pulse pressure was associated with a 26-µm increase in IMT, in accord with previous estimates.31 After accounting for the effect of these and other predictors, the converter status was still characterized by an increase in CCA-IMT, which was equivalent to {approx}8 years of aging in women and twice as many in men. In addition, we could not identify any other phenotypic characteristic (eg, waist girth, HDL-cholesterol, plasma insulin levels) that would replace the converter status in multivariate analyses. With regard to inflammatory markers, previous studies reported an association of raised hsCRP levels with ischemic stroke32 but not with carotid IMT.33 Accordingly, we found higher hsCRP in association with diabetes but not with high BP or CCA-IMT (Table 1). It is therefore conceivable that, in confirmed prehypertensives it is the BP exposure—ie, the duration of the increase in BP values—that eventually leads to thickening of vascular walls.

Due to both anatomic and hemodynamic reasons, IMT measurements are 3 times more variable in ICA than CCA segments, and there are relatively scarce data on ICA-IMT.34 In our population, IMT measures in CCA and ICA were only weakly correlated. However, there was remarkable congruence of IMT predictors in the 2 segments. Thus, sex, age, cholesterol, and BP were common correlates, whereas smoking status replaced BMI as a risk factor for increased IMT in ICA viz CCA (Table 2 and supplemental Table II). After adjusting for risk factors, converter status was not a significant predictor of ICA-IMT, whereas it was so for CCA-IMT. Although this difference may be attributable to sample size and measurement variability, it is possible that BP exposure may have a stronger impact on proximal carotid segments than on downstream segments.

In our population, progression of CCA-IMT averaged {approx}10 µm per year. This rate is similar to those reported in ARIC and the Cardiovascular Health Study.31,35 Significant, independent predictors of a time-related CCA-IMT change falling into the top quintile (ie, >110 µm, median=185 µm) were gender, age, mean BP, and diabetes. Thus, 8 years of age and 9 mm Hg of mean BP at baseline each predicted a {approx}15% enhanced risk of a CCA-IMT progression in the highest quintile; women were protected and diabetes conferred an independent risk. Progression, however, was not accelerated in prehypertensives above and beyond what their baseline BP predicted (Figure 2). It should be mentioned that the value of IMT progression in signaling risk of CVD events is not well established. In fact, whereas a single high measure of carotid IMT is equivalent to commonly used risk factors in the prediction of CVD,36 some longitudinal studies have indicated that baseline IMT may be a better predictor of incident vascular events than IMT progression. This finding may be related to the larger amount of information available for baseline IMT than IMT progression, the higher within-subject variability of IMT changes, and the loss of precision occurring with time-related shifts in scanning and reading protocols.37 It has been suggested that baseline measurements of IMT are likely to reflect past long-term exposure to risk factors, whereas IMT progression may be influenced more by short-term changes in risk factor burden.38

With regard to the potential association between polymorphisms of the adiponectin gene and hypertension or carotid IMT, some of the 10 APM1 SNPs so far identified39 have been associated with insulin resistance, DM2 or other features of the metabolic syndrome,40–42 and coronary artery disease.43 In a case-control study, Iwashima et al44 found the I164T polymorphism associated with hypertension in men only, whereas Mousavinasab et al45 reported that the APM1 T276T genotype was associated with elevated diastolic BP in 252 Finnish men. The only study searching for an association between the 2 most common APM1 haplotypes (45 to 276) found no association with carotid IMT.22 In our population, APM1 SNP45 was not associated with the hypertensive state; the G allele, however, was more frequent among subjects in the top CCA-IMT quintile. Perhaps more importantly, this association with high IMT was independent of the observed set of predictors (Table 2), lending some support to the interpretation that variants of the adiponectin gene may have some influence on vascular walls. Circulating adiponectin levels were not measured in the present study. However, none of the mentioned gene variants has been clearly associated with changes in plasma adiponectin, and total adiponectin levels have been reported not to be associated with IMT.22 We cannot exclude that the high-molecular weight isoform of the adipokine, which is believed to carry most of the biological value,46 may relate to some aspect of vascular structure or function.

A limitation of this study was the fact that BP was measured on a single occasion, which may introduce a misclassification bias. The relatively large number of converters and their overall clinical phenotype provide some protection against this problem. Another limitation is the lack of measurements of vessel internal diameter, which prevents interpreting the thickened IMT in terms of an adaptive remodeling response.47


*    Acknowledgments
 
Sources of Funding

This work was supported in part by funds from the Italian Ministry of University and Research.

Disclosures

None.


*    Footnotes
 
Original received April 19, 2007; final version accepted July 1, 2007.


*    References
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