(Circulation. 1995;91:1432-1443.)
© 1995 American Heart Association, Inc.
Articles |
Non–Insulin-Dependent Diabetes Mellitus and Fasting Glucose and Insulin Concentrations Are Associated With Arterial Stiffness Indexes
The ARIC Study
From the National Public Health Institute, Department of Epidemiology and Health Promotion, Helsinki, Finland (V.S.); the Department of Neurology, Bowman Gray School of Medicine, Winston-Salem, NC (W.R.); the Department of Social Medicine, Hadassah Medical Organization and Hebrew University, Hadassah School of Public Health, Jerusalem, Israel (J.D.K.); the Department of Epidemiology, University of North Carolina, Chapel Hill (C.N.); and the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (A.R.F).
Correspondence to Dr Veikko Salomaa, National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
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Abstract |
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Background Cardiovascular diseases are the most common cause of disability and death among subjects with non–insulin-dependent diabetes mellitus (NIDDM). The atherosclerotic process begins during the prediabetic phase characterized by impaired glucose tolerance, hyperinsulinemia, and insulin resistance. In vitro studies have suggested that glucose and insulin can substantially alter the structure and function of the arterial wall and affect the development of atherosclerosis.
Methods and Results We performed a cross-sectional study of the relation of arterial stiffness indexes with glucose tolerance and serum insulin concentrations. Several indexes of common carotid artery stiffness were assessed with noninvasive ultrasound methods in a biracial sample of 4701 men and women 45 to 64 years of age in the Atherosclerosis Risk in Communities (ARIC) Study. Arterial compliance (AC), stiffness index (SI), pressure-strain elastic modulus (Ep), and Young's elastic modulus (YEM) were calculated. YEM includes wall (intima-media) thickness and thus gives an estimate of arterial stiffness controlling for wall thickness. All indexes of arterial stiffness were higher with increasing concentrations of fasting glucose. This finding was consistent in both black and white examinees and in both sexes. A 25% increase in fasting glucose (approximately 1 SD) was associated in nondiabetic white men with a 5.8% (95% CI, -9.6% to -1.9%; P=.004) decrease in AC and increases of 5.8% (95% CI, 2.0% to 9.7%; P=.002) in SI, 11.3% (95% CI, 6.9% to 15.9%; P<.001) in Ep, and 11.2% (95% CI, 6.2% to 16.6%; P<.001) in YEM. In nondiabetic white women, the corresponding predicted changes were a decrease of 15.0% (95% CI, -18.2% to -11.7%; P<.001) in AC and increases of 16.6% (95% CI, 12.5% to 20.8%; P<.001) in SI, 23.2% (95% CI, 18.4% to 28.2%; P<.001) in Ep, and 19.2% (95% CI, 14.0% to 24.7%; P<.001) in YEM. Glucose and insulin contributed synergistically to the increase in stiffness indexes. Insulin and triglycerides also had a synergistic association with stiffness indexes.
Conclusions Our findings are compatible with the view that persons with NIDDM or borderline glucose intolerance have stiffer arteries than their counterparts with normal glucose tolerance and that the decreased elasticity is independent of artery wall thickness. The joint effect of elevated glucose, insulin, and triglycerides can have a considerable impact on arterial stiffness and play an important role in the early pathophysiology of macrovascular disease in NIDDM.
Key Words: glucose • insulin • diabetes mellitus • arteries • ultrasonics
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Introduction |
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The most common cause of disability and death among subjects with non–insulin-dependent diabetes mellitus (NIDDM) is macrovascular disease. In the United States, 11% of diabetic men and 6% of diabetic women 45 to 64 years of age reported having had a heart attack.1 These percentages are 2.5 times higher in men and 4.0 times higher in women than in the nondiabetic population. Increased risk of atherosclerosis is found even in prediabetic individuals,2 and in populations at high risk of coronary heart disease (CHD), almost half of middle-aged men and women with NIDDM have symptomatic CHD at the moment their diabetes is diagnosed.3 These findings indicate that atherosclerosis develops gradually during the long latent phase of hyperinsulinemia and glucose intolerance before the actual onset of NIDDM.
The reasons and mechanisms for the macrovascular disease in subjects with NIDDM are insufficiently known. There is evidence, however, that insulin resistance and high insulin concentrations play an important role.4 5 Insulin resistance is associated with high triglyceride and low HDL cholesterol concentrations and with an increased tendency to hypertension.6 In addition to its lipid effects, insulin may have an effect on the thickness and structure of the arterial wall. In vitro studies have shown that insulin concentrations commonly found in humans can cause proliferation of cultured smooth muscle cells.7 8 It also stimulates DNA synthesis in rat aorta and causes the outgrowth of smooth muscle cells from cultured arterial pieces of diabetes-prone rats.9 10 Hyperglycemia, in turn, can cause nonenzymatic glycosylation of several proteins, including collagen and elastin,11 and the amount of glycosylated collagen is associated with increased stiffness of joints and arteries in subjects with insulin-dependent diabetes mellitus.12
Investigation of the function of the arterial wall in living subjects has been difficult. The pioneering works in this area were done by measurement of the pulse-wave velocity in the arterial three with animal experiments or preparates obtained from cadavers.13 14 In diabetic patients, at least four small studies reported higher pulse-wave velocity, suggesting stiffer arteries or lower arterial compliance compared with nondiabetic control subjects.15 16 17 18 Furthermore, at least two small studies suggested that plasma insulin is associated with decreased compliance or increased stiffness of the arteries.19 20 Modern ultrasound technology has permitted noninvasive and repeatable assessment of arterial stiffness. Several stiffness indexes, combining ultrasound measurements of arterial diameter with blood pressure measurements, have been proposed for the assessment of arterial stiffness.21 22 The common principle is to measure the ability of the arteries to expand as a response to pulse pressure. The Atherosclerosis Risk in Communities (ARIC) Study23 was the first to implement this technique in a large population survey. In the present study, we examined the relation of arterial stiffness indexes to diabetic status and to fasting blood glucose and insulin concentrations using data collected during the first examination of the ARIC cohort.
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Methods |
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The ARIC Study is a prospective investigation of the etiology and natural history of atherosclerosis in four US communities: Forsyth County, North Carolina; Jackson, Miss; the northwest suburbs of Minneapolis, Minn; and Washington County, Maryland. The study design and sampling strategies were described previously.23 A probability sample of residents 45 to 64 years of age was drawn from each community to take part in an extensive examination of cardiovascular risk factors and their sequelae. The participation rate was 46% in Jackson, where exclusively blacks were sampled, and 65% to 66% in the other three communities.
ARIC participants examined at baseline with ultrasound measurements necessary for the calculation of the indexes of arterial stiffness are the subjects of the present study. Measurements of the diameters of the carotid artery, necessary for the calculation of stiffness indexes, were incorporated into the ARIC Study in 1988. For the present study, the first 4 weeks of stiffness measurements in each center were considered a standardization period and were excluded from the analyses. All indexes of arterial elasticity were available in 55% of subjects examined after this initial period. If any of these indexes were missing, the individual was excluded (4077 persons). Reasons for missing data were instrument malfunction, which occurred randomly but was responsible only for a small proportion of cases (26%), and poor electronic tracking of the arterial boundaries, which was responsible for the majority of cases (74%) and usually was due to obesity. We also excluded subjects who were not black or white, subjects receiving insulin injections or missing information on antidiabetic medication use, subjects with fasting time less than 8 hours, or subjects missing information on such key variables as fasting glucose, insulin, blood lipids, body mass index (BMI), cigarette-years, and hypertension status (350 persons total). After these exclusions, 4701 men and women were included in the analyses.
Noninvasive ultrasonic B-mode imaging techniques were used to measure arterial wall (intima plus media) thickness from three segments of both extracranial carotid arteries as described previously.24 25 All measurements were collected and read according to standardized protocols under stringent quality control.26 The scanning protocol was common to the four field centers, and the scans were recorded on broadcast-quality videocassettes that were read centrally at the Ultrasound Reading Center in Winston-Salem, NC. The intraclass correlation coefficient between scans repeated by the same sonographer during the same clinic visit was 0.81 for maximal far wall thickness at the carotid bifurcation. For the same site, the correlation coefficient between blinded repeated readings of the same scan performed by different readers was 0.93.26 The ultrasound observers were unaware of the results of blood tests, including glucose and insulin concentrations. If the visualization was poor in some segments, the values for the missing boundaries were extrapolated from the visualized boundaries. Extrapolation was performed with sex- and race-specific multivariate linear models, with the visualized boundaries, BMI, and artery depth as predictors.27
The continuous variation of arterial diameter throughout the cardiac cycle was measured from the left common carotid artery with echo tracking techniques.21 28 The echoes corresponding to the diametrically opposite media-adventitia interfaces were identified on an oscilloscope screen, and electronic gates were positioned to track these two interfaces to precisely measure on-line the time interval between the arrival of these two echoes with an arterial wall tracker (AUTREC 4881-AWT) that uses phase-locked loop techniques. With a speed of sound in soft tissue of 1540 m/s assumed, the distance between these interfaces as a function of time during consecutive cardiac cycles was automatically calculated, digitized, and displayed on a strip-chart recording for immediate sonographer review.
Supine blood pressure was measured automatically (with Dinamap equipment) from the right brachial artery at 5-minute intervals during the ultrasound examination and immediately before and after the arterial distensibility measurements were obtained. The Dinamap Vital Signs monitor uses the oscillometric method as a basis for measuring blood pressure. After cuff inflation, the Dinamap begins a stepped deflation sequence that determines systole, mean arterial pressure, diastole, and pulse rate from pulses induced in the cuff at the various pressure levels. This is accomplished by a sensitive mechanical transducer positioned within the cuff that measures not only cuff pressure but also small oscillations within the cuff that arise at systole and diastole in response to the displacement of the arterial wall and that depend on the difference in cuff pressure and arterial pressure.
On the basis of the ultrasound measurements and concomitant supine blood pressure measurements, the following indexes of arterial elasticity were calculated: arterial compliance (AC), pressure-strain elastic modulus (Ep),21 22 stiffness index (SI),22 29 and Young's elastic modulus (YEM).30 31 Arterial compliance is defined as the absolute volume increase within an arterial segment during the cardiac cycle divided by the arterial pulse pressure. The arterial compliance per unit length (1 mm) is
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where D(s) and D(d) are the systolic and diastolic diameters of the artery and P(s) and P(d) are the systolic and diastolic pressures, respectively. AC is given in millimeters squared per kilopascal (1 kPa=7.6 mm Hg).
SI is defined as the natural logarithm of the ratio of systolic blood pressure to diastolic blood pressure divided by the circumferential arterial strain (CAS), which is the fractional increase in arterial diameter during the cardiac cycle:
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where
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SI is a unitless quantity that is considered to be relatively independent of blood pressure.22 29
The Ep is defined as the arterial pulse pressure divided by the CAS:
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Ep is measured in kilopascals.
YEM, which measures arterial wall stiffness controlling for wall (intima-media) thickness, is defined as the ratio of stress (force per unit area) to strain:
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where R is the outer radius of the artery and WT is the wall thickness (intima plus media). YEM is given in kilopascals. In 17.5% of YEMs, wall thickness was based on extrapolated data; the rest were based on direct measurements. The main statistical analyses of YEM were carried out both including and excluding the extrapolated values, and the findings were essentially similar. The former is reported to give YEM the same N as for the other indexes.
When arterial stiffness increases, AC decreases but Ep, SI, and YEM increase. These parameters measure somewhat different aspects of arterial elasticity21 22 31 ; therefore, they were all included in the analyses. The use of the measurement technique and the calculation of the stiffness indexes presented above is based on the assumption that the brachial pulse pressure measured noninvasively by the Dinamap equipment is an acceptable approximation of the intra-arterial pulse pressure at the common carotid artery. The validity of this assumption was demonstrated by Borow and Newburger,32 who showed an excellent correlation of .984 between the systolic blood pressures measured invasively from the ascending aorta and nonivasively from the brachial artery using Dinamap equipment. The corresponding correlation for diastolic blood pressures was also very high (r=.969). Other investigators reported analogous validation studies.33 34 Accordingly, techniques similar to those in the present study have been used widely.20 22 35 36
Blood was drawn from the antecubital vein with the subject sitting. Specimens were collected into vacuum tubes containing silicon (insulin and glucose) and EDTA (lipids). The tubes were centrifuged at 3000g for 10 minutes at 4°C. After separation, aliquots were quickly frozen at -70°C until analysis within a few weeks. Insulin was measured with a commercial radioimmunoassay (Cambridge Biomedical), and glucose was measured by a hexokinase method on a Coulter DACOS (Coulter Instruments). Based on our internal quality control materials (lyophilized human serum) that were included in each analytical batch, the interassay analytical SD was 1.3 mg/dL (CV, 1.6%) at 79.3 mg/dL for glucose and 2.3 mU/L (CV, 17%) at 13.5 mU/L for insulin. Total cholesterol37 and triglycerides38 were measured by enzymatic methods, and HDL cholesterol was measured after dextran-magnesium precipitation.39
Height and weight were measured with the subject in light clothing and
no shoes. BMI (kilograms per meter squared) was computed. Smoking and
medication were assessed by interviews. Sitting blood pressure was
measured three times in the right arm of seated participants with a
random-zero sphygmomanometer after a rest period of 5 minutes. The
fifth phase of Korotkoff sounds was used to mark diastolic blood
pressure. The mean of the last two measurements was used in the
analyses. Prevalent hypertension was defined as sitting systolic blood
pressure 
140 mm Hg, diastolic 90 mm Hg, or use of
antihypertensive medications.
Glucose tolerance was divided into three categories: normal,
borderline, and abnormal (NIDDM). NIDDM was defined as fasting blood
glucose 140 mg/dL and/or a history of diabetes or oral hypoglycemic
medication. Borderline glucose tolerance was defined as a fasting blood
glucose of 115 to 139 mg/dL and no history of or treatment for
diabetes. If fasting blood glucose was <115 mg/dL, the glucose
tolerance was considered normal.
Statistical Methods
Although the total sample size was quite
large, stratified
analyses resulted in smaller cell sizes (none smaller than 103),
especially in nondiabetic black men. Therefore, log-transformed values
(natural logarithms) of arterial stiffness indexes and blood glucose,
serum insulin, and triglycerides were used for regression models and
hypothesis testing to satisfy normality assumptions. Untransformed
values, however, are shown in figures and tables for ease of
interpretation. The t and 
2 tests were
used to examine differences in the means and proportions between ARIC
participants included in this study and excluded from it. Smoking was
expressed in cigarette-years and handled in multivariate models as a
three-level, ordinal scale variable. ANCOVA was used to examine
differences in the means of the arterial stiffness indexes between the
three glucose tolerance groups. Multiple linear regression analysis
was used to examine the association of glucose and insulin with
stiffness indexes. These analyses were restricted to the nondiabetic
population (normal plus borderline glucose tolerance) because the
treatment of NIDDM modifies glucose and insulin concentrations and
because insulin levels tend to decline with the duration of diabetes.
Biologically relevant interactions were tested. As can be expected,
however, the glucose by insulin interaction term turned out to be
collinear with the main effects of its components, and stratified
analyses were used to assess the joint effect of these factors. The
difference between two regression lines was examined with a test of
coincidence.40 Probability values <.05 (two-tailed tests)
were considered statistically significant. The STATISTICAL
ANALYSIS SYSTEM (SAS) was used.41
In both the ANCOVA and multiple linear regression analyses, the primary focus was on models adjusted for age, smoking, and total cholesterol. Further adjustment was made for BMI, HDL cholesterol, triglycerides, and hypertension status, but because these variables are closely associated with NIDDM and insulin, they can be considered intervening variables rather than confounders. YEM includes arterial wall thickness in its measurement and is considered to give an estimate of arterial stiffness that is independent of wall thickness. We repeated the ANCOVA and regression models for AC, SI, and Ep by adding the mean arterial wall thickness as a covariate. The results of these models were essentially similar to those of models with YEM as an independent variable; therefore, only the latter is reported.
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Results |
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Tables 1
and 2 give the
characteristics of eligible white and black ARIC participants included
in and excluded from this study. The mean age of the included subjects
in different race-sex groups was between 53 and 54 years, and mean BMI
ranged from 25.8 to 28.8 kg/m2. Approximately a quarter of
the white and almost half of the black examinees were hypertensive. The
prevalence of NIDDM among the persons included in this study ranged
from 4.1% in white women to 10.0% in black women. The main systematic
difference between excluded and included ARIC baseline examination
participants was that the excluded persons were somewhat heavier than
the included. Accordingly, they also had somewhat higher fasting
glucose, insulin, and triglyceride concentrations as well as higher
systolic blood pressure and lower HDL cholesterol. Among white
examinees, the excluded men and women also smoked more than the
included.
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All indexes of arterial stiffness were higher when fasting glucose was
above the normal level (Fig 1). The association was
similar in both races. After adjustment for age, smoking, and total
cholesterol, the differences in mean AC, SI, Ep, and YEM between the
glucose-tolerance groups remained statistically significant in white
men and women and in black women; in black men, however, YEM did not
remain significantly different. Further adjustment for BMI,
triglycerides, HDL cholesterol, and hypertension status attenuated most
of the differences to a nonsignificant level, but Ep in white men and
YEM in black women remained statistically significant.
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Even in nondiabetic participants, fasting glucose showed in univariate analyses a statistically significant association with arterial stiffness indexes. Thus, for example, a 25% increase (approximately 1 SD) in fasting glucose corresponded to a predicted decrease of 5.8% (95% CI, -9.6% to -1.9%; P=.004) in AC among white men and 15.0% (95% CI, -18.2% to -11.7%; P<.001) among white women. Respective predicted increases of SI, Ep, and YEM were 5.8% (95% CI, 2.0% to 9.7%; P=.002), 11.3% (95% CI, 6.9% to 15.9%; P<.001), and 11.2% (95% CI, 6.2% to 16.6%, P<.001) in white men, and 16.6% (95% CI, 12.5% to 20.8%; P<.001), 23.2% (95% CI, 18.4% to 28.2%; P<.001), and 19.2% (95% CI, 14.0% to 24.7%; P<.001) in white women.
Fasting serum insulin concentration was significantly associated in
univariate analyses with indexes of arterial stiffness in nondiabetic
participants of all race-sex groups (Fig 2). Thus, for
example, an 80% increase in serum insulin (approximately 1 SD)
predicted a 5.1% (95% CI, 3.2% to 7.1%; P<.001)
increase in YEM in white men and 7.5% (95% CI, 5.8% to 9.2%;
P<.001) increase in white women.
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In multivariate analyses adjusted for age, cigarette-years, and total
cholesterol (Table 3), fasting glucose remained a
significant predictor of all arterial stiffness indexes in white men
and women and in black women. In black men, none of the stiffness
indexes remained significantly associated with glucose. These models
explained 6.1% to 21.1% of the variance of arterial stiffness indexes
in whites and 3.7% to 15.2% in blacks. Fasting serum insulin remained
a strong predictor of arterial stiffness indexes in all four race-sex
groups (Table 4). The models containing insulin
explained 6.6% to 22.5% of the variance of stiffness indexes in
whites and 6.0% to 15.6% in blacks.
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After further adjustment for BMI, triglycerides, HDL cholesterol, and hypertension status, glucose still remained a significant predictor of all stiffness indexes in white women and of AC, Ep, and YEM in black women. Only YEM in white men and no stiffness indexes in black men remained significantly associated with fasting glucose. Serum insulin remained a significant predictor of all stiffness indexes in white women and of AC, SI, and Ep in white men. In black examinees, insulin did not remain significantly associated with any stiffness indexes.
Because all the indexes of arterial stiffness used in this study contain the pulse pressure or systolic or diastolic pressure as a component of their formulas, the role of blood pressure was examined more closely. Of the stiffness indexes, Ep had the highest correlation with sitting systolic blood pressure (Pearson r, adjusted for age, ranging from .33 to .52 in different race-sex groups), and SI had the lowest correlation (r=.14 to .26). Sitting diastolic blood pressure correlated approximately similarly with the indexes of arterial stiffness as systolic blood pressure. On the other hand, insulin and glucose had rather low correlations with systolic blood pressure, ranging from .004 to .18 and .14 to .20, respectively. When systolic blood pressure was added to the regression models containing glucose, age, total cholesterol, and smoking, glucose still remained a significant predictor of all stiffness indexes in white and black women. In white men, fasting glucose remained significantly associated with Ep and YEM, whereas in black men no significant associations were observed. Respective models for serum insulin showed that it remained a significant predictor of all stiffness indexes in all race-sex groups.
The instantaneous effect of blood pressure on stiffness measurements
was examined by plotting Ep and SI against mean arterial pressure (MAP)
measured with subjects in the supine position during the
ultrasound examination with Dinamap equipment. Separate regression
slopes were drawn, eg, for nondiabetic white women belonging to the
race- and sex-specific highest tertile of both glucose and insulin and
for nondiabetic white women belonging to the lowest tertile of both
glucose and insulin. Fig 3 shows that although Ep
increases with increasing MAP, the lines for the two groups remain
clearly separate (P=.0001 for the difference between the
regression lines). SI increases only slightly with increasing MAP, and
the group with high glucose and insulin concentrations has, at all MAP
levels, higher SI than the group with low glucose and insulin
concentrations (P=.0001 for the difference between the
regression lines).
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Glucose and insulin had a synergistic association with arterial
stiffness indexes, especially in white women. Fig 4
shows the unadjusted mean AC, SI, Ep, and YEM for white women by
tertiles of fasting glucose and tertiles of fasting insulin. When
calculated, for example, for a white woman, a 25% increase in glucose
was associated with an age-adjusted decrease of 0.4% (95% CI, -8.1%
to 8.0%) in AC in the lowest tertile of serum insulin but an
age-adjusted decrease of 13.2% (95% CI, -17.9% to -8.2%) in the
highest tertile of serum insulin. The corresponding age-adjusted
increases for a 25% increase in glucose in the lowest versus highest
tertile of insulin were 0.9% (95% CI, -5.8% to 8.0%) and 15.2%
(95% CI, 9.7% to 21.1%) in SI, 4.2% (95% CI, -3.5% to 12.4%)
and 19.0% (95% CI, 12.5% to 25.8%) in Ep, and 3.7% (95% CI,
-5.4% to 13.6%) and 18.1% (95% CI, 10.5% to 26.1%) in YEM. On
the other hand, an 80% increase in serum insulin was associated with a
2.4% (95% CI, -4.8% to 0.0%) age-adjusted decrease of AC in the
lowest tertile of fasting glucose but 6.3% (95% CI, -8.5% to
-3.9%) in the highest tertile of glucose. The respective age-adjusted
increases were 3.2% (95% CI, 1.1% to 5.5%) and 8.1% (95% CI,
5.7% to 10.5%) in SI, 5.1% (95% CI, 2.7% to 7.6%) and 9.2% (95%
CI, 6.5% to 11.9%) in Ep, and 5.9% (95% CI, 2.9% to 9.0%) and
8.1% (95% CI, 5.0% to 11.2%) in YEM. In white men, the results were
in the same direction but weaker than in white women. Among blacks, the
findings were inconsistent, probably because of the small number of
subjects.
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Serum insulin also showed a synergistic association with
triglycerides, as shown for white women in Fig 5. For
example, an increase of 80% in serum insulin concentration in a white
woman was associated with an age-adjusted decrease of 0.1% (95% CI,
-2.6% to 2.5%) in AC and age-adjusted increases of 1.3% (95% CI,
-0.9% to 3.5%), 2.2% (95% CI, -0.3% to 4.7%), and 3.3% (95%
CI, 0.3% to 6.4%) in SI, Ep, and YEM, respectively, in the lowest
tertile of serum triglycerides but an age-adjusted decrease of 6.4%
(95% CI, -8.7% to -4.1%) in AC and age-adjusted increases of 7.0%
(95% CI, 4.7% to 9.3%) in SI, 8.5% (95% CI, 5.9% to 11.2%) in
Ep, and 7.6% (95% CI, 4.6% to 10.8%) in YEM in the highest tertile
of serum triglycerides. Formal statistical testing of insulin by
triglyceride interaction was also carried out with insulin and
triglycerides as continuous variables. After adjustment for age, total
cholesterol, and smoking, the coefficients (±SEMs) of insulin by
triglyceride interaction term were, eg, in white women, as follows:
-0.071±0.024 (P=.003) on AC, 0.072±0.021
(P=.0006) on SI, 0.069±0.024 (P=.004)
on Ep, and
0.047±0.028 (P=.10) on YEM. The contribution of the
interaction term to the r2 values of
these models was 1.1% to 2.8%. Collinearity diagnostics indicated
some degree of collinearity between the interaction term and the main
effects of insulin and triglycerides, but that does not negate the
finding that the joint effect was more than additive. In white men, the
pattern was similar to that in white women, but among blacks the number
of subjects became small and the results were inconsistent. No
interaction was found between blood glucose and triglycerides or
between insulin and total cholesterol.
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Discussion |
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Most studies of atherosclerosis have addressed atherosis, the component of the disease related to lipid deposition. Information on sclerosis, the gradual stiffening of the arterial wall, has been scarce.42 A few earlier studies, however, suggested that diabetes15 16 17 18 and insulin19 20 are associated with increased stiffening of the arterial wall. Furthermore, ultrasound examinations of the heart of diabetic patients suggested that they often have a cardiomyopathy, even in the absence of atherosis and hypertension.43 44 45 A disordered collagen metabolism is thought to play a role in this, and it may well be the same generalized phenomenon affecting both heart and arteries. The findings from our study are in agreement with earlier reports of increased arterial stiffness in diabetes and show in addition that arterial stiffness indexes are associated with glucose and insulin concentrations long before the appearance of clinically manifest diabetes. A previous report of the ARIC Study showed that higher glucose and insulin concentrations are associated with increased intima-media thickness.46 Our findings on YEM, which were confirmed by ANCOVA with mean wall thickness as a covariate, suggest that the increase in arterial wall stiffness is independent of the simultaneous increase in wall thickness.
Prospective studies have shown that a high blood glucose level is associated with future cardiovascular events.47 48 49 Furthermore, three prospective studies showed that high plasma insulin is a risk factor for CHD in men.49 50 51 In some of these studies, the association between glucose and insulin levels and CHD events has been nonlinear, with an abrupt increase in risk in the uppermost decile of blood glucose49 50 52 or plasma insulin.49 In the present study, the increase in arterial wall stiffness in the uppermost deciles of fasting blood glucose and serum insulin was approximately linear, with no evidence of a threshold effect.
Several studies suggested that women tend to lose their protection from
CHD relative to men if they become
diabetic.53 54 55 In the
present study, the regression coefficients of blood glucose were
for all indexes of arterial stiffness about twice as high in women as
in men (Table 3
). When both sexes were included in the same
model,
there was a statistically significant glucose-by-sex interaction,
suggesting a stronger association of blood glucose with arterial
stiffness indexes in women than in men. We had the opportunity to check
this finding on a sample of the data collected during the (still
incomplete) second examination of the ARIC cohort 3 years after the
baseline visit. The association of blood glucose with arterial
stiffness indexes was now equally strong for both men and women, and
there was no indication of glucose-by-sex interaction. The increase in
age did not explain this change. Thus, the stronger association of
blood glucose with arterial stiffness indexes in women than in men in
data from the first ARIC visit may be a chance finding.
The association of insulin with arterial stiffness indexes also tended to be stronger in women than in men, and the difference was statistically significant for YEM. It was not possible to check this result in the second ARIC visit because insulin determinations were not performed, but clearly this finding also should be interpreted with caution. A cross-sectional study from Israel recently reported a gender-by-hyperinsulinemia interaction different from ours, with hyperinsulinemia associated with prevalent cardiovascular disease in men but not in women.56 The Busselton Study from Australia was also unable to find an association between cardiovascular disease risk and insulin concentration in women.51 Both of these studies, however, were based on a small number of cases in women. In the Framingham Heart Study, the incidence of ultrasonically diagnosed ventricular hypertrophy among subjects with glucose intolerance or diabetes was greater in women than in men.57 Obviously, more prospective studies need to be performed before the possible sex differential in the role of glucose and insulin as cardiovascular risk factors can be characterized in more detail.
Our report is based on cross-sectional information, but modern ultrasound methods provided us with continuous outcome variables that enable detection of incipient changes in the sclerotic process. This increased the statistical power of our study and provides some reassurance against the potential biases of a cross-sectional study, such as lifestyle changes caused by existing symptomatic disease. It seems reasonable to assume that the stiffness of the carotid arteries measured with ultrasound is associated with atherosclerosis of the coronaries and future CHD events, although so far no prospective studies prove this. It has long been known, however, that arterial stiffness is an important determinant of myocardial oxygen demand.13 58 In the Bogalusa Heart Study, the decreased elasticity of carotid arteries in the young was associated with high serum cholesterol and systolic blood pressure, as well as parental history of myocardial infarction.28 In a Japanese study,22 patients with angiographically proven CHD also had stiffer carotid arteries than healthy control subjects, as assessed with ultrasound measurements of SI and Ep, and arterial stiffness was proportional to the degree of coronary atherosclerosis. Another study from the same group demonstrated that the SI of the carotid arteries measured ultrasonically during life correlated well with the severity grade of atherosclerosis of the same arteries as determined subsequently at autopsy.35
Ideally, arterial pressures and dimensions should be measured at the site where arterial stiffness is estimated. The brachial artery, however, is more accessible for blood pressure measurements than the carotid artery; therefore, it is practical to substitute brachial artery pressures for carotid artery pressures in calculations of stiffness indexes. This approach has the problem that pulse pressure increases by an average of 18% to 31% between the aorta and the brachial artery.59 60 The increase is a consequence of pulse wave reflection from the periphery, which augments the peak of the pressure wave in peripheral arteries close to the reflection sites.58 61 62 However, this phenomenon has been described to occur mainly in young and healthy individuals with very elastic arteries.63 64 65 With increasing age, the pulse wave velocity increases so that the pressure wave augmentation also occurs in central arteries. Thus, pulse pressure differences between central and peripheral arteries tend to diminish with age. Furthermore, cuff-based indirect measurements of brachial artery blood pressure consistently underestimate systolic and pulse pressures. The sum of these conflicting effects is that in middle-aged persons examined in controlled conditions as in the present study, the indirectly measured brachial artery pressure is a reasonably good approximation of the pressure in central arteries. Several groups showed the validity of this approximation,32 33 34 66 67 and similar or comparable methods have been used commonly in published research.20 22 28 29 35 36
Persons with borderline glucose tolerance or NIDDM have a well-known tendency toward high blood pressure,54 55 68 and insulin resistance may contribute to the pathogenesis of hypertension.69 70 Therefore, in the present study, blood pressure can be considered an intervening variable rather than a confounder. Moreover, systolic blood pressure and arterial elasticity are closely related physiologically, and it is very difficult to distinguish clearly between these two factors. Our data suggest, however, that fasting blood glucose and serum insulin are associated with decreased arterial elasticity even after adjustment for systolic blood pressure. Also, the plots of Ep and SI against MAP indicate different arterial characteristics in persons who are nondiabetic but at the high end of glucose and insulin distributions compared with persons who are at the low end of those distributions.
Hirai and coworkers22 performed repeated measurements of Ep and SI during sodium nitroprusside infusion and found that Ep decreased considerably with decreasing blood pressure, whereas SI remained unchanged. They concluded that SI is fairly independent of blood pressure level. This design may have a pitfall, however, because in various clinical conditions, eg, after nitroglycerin administration, the changes in brachial artery pressure measured by the conventional cuff method do not reflect very well the changes in blood pressure in central arteries.61 71 72 Our data were collected with a different approach: by cross-sectional examination of a large number of individuals with different blood pressures. Despite this difference in data collection, our findings are consistent with those of Hirai and coworkers.22 The SI is considerably less dependent on blood pressure than Ep. The fact that the SI behaved similarly to the other stiffness indexes in relation to glucose tolerance status and serum insulin, together with the low correlations of insulin and glucose with blood pressure, further supports the idea that blood glucose and serum insulin are associated with decreased arterial distensibility over and above their association with blood pressure.
A concern in our study is the amount of missing data and the fact that "missingness" was not a random phenomenon. Therefore, the study population included in our analyses is not a random population sample. This complicates the inference of the findings and their generalizability to the population as a whole. However, the absolute differences between persons with existing and missing data were not large. The high statistical significance in some variables reflects the large number of examinees rather than the biological meaningfulness of differences. The main systematic factor responsible for unavailable measurements was obesity, which increases the depth of carotid arteries and makes reliable visualization of their boundaries more difficult. We examined possible effect modification by obesity on the relation of insulin with arterial stiffness indexes and found a modest positive interaction. Hence, the effect of insulin is slightly stronger among obese people than among their leaner counterparts. This is in agreement with the synergistic action of insulin with glucose and triglycerides, which are associated with obesity.
The representativeness of our findings is further compromised by the low participation rate, especially among blacks. We can only speculate about the effects of nonresponse on our findings, but other epidemiological studies reported that the nonresponders tend to be less health conscious and more overweight than the participants.73 74 Apart from obesity and factors related to it, we have no reason to suspect that the relation of arterial stiffness indexes to insulin or blood glucose would be different among nonresponders or subjects with missing data than among subjects with existing data. Accordingly, the effect of missing data and nonresponse is likely to be small and in a conservative direction.
Elevation of plasma triglycerides is a common finding in subjects with NIDDM and impaired glucose tolerance. Although the role of serum triglyceride concentration as a cardiovascular risk factor in the general population remains controversial,75 it seems to have a stronger impact in diabetics.76 77 78 Our finding of a joint association of triglycerides and insulin on arterial stiffness indexes is in good agreement with similar data from clinical studies. In practice, this association is likely to be stronger than described in the present study because the intraindividual variability of serum triglyceride concentration is notoriously high, making it difficult to recognize its association with disease.75 79 Glucose, insulin, and triglycerides commonly increase simultaneously, eg, as a consequence of increasing weight. Our results suggest that this joint relation can have a substantial impact on the stiffening of the arteries and in the early pathophysiology of macrovascular disease in NIDDM. Fortunately, all three factors are amenable to lifestyle and/or medical intervention, and there is at least some evidence42 that the sclerotic process can be halted and possibly even reversed.
The technology for noninvasive measurements of arterial distensibility in vivo is still young, and large-scale population-based studies have become possible only recently. Our knowledge of the determinants and the biological and prognostic significance of the distensibility indexes is as yet limited. Therefore, reports in this field, including the present one, need to be interpreted cautiously. It is likely, however, that in the near future, rapid technological progress will enable us to reach a more versatile understanding of atherosclerosis by examining sclerosis in addition to the already abundant literature on atherosis.
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Acknowledgments |
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This research was supported by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the NHLBI. Dr Salomaa was supported in part by the Meilahti Foundation, Helsinki, Finland. We wish to thank the staff at the ARIC field centers, the Ultrasound Reading Center and Coordinating Center. In particular, the following persons are acknowledged: Ming Zhong, Ding-yi Zhou, Sharon Kerrick, and Myra Carpenter from the ARIC Coordinating Center; Jeannette Bensen, Catherine Paton, Amy Haire, and Delilah Posey from the Forsyth County Field Center; Royanne Barry, Faye Blackburn, Rajam Radhakrishman, and Seshadri Raju from the Jackson Field Center; Marilyn Bowers, Bryna Lester, Garil Murton, and Virginia Wyum from the Minneapolis Field Center; and Carol Christman, Sonny Harrell, Joel Hill, and Joan Nelling from the Washington County Field Center.
Received June 13, 1994; revision received September 8, 1994; accepted September 28, 1994.
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T. Siegmund, P.-M. Schumm-Draeger, D. Antoni, and H. Von Bibra Beneficial effects of ramipril on myocardial diastolic function in patients with type 2 diabetes mellitus, normal LV systolic function and without coronary artery disease: a prospective study using tissue Doppler Diabetes and Vascular Disease Research, December 1, 2007; 4(4): 358 - 364. [Abstract] [PDF]
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E. H. Serne, R. T. de Jongh, E. C. Eringa, R. G. IJzerman, and C. D.A. Stehouwer Microvascular Dysfunction: A Potential Pathophysiological Role in the Metabolic Syndrome Hypertension, July 1, 2007; 50(1): 204 - 211. [Full Text] [PDF]
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J. M. Lee, C. Shirodaria, C. E Jackson, M. D Robson, C. Antoniades, J. M Francis, F. Wiesmann, K. M Channon, S. Neubauer, and R. P Choudhury Multi-modal magnetic resonance imaging quantifies atherosclerosis and vascular dysfunction in patients with type 2 diabetes mellitus Diabetes and Vascular Disease Research, March 1, 2007; 4(1): 44 - 48. [Abstract] [PDF]
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S. Aronson, M. L. Fontes, Y. Miao, D. T. Mangano, and for the Investigators of the Multicenter Study of Risk Index for Perioperative Renal Dysfunction/Failure: Critical Dependence on Pulse Pressure Hypertension Circulation, February 13, 2007; 115(6): 733 - 742. [Abstract] [Full Text] [PDF]
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C. Bouvet, W. Peeters, S. Moreau, D. deBlois, and P. Moreau A new rat model of diabetic macrovascular complication Cardiovasc Res, February 1, 2007; 73(3): 504 - 511. [Abstract] [Full Text] [PDF]
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E. Barinas-Mitchell, L. H. Kuller, K. Sutton-Tyrrell, R. Hegazi, P. Harper, J. Mancino, and D. E. Kelley Effect of Weight Loss and Nutritional Intervention on Arterial Stiffness in Type 2 Diabetes Diabetes Care, October 1, 2006; 29(10): 2218 - 2222. [Abstract] [Full Text] [PDF]
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M.-C. Alessi and I. Juhan-Vague PAI-1 and the Metabolic Syndrome: Links, Causes, and Consequences Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2200 - 2207. [Abstract] [Full Text] [PDF]
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A. G. Huebschmann, J. G. Regensteiner, H. Vlassara, and J. E.B. Reusch Diabetes and Advanced Glycoxidation End Products. Diabetes Care, June 1, 2006; 29(6): 1420 - 1432. [Full Text] [PDF]
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K. Guan, C. Hudson, T. Wong, M. Kisilevsky, R. K. Nrusimhadevara, W. C. Lam, M. Mandelcorn, R. G. Devenyi, and J. G. Flanagan Retinal Hemodynamics in Early Diabetic Macular Edema Diabetes, March 1, 2006; 55(3): 813 - 818. [Abstract] [Full Text] [PDF]
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M. Ronnback, B. Isomaa, J. Fagerudd, C. Forsblom, P.-H. Groop, T. Tuomi, L. Groop, and for the Botnia Study Group Complex Relationship Between Blood Pressure and Mortality in Type 2 Diabetic Patients: A Follow-Up of the Botnia Study Hypertension, February 1, 2006; 47(2): 168 - 173. [Abstract] [Full Text] [PDF]
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G. F. Mitchell, J. A. Vita, M. G. Larson, H. Parise, M. J. Keyes, E. Warner, R. S. Vasan, D. Levy, and E. J. Benjamin Cross-Sectional Relations of Peripheral Microvascular Function, Cardiovascular Disease Risk Factors, and Aortic Stiffness: The Framingham Heart Study Circulation, December 13, 2005; 112(24): 3722 - 3728. [Abstract] [Full Text] [PDF]
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P.H. Whincup, J.A. Gilg, A.E. Donald, M. Katterhorn, C. Oliver, D.G. Cook, and J.E. Deanfield Arterial Distensibility in Adolescents: The Influence of Adiposity, the Metabolic Syndrome, and Classic Risk Factors Circulation, September 20, 2005; 112(12): 1789 - 1797. [Abstract] [Full Text] [PDF]
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M. Juonala, M. J. Jarvisalo, N. Maki-Torkko, M. Kahonen, J. S.A. Viikari, and O. T. Raitakari Risk Factors Identified in Childhood and Decreased Carotid Artery Elasticity in Adulthood: The Cardiovascular Risk in Young Finns Study Circulation, September 6, 2005; 112(10): 1486 - 1493. [Abstract] [Full Text] [PDF]
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R. R. Sankatsing, S. W. Fouchier, S. de Haan, B. A. Hutten, E. de Groot, J. J.P. Kastelein, and E. S.G. Stroes Hepatic and Cardiovascular Consequences of Familial Hypobetalipoproteinemia Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1979 - 1984. [Abstract] [Full Text] [PDF]
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M. J. Roman, R. B. Devereux, J. E. Schwartz, M. D. Lockshin, S. A. Paget, A. Davis, M. K. Crow, L. Sammaritano, D. M. Levine, B.-A. Shankar, et al. Arterial Stiffness in Chronic Inflammatory Diseases Hypertension, July 1, 2005; 46(1): 194 - 199. [Abstract] [Full Text] [PDF]
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K. Sutton-Tyrrell, S. S. Najjar, R. M. Boudreau, L. Venkitachalam, V. Kupelian, E. M. Simonsick, R. Havlik, E. G. Lakatta, H. Spurgeon, S. Kritchevsky, et al. Elevated Aortic Pulse Wave Velocity, a Marker of Arterial Stiffness, Predicts Cardiovascular Events in Well-Functioning Older Adults Circulation, June 28, 2005; 111(25): 3384 - 3390. [Abstract] [Full Text] [PDF]
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M. R. Rubin, M. S. Maurer, D. J. McMahon, J. P. Bilezikian, and S. J. Silverberg Arterial Stiffness in Mild Primary Hyperparathyroidism J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3326 - 3330. [Abstract] [Full Text] [PDF]
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D. M. Sengstock, P. V. Vaitkevicius, and M. A. Supiano Arterial Stiffness Is Related to Insulin Resistance in Nondiabetic Hypertensive Older Adults J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2823 - 2827. [Abstract] [Full Text] [PDF]
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S. J. Zieman, V. Melenovsky, and D. A. Kass Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 932 - 943. [Abstract] [Full Text] [PDF]
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M. Diamant, H. J. Lamb, M. A. van de Ree, E. L. Endert, Y. Groeneveld, M. L. Bots, P. J. Kostense, and J. K. Radder The Association between Abdominal Visceral Fat and Carotid Stiffness Is Mediated by Circulating Inflammatory Markers in Uncomplicated Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1495 - 1501. [Abstract] [Full Text] [PDF]
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S. Nakano, K. Konishi, K. Furuya, K. Uehara, M. Nishizawa, A. Nakagawa, T. Kigoshi, and K. Uchida A Prognostic Role of Mean 24-h Pulse Pressure Level for Cardiovascular Events in Type 2 Diabetic Subjects Under 60 Years of Age Diabetes Care, January 1, 2005; 28(1): 95 - 100. [Abstract] [Full Text] [PDF]
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L. De Angelis, S. C. Millasseau, A. Smith, G. Viberti, R. H. Jones, J. M. Ritter, and P. J. Chowienczyk Sex Differences in Age-Related Stiffening of the Aorta in Subjects With Type 2 Diabetes Hypertension, July 1, 2004; 44(1): 67 - 71. [Abstract] [Full Text] [PDF]
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A. Scuteri, S. S. Najjar, D. C. Muller, R. Andres, H. Hougaku, E. J. Metter, and E. G. Lakatta Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1388 - 1395. [Abstract] [Full Text] [PDF]
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D. Liao, T. Y. Wong, R. Klein, D. Jones, L. Hubbard, and A. R. Sharrett Relationship Between Carotid Artery Stiffness and Retinal Arteriolar Narrowing in Healthy Middle-Aged Persons Stroke, April 1, 2004; 35(4): 837 - 842. [Abstract] [Full Text] [PDF]
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S. A. Hope, D. B. Tay, I. T. Meredith, and J. D. Cameron Use of Arterial Transfer Functions for the Derivation of Central Aortic Waveform Characteristics in Subjects With Type 2 Diabetes and Cardiovascular Disease Diabetes Care, March 1, 2004; 27(3): 746 - 751. [Abstract] [Full Text] [PDF]
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K. Mather and R. Lewanczuk Measurement of Arterial Stiffness in Diabetes: A cautionary tale Diabetes Care, March 1, 2004; 27(3): 831 - 833. [Full Text] [PDF]
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D. H. Endemann, Q. Pu, C. De Ciuceis, C. Savoia, A. Virdis, M. F. Neves, R. M. Touyz, and E. L. Schiffrin Persistent Remodeling of Resistance Arteries in Type 2 Diabetic Patients on Antihypertensive Treatment Hypertension, February 1, 2004; 43(2): 399 - 404. [Abstract] [Full Text] [PDF]
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X. Guo and G. S. Kassab Variation of mechanical properties along the length of the aorta in C57bl/6 mice Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2614 - H2622. [Abstract] [Full Text] [PDF]
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H. Koyama, T. Maeno, S. Fukumoto, T. Shoji, T. Yamane, H. Yokoyama, M. Emoto, T. Shoji, H. Tahara, M. Inaba, et al. Platelet P-Selectin Expression Is Associated With Atherosclerotic Wall Thickness in Carotid Artery in Humans Circulation, August 5, 2003; 108(5): 524 - 529. [Abstract] [Full Text] [PDF]
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A. Becker, G. Bos, F. de Vegt, P. J Kostense, J. M Dekker, G. Nijpels, R. J Heine, L. M Bouter, and C. D.A Stehouwer Cardiovascular events in type 2 diabetes: comparison with nondiabetic individuals without and with prior cardiovascular disease: 10-year follow-up of the Hoorn Study Eur. Heart J., August 1, 2003; 24(15): 1406 - 1413. [Abstract] [Full Text] [PDF]
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R. M.A. Henry, P. J. Kostense, A. M.W. Spijkerman, J. M. Dekker, G. Nijpels, R. J. Heine, O. Kamp, N. Westerhof, L. M. Bouter, and C. D.A. Stehouwer Arterial Stiffness Increases With Deteriorating Glucose Tolerance Status: The Hoorn Study Circulation, April 29, 2003; 107(16): 2089 - 2095. [Abstract] [Full Text] [PDF]
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D. N. O'Neal, G. Dragicevic, K. G. Rowley, M. Z. Ansari, N. Balazs, A. Jenkins, and J. D. Best A Cross-Sectional Study of the Effects of Type 2 Diabetes and Other Cardiovascular Risk Factors on Structure and Function of Nonstenotic Arteries of the Lower Limb Diabetes Care, January 1, 2003; 26(1): 199 - 205. [Abstract] [Full Text] [PDF]
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M. Tamminen, J. Westerbacka, S. Vehkavaara, and H. Yki-Jarvinen Insulin-Induced Decreases in Aortic Wave Reflection and Central Systolic Pressure Are Impaired in Type 2 Diabetes Diabetes Care, December 1, 2002; 25(12): 2314 - 2319. [Abstract] [Full Text] [PDF]
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P. Henry, F. Thomas, A. Benetos, and L. Guize Impaired Fasting Glucose, Blood Pressure and Cardiovascular Disease Mortality Hypertension, October 1, 2002; 40(4): 458 - 463. [Abstract] [Full Text] [PDF]
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E. Suzuki, A. Kashiwagi, Y. Nishio, K. Egawa, S. Shimizu, H. Maegawa, M. Haneda, H. Yasuda, S. Morikawa, T. Inubushi, et al. Increased Arterial Wall Stiffness Limits Flow Volume in the Lower Extremities in Type 2 Diabetic Patients Diabetes Care, December 1, 2001; 24(12): 2107 - 2114. [Abstract] [Full Text] [PDF]
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J. Westerbacka, A. Seppala-Lindroos, and H. Yki-Jarvinen Resistance to Acute Insulin Induced Decreases in Large Artery Stiffness Accompanies the Insulin Resistance Syndrome J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5262 - 5268. [Abstract] [Full Text] [PDF]
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M. Domanski, J. Norman, M. Wolz, G. Mitchell, and M. Pfeffer Cardiovascular Risk Assessment Using Pulse Pressure in the First National Health and Nutrition Examination Survey (NHANES I) Hypertension, October 1, 2001; 38(4): 793 - 797. [Abstract] [Full Text] [PDF]
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K. Sutton-Tyrrell, A. Newman, E. M. Simonsick, R. Havlik, M. Pahor, E. Lakatta, H. Spurgeon, and P. Vaitkevicius Aortic Stiffness Is Associated With Visceral Adiposity in Older Adults Enrolled in the Study of Health, Aging, and Body Composition Hypertension, September 1, 2001; 38(3): 429 - 433. [Abstract] [Full Text] [PDF]
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N. Hosomi, K. Mizushige, H. Ohyama, T. Takahashi, M. Kitadai, Y. Hatanaka, H. Matsuo, M. Kohno, and J. A. Koziol Angiotensin-Converting Enzyme Inhibition With Enalapril Slows Progressive Intima-Media Thickening of the Common Carotid Artery in Patients With Non-Insulin-Dependent Diabetes Mellitus Stroke, July 1, 2001; 32(7): 1539 - 1545. [Abstract] [Full Text] [PDF]
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U. Lindblad, R. D. Langer, D. L. Wingard, R. G. Thomas, and E. L. Barrett-Connor Metabolic Syndrome and Ischemic Heart Disease in Elderly Men and Women Am. J. Epidemiol., March 1, 2001; 153(5): 481 - 489. [Abstract] [Full Text] [PDF]
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S. I. McFarlane, M. Banerji, and J. R. Sowers Insulin Resistance and Cardiovascular Disease J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 713 - 718. [Full Text]
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Shonni J. Silverberg; Cardiovascular Disease in Primary Hyperparathyroidism J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3513 - 3514. [Full Text]
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R. Din-Dzietham, D. Liao, A. Diez-Roux, F. J. Nieto, C. Paton, G. Howard, A. Brown, M. Carnethon, and H. A. Tyroler Association of Educational Achievement with Pulsatile Arterial Diameter Change of the Common Crotid Artery The Atherosclerosis Risk in Communities (ARIC) Study, 1987-1992 Am. J. Epidemiol., October 1, 2000; 152(7): 617 - 627. [Abstract] [Full Text] [PDF]
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C. Espinola-Klein, H.-J. Rupprecht, S. Blankenberg, C. Bickel, H. Kopp, G. Rippin, G. Hafner, U. Pfeifer, and J. Meyer Are Morphological or Functional Changes in the Carotid Artery Wall Associated With Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus, or Herpes Simplex Virus Infection? Stroke, September 1, 2000; 31(9): 2127 - 2133. [Abstract] [Full Text] [PDF]
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E. Jeanclos, N. J. Schork, K. O. Kyvik, M. Kimura, J. H. Skurnick, and A. Aviv Telomere Length Inversely Correlates With Pulse Pressure and Is Highly Familial Hypertension, August 1, 2000; 36(2): 195 - 200. [Abstract] [Full Text] [PDF]
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H. F. Kuecherer, A. Just, and H. Kirchheim Evaluation of aortic compliance in humans Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1411 - H1413. [Full Text] [PDF]
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H.-M. Lakka, T. A. Lakka, J. Tuomilehto, J. Sivenius, and J. T. Salonen Hyperinsulinemia and the Risk of Cardiovascular Death and Acute Coronary and Cerebrovascular Events in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study Arch Intern Med, April 24, 2000; 160(8): 1160 - 1168. [Abstract] [Full Text] [PDF]
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S Manzi, L H Kuller, D Edmundowicz, and K Sutton-Tyrrell Vascular imaging: changing the face of cardiovascular research Lupus, March 1, 2000; 9(3): 176 - 182. [Abstract] [PDF]
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E. J. Giltay, J. Lambert, L. J. G. Gooren, J. M. H. Elbers, M. Steyn, and C. D. A. Stehouwer Sex Steroids, Insulin, and Arterial Stiffness in Women and Men Hypertension, October 1, 1999; 34(4): 590 - 597. [Abstract] [Full Text] [PDF]
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M. J. Domanski, B. R. Davis, M. A. Pfeffer, M. Kastantin, and G. F. Mitchell Isolated Systolic Hypertension : Prognostic Information Provided by Pulse Pressure Hypertension, September 1, 1999; 34(3): 375 - 380. [Abstract] [Full Text] [PDF]
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P. C. G. Simons, A. Algra, M. L. Bots, D. E. Grobbee, and Y. van der Graaf Common Carotid Intima-Media Thickness and Arterial Stiffness : Indicators of Cardiovascular Risk in High-Risk PatientsThe SMART Study (Second Manifestations of ARTerial disease) Circulation, August 31, 1999; 100(9): 951 - 957. [Abstract] [Full Text] [PDF]
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D. Liao, D. K. Arnett, H. A. Tyroler, W. A. Riley, L. E. Chambless, M. Szklo, and G. Heiss Arterial Stiffness and the Development of Hypertension : The ARIC Study Hypertension, August 1, 1999; 34(2): 201 - 206. [Abstract] [Full Text] [PDF]
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K. L. Berry, R. A. P. Skyrme-Jones, J. D. Cameron, R. C. O'Brien, and I. T. Meredith Systemic arterial compliance is reduced in young patients with IDDM Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H1839 - H1845. [Abstract] [Full Text] [PDF]
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M. J. Domanski, G. F. Mitchell, J. E. Norman, D. V. Exner, B. Pitt, and M. A. Pfeffer Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction J. Am. Coll. Cardiol., March 15, 1999; 33(4): 951 - 958. [Abstract] [Full Text] [PDF]
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J. N. Bella, M. J. Roman, R. Pini, J. E. Schwartz, T. G. Pickering, and R. B. Devereux Assessment of Arterial Compliance by Carotid Midwall Strain-Stress Relation in Normotensive Adults Hypertension, March 1, 1999; 33(3): 787 - 792. [Abstract] [Full Text] [PDF]
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J. N. Bella, M. J. Roman, R. Pini, J. E. Schwartz, T. G. Pickering, and R. B. Devereux Assessment of Arterial Compliance by Carotid Midwall Strain-Stress Relation in Hypertension Hypertension, March 1, 1999; 33(3): 793 - 799. [Abstract] [Full Text] [PDF]
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J. O. Toikka, P. Niemi, M. Ahotupa, H. Niinikoski, J. S. A. Viikari, T. Ronnemaa, J. J. Hartiala, and O. T. Raitakari Large-Artery Elastic Properties in Young Men : Relationships to Serum Lipoproteins and Oxidized Low-Density Lipoproteins Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 436 - 441. [Abstract] [Full Text] [PDF]
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Y. Nagai, C. J. Earley, M. K. Kemper, C. S. Bacal, and E.J. Metter Influence of age and postmenopausal estrogen replacement therapy on carotid arterial stiffness in women Cardiovasc Res, January 1, 1999; 41(1): 307 - 311. [Abstract] [Full Text] [PDF]
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 D. A. Towler, M. Bidder, T. Latifi, T. Coleman, and C. F. Semenkovich Diet-induced Diabetes Activates an Osteogenic Gene Regulatory Program in the Aortas of Low Density Lipoprotein Receptor-deficient Mice J. Biol. Chem., November 13, 1998; 273(46): 30427 - 30434. [Abstract] [Full Text] [PDF]
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 M. L. Goalstone, R. Natarajan, P. R. Standley, M. F. Walsh, J. W. Leitner, K. Carel, S. Scott, J. Nadler, J. R. Sowers, and B. Draznin Insulin Potentiates Platelet-Derived Growth Factor Action in Vascular Smooth Muscle Cells Endocrinology, October 1, 1998; 139(10): 4067 - 4072. [Abstract] [Full Text] [PDF]
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B. P. McGrath, Y.-L. Liang, H. Teede, L. M. Shiel, J. D. Cameron, and A. Dart Age-Related Deterioration in Arterial Structure and Function in Postmenopausal Women : Impact of Hormone Replacement Therapy Arterioscler Thromb Vasc Biol, July 1, 1998; 18(7): 1149 - 1156. [Abstract] [Full Text] [PDF]
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C. M. Burchfiel, D. S. Sharp, J. D. Curb, B. L. Rodriguez, R. D. Abbott, R. Arakaki, and K. Yano Hyperinsulinemia and Cardiovascular Disease in Elderly Men : The Honolulu Heart Program Arterioscler Thromb Vasc Biol, March 1, 1998; 18(3): 450 - 457. [Abstract] [Full Text] [PDF]
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G. F. Mitchell, L. A. Moye, E. Braunwald, J.-L. Rouleau, V. Bernstein, E. M. Geltman, G. C. Flaker, M. A. Pfeffer, and f. t. S. Investigators Sphygmomanometrically Determined Pulse Pressure Is a Powerful Independent Predictor of Recurrent Events After Myocardial Infarction in Patients With Impaired Left Ventricular Function Circulation, December 16, 1997; 96(12): 4254 - 4260. [Abstract] [Full Text]
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