© 1999 American Heart Association, Inc.
Vascular Biology |
Endothelial Cell Dysfunction and Arterial Wall Hypertrophy Are Associated With Disturbed Carbohydrate Metabolism in Patients at Risk for Cardiovascular Disease
From the Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Universitätsklinikum Charité, Medical Faculty of Humboldt University, Campus Berlin-Buch, Berlin, Germany.
Correspondence to Hermann Haller, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail haller{at}fvk-berlin.de
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Abstract |
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Abstract—To investigate the effects of fasting and postprandial glucose on endothelial cell function and intima-media thickness, we studied 60 men with cardiovascular risk factors. Postischemic, endothelium-dependent vasodilatation was measured after 3 minutes of ischemia at the radial artery with high-resolution echo tracking. Common carotid artery intima-media thickness was measured by B-mode ultrasound. Glucose tolerance was determined by a 75-g oral glucose load. Fasting glucose levels were inversely correlated with postischemic, endothelium-dependent vasodilatation (r=-0.24, P<0.05) and directly correlated with intima-media thickness (r=0.26, P<0.05). However, postischemic, endothelium-dependent vasodilatation and intima-media thickness were not correlated. All subjects with normal postischemic, endothelium-dependent vasodilatation also had a normal intima-media thickness, whereas some subjects with impaired postischemic, endothelium-dependent vasodilatation also had a normal intima-media thickness. Multiple regression analysis revealed a profound influence of age on intima-media thickness to the exclusion of all other variables. The same age-adjusted analysis for postischemic, endothelium-dependent vasodilatation accepted fasting glucose, followed by 2-hour postprandial glucose, as variables, but no others. Subjects with fasting glucose values >100 mg/dL showed reduced postischemic, endothelium-dependent vasodilatation (59 versus 120 µm, P<0.05) and a higher intima-media thickness (right: 0.76 versus 0.62 mm, P<0.05; left: 0.78 versus 0.63 mm, P<0.05) compared with those with fasting glucose values <100 mg/dL. Subjects with 2-hour postprandial glucose values >125 mg/dL had no reduced postischemic, endothelium-dependent vasodilatation compared with subjects with a 2-hour postprandial glucose >125 mg/dL; however, their intima-media thickness (right: 0.66 versus 0.62 mm; left: 0.68 versus 0.62 mm; P<0.05 for both) was greater. Thus, high fasting rather than postprandial glucose values are associated with both postischemic, endothelium-dependent vasodilatation and increased intima-media thickness. Postischemic endothelium-dependent vasodilatation may precede increased intima-media thickness.
Key Words: arteriosclerosis • impaired glucose tolerance • B-mode ultrasound • intima-media thickness • endothelial dysfunction
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Introduction |
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Metabolic disturbances in middle-aged men are important risk factors for chronic vascular disease.1 Both metabolic disturbances and chronic vascular disease develop over years to decades.2 Postprandial plasma glucose concentrations are elevated before any pathological changes in fasting plasma glucose levels can be detected and may directly influence the progression of vascular disease. Yamasaki et al3 have shown that asymptomatic hyperglycemia is associated with increased carotid artery intima-media thickness. Furthermore, increased intima-media thickness was identified before the appearance of hyperlipidemia.4 5 Early changes of the vascular wall were assessed by ultrasound determinations in these studies.6 7 8 Recently, endothelial dysfunction, viz, the disturbed ability of the endothelium to respond to a vasodilatory signal, has been described and introduced under the assumption that this disturbance is an early marker of vascular damage.9 10 Endothelial dysfunction may play a role in the pathogenesis of atherosclerosis.11 12 13 14 Several authors have demonstrated that endothelial dysfunction is commonly present in patients with hypertension,15 hyperlipidemia,16 and diabetes mellitus.17 18 Presumably, endothelial cell dysfunction leads to structural alterations resulting in an increase in intima-media thickness. Metabolic risk factors may influence both parameters. However, the associations between elevated fasting glucose concentrations or elevated postprandial increases in glucose with changes in vascular function and structure are unclear. Furthermore, the assumption that endothelial dysfunction precedes, or is a prerequisite for, increased intima-media thickness has not been proved. We investigated the effects of elevated fasting glucose concentrations, as well the 2-hour postprandial glucose, on vascular wall function and structure. We found that fasting glucose levels were a stronger predictor of endothelial cell dysfunction and intima-media thickness than were postprandial levels. Furthermore, although endothelial dysfunction and intima-media thickness were not correlated, increased intima-media thickness was never present without endothelial dysfunction.
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Methods |
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Subjects
Sixty male subjects aged 25 to 70 years with cardiovascular risk factors, such as obesity, hyperlipidemia, borderline hypertension, or a family history of hypertension, diabetes mellitus, or premature myocardial infarction, were recruited by advertisement. None was ingesting any medications and none had known cardiovascular disease, angina pectoris, or previous myocardial infarction. There were no smokers included in this study. Written, informed consent was obtained from each person before entry into the study. The protocol was approved by the University's committee on research in human subjects. The investigation was performed between 8 and 11 AM in a temperature-controlled environment maintained at 22±2°C. Resting blood pressure and heart rate were measured by an oscillometric method (Bosotron 2, Bosch und Sohn). Height and weight were obtained and the subjects underwent a physical examination. Fasting blood samples were obtained for complete blood count, electrolytes, liver function studies, total cholesterol, HDL cholesterol, triglycerides, and fibrinogen concentrations. LDL cholesterol concentrations were calculated with the Friedewald formula, provided that the triglyceride values were <400 mg/dL. Glucose tolerance was measured by means of an oral 75-g glucose load after which the plasma glucose concentration was measured at 2 hours. We divided the glucose values in the fasting and postprandial states into percentiles. Persons above the 75th percentile had glucose values in the fasting and postprandial state of >100 and >125 mg/dL, respectively, and were defined as abnormal.
Assessment of Endothelial Dysfunction (Radial
Artery)
The high-resolution-ultrasound echo-tracking system NIUS 02
(SMH, marketed by Capital Medical Services) used in this study has been
previously described and validated for the measurement of radial artery
diameter and its systolic-diastolic
variations.19 20 The same observer, who was not aware of
the patient's status, performed all of the ultrasound studies. Radial
artery parameters were studied in the supine position after
a 10-minute rest. The radial artery was studied 2 cm from the wrist in
the right arm after the forearm was secured comfortably on a splint.
Internal radial artery diameter (µm) and blood pressure (mm Hg) were
recorded. The reliability (test-retest correlation) is 0.89.
Continuous registration of the radial artery diameter and blood
pressure (Finapres) was done over a period of 
10 minutes. After a
1-minute steady-state determination of the radial artery diameter, a
3-minute ischemia of the forearm was produced with an
inflatable cuff. Postischemic,
endothelium-dependent vasodilatation was defined as the
maximal increase in the radial artery diameter (µm) during reactive
hyperemia. A representative tracing of a
measurement is shown in Figure 1
.
Vasodilation was induced by a 3-minute occlusion of the brachial
artery. Release of the arterial occlusion resulted in
stimulation of the endothelium and an increase in blood
flow.
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Assessment of Intima-Media Thickness (Carotid Artery)
Subjects were examined in the supine position with an ultrasound
scanner (Sonos 2000, Hewlett-Packard Co) equipped with a 7.5-MHz
transducer. Intima-media thickness of the right and left common carotid
arteries was measured 2 cm proximal to the carotid bulb. Intima-media
thickness (mm) was defined as the distance from the lumen-intima
interface to the media-adventitia interface of the posterior wall, as
described in previous studies.6 21 22 23 Intima-media
thickness was measured 4 times (see Figure 2) and the mean value was used for
statistical analysis. The measurement of intima-media thickness
has been standardized in our vascular laboratory with good
reproducibility. The reliability (test-retest correlation) is between
0.87 and 0.98. Figure 2 shows a representative
photograph of a measurement. The same investigator performed all of the
ultrasound studies. He was not aware of any patient's status.
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Statistical Analysis
The statistical analyses were calculated by the
SPSS computer program (SPSS Inc). Differences between
groups in the clinical data were tested by t tests for
independent samples. To test the relationship between variables,
Pearson's correlation coefficients were calculated. A multiple
stepwise regression analysis was performed with intima-media
thickness or postischemic,
endothelium-dependent vasodilatation as the dependent
variable. A value of P<0.05 was considered
statistically significant. All data are presented as mean±SD
and range.
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Results |
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The clinical and laboratory parameters of all subjects are shown in Table 1
. The subjects were
above ideal body weight and body mass index and had elevated blood
pressures according to World Health Organization criteria. Furthermore,
the subjects generally had serum cholesterol and
triglyceride levels above the age-adjusted normal range.
The fasting blood glucose and 2-hour postprandial blood glucose values
were borderline-elevated. The fasting blood glucose concentrations and
the their respective postprandial values were correlated with one
another at every time point. (r=0.55 at 1 hour,
r=0.40 at 2 hours). For all subjects, fasting blood glucose
concentrations were inversely correlated with postischemic
endothelial dilatation (r=-0.24,
P<0.05). No such correlation could be found for 2-hour
postprandial glucose. For all subjects, fasting blood glucose was
directly correlated with intima-media thickness (r=0.27,
P<0.05) and with 2-hour postprandial glucose
(r=0.27, P<0.05).
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A multiple regression analysis with intima-media thickness as the dependent variable revealed that only age entered the relationship. The influence of age was so great as to preclude the inclusion of any other variable, and age-adjusted analyses were not possible. When age-adjusted endothelial function was used as the dependent variable, fasting blood glucose entered the relationship, followed by the 2-hour postprandial blood glucose. There was no effect of age, intima-media thickness, or any other study variable.
Figure 3 shows the relationship between
intima-media thickness on the abscissa and postischemic
endothelial dilatation on the ordinate. A
postischemic, endothelium-dependent
vasodilatation of 200 µm was arbitrarily chosen as a mean normal
value (n>50 healthy volunteers). Normal intima-media thickness was
arbitrarily chosen as 0.8 mm. Intima-media thickness and
postischemic, endothelium-dependent
vasodilatation showed no linear relationship. However, the distribution
of the values was not random. Subjects with diminished
postischemic, endothelium-dependent
vasodilatation had either a normal or an increased intima-media
thickness. Subjects with normal postischemic,
endothelium-dependent vasodilatation invariably had a
normal intima-media thickness. No subject with normal
postischemic, endothelium-dependent
vasodilatation had an increased intima-media thickness.
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We next compared the subjects in terms of fasting glucose
concentrations of <100 mg/dL or >100 mg/dL, as shown in Figure 3
. Seven subjects with normal postischemic,
endothelium-dependent vasodilatation and normal
intima-media thickness had low fasting glucose concentrations. However,
23 subjects with low fasting glucose values had impaired
postischemic, endothelium-dependent
vasodilatation but a normal intima-media thickness. Only 4 subjects
with low fasting glucose concentrations had impaired
postischemic, endothelium-dependent
vasodilatation and increased intima-media thickness. On the other hand,
no subject with an elevated fasting glucose value had normal
postischemic, endothelium-dependent
vasodilatation. Six subjects with high fasting glucose values had a
normal intima-media thickness, whereas 7 had increased intima-media
thickness.
To examine the effect of fasting blood sugar further, we divided the
subjects into those with a fasting blood sugar >100 mg/dL and those
with values below this. The values of these 2 groups are shown in Table 2. The groups differed in terms of
fasting blood sugar by definition and in terms of responses to an oral
glucose load. The patients with the higher fasting blood glucose
concentrations had higher postprandial values at every time point
tested. Interestingly, the subjects with the lower fasting blood
glucose concentrations had higher LDL cholesterol
concentrations. The upper panel of Figure 4 shows the postischemic,
endothelium-dependent vasodilatation in subjects with
fasting glucose values of <100 mg/dL and >100 mg/dL. The
postischemic, endothelium-dependent
vasodilatation was greater in the group with the lower fasting glucose
values than in the group with higher fasting glucose values. This
finding suggests an impairment of endothelial function
in the group with higher fasting blood glucose concentrations. The
lower panel of Figure 4 shows the intima-media thickness of
subjects with fasting blood glucose values <100 mg/dL compared with
those whose values were >100 mg/dL. Subjects with the higher fasting
glucose values had a greater intima-media thickness compared with those
with lower fasting glucose values.
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100 mg/dL) Fasting Blood Glucose Concentrations
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We also compared subjects with 2-hour postprandial glucose
concentrations of <125 and >125 mg/dL. These data are shown in Table 3. According to this
dichotomization, no significant differences between the 2 groups were
observed, with the exception of glucose values and age. The upper panel
of Figure 5 shows the
postischemic, endothelium-dependent
vasodilatation in the subjects compared on the basis of 2-hour
postprandial glucose values of <125 or >125 mg/dL. With this
categorization, no difference in postischemic,
endothelium-dependent vasodilatation could be
determined. The lower panel of Figure 5 shows the intima-media
thickness of subjects with 2-hour postprandial glucose concentrations
<125 mg/dL compared with those whose values were >125 mg/dL. Again,
subjects with the higher 2-hour postprandial glucose values had a
higher intima-media thickness than did those with lower glucose values.
Thus, irrespective of whether fasting or 2-hour glucose concentrations
were considered, subjects with higher glucose values had higher
intima-media thickness scores.
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Discussion |
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The important findings in this study are that in a group of men without established cardiovascular disease but who nonetheless have known risk factors to develop cardiovascular disease prematurely, a diminished postischemic, endothelium-dependent vasodilatation and an increased intima-media thickness were common, were correlated with increasing age, but were not correlated with each other. Fasting glucose concentration was the single variable that was correlated both with postischemic, endothelium-dependent vasodilatation and increased intima-media thickness. The 2-hour postprandial glucose concentration was correlated only with increased intima-media thickness. Other risk factors, such as body mass index, lipid values, fibrinogen, and blood pressure, did not interact with postischemic, endothelium-dependent vasodilatation and intima-media thickness in this small number of subjects. The data underscore the effect of fasting glucose concentrations on vascular function and structure. Furthermore, our findings are consistent with the notion that decreased postischemic, endothelium-dependent vasodilatation may be a forerunner of increased intima-media thickness.
We reasoned that the thrice-daily increase in 2-hour postprandial glucose, which we believe precedes the development of increased fasting glucose values, would be a better indicator of vascular functional and structural alterations. However, we observed that fasting blood glucose levels >100 mg/dL were associated with both endothelial cell dysfunction and increased intima-media thickness. The 2-hour postprandial glucose levels were not correlated with postischemic, endothelium-dependent vasodilatation but only with intima-media thickness. Thus, we must modify our view. The fasting glucose values appear to be a better indicator of glucose-related effects on the vascular wall than are the postprandial concentrations.
Our data show that carotid artery wall hypertrophy is present in patients with both high fasting and postprandial glucose levels. An increase in intima-media thickness as determined by ultrasound imaging suggests structural changes of the vessel wall.24 Our observation that subjects with disturbed glucose regulation have an increase in intima-media thickness is supported by the findings of Yamasaki et al,3 who also found an increased intima-media thickness in asymptomatic patients with hyperglycemia and in young type 1 diabetic patients.25 Data from the Atherosclerosis Risk in Communities (ARIC) Study showed that abdominal obesity, physical inactivity, and elevated fasting glucose concentrations are directly correlated with carotid intima-media thickness, suggesting that these factors contribute to atherogenesis.26
We also investigated the functional properties of the vessel wall and showed that reduced endothelium-dependent vasodilation is associated with increased fasting glucose levels. Similar results have been obtained by others.17 18 However, in these other studies, the investigators examined patients with long-standing diabetes mellitus. In addition, their patients did not necessarily exhibit other metabolic disturbances such as hyperlipidemia. In our study population, glucose disturbances were the only parameters influencing vascular function and structure. The numbers in our study are small and clearly cannot illustrate the importance of elevated blood pressure, lipid disturbances, altered coagulation, smoking, and other factors that influence endothelial function. Nevertheless, our data suggest that disturbed carbohydrate tolerance is perhaps the most important and earliest detectable factor adversely affecting blood vessels.
Our results concerning 2-hour postprandial hyperglycemia are more complex. We identified endothelial cell dysfunction only in a subgroup of subjects with elevated 2-hour postprandial glucose levels. These patients did not differ in terms of cholesterol levels and blood pressure. We do not know which factors are responsible for the decreased postischemic, endothelium-dependent vasodilatation in these patients. The effect of impaired glucose tolerance on endothelial cell function as determined by echo tracking has not been investigated thus far. However, diabetic subjects show an impaired endothelium-dependent vasodilatation as measured by plethysmography.17 18 Possibly, the different methods contribute to the divergent results. The echo-tracking device assesses the functional characteristics of the radial artery, whereas plethysmography examines both the arterial and venous vascular beds.27 Possibly other risk factors not considered in our study confounded our results. Impaired endothelium-dependent vasodilatation has been demonstrated in hypertension,15 28 29 30 hyperlipidemia,16 and smoking.31 32 Although all of these risk factors were not different in our subgroups, conceivably other factors, such as hyperuricemia or hyperhomocyst(e)inemia, were responsible.33
Our study was based on the assumption that there is a pathophysiological relationship between functional endothelial disturbances and structural changes in the vessel wall. Endothelial functional alterations would thereby precede structural changes. Such a hypothesis has been advanced by us10 and others2 ; however, the relationship is complex. First, it is no surprise that the effects of age on intima-media thickness were overriding. Second, endothelial dysfunction and intima-media thickness frequently coincided in our study population. Nevertheless, in 29 subjects, endothelial function had decreased while intima-media thickness had not yet increased. Seven of these subjects had elevated fasting glucose values. Our numbers are too small to draw firm conclusions about this subgroup. It is possible that genetic background or other risk factors influence this relationship. We suggest that these subjects will develop increased intima-media thickness in the future and have not discarded our hypothesis that endothelial dysfunction precedes intima-media thickening. Finally, we concede that the vascular beds in which postischemic, endothelium-dependent vasodilatation and intima-media thickness were measured were different. We recognize the fact that the radial artery has a far lower propensity to develop arteriosclerosis than does the carotid artery and that the reasons for this discrepancy are not clear.
We are aware that our noninvasive methods have limitations. We measured postischemic vasodilatation and interpreted the dilatation as being principally the result of NO release; however, other mediators, such as changes in hydrogen ion concentration or metabolites produced in response to ischemia, could also have been involved. However, invasive studies relying on intra-arterial infusions of NG-monomethyl-L-arginine and direct measurements of forearm blood flow support our conclusion that flow increases in response to ischemia are primarily NO mediated.34 Intra-arterial NG-monomethyl-L-arginine reduced the peak hyperemic flow in response to ischemia substantially, indicating that NO production is primarily important and thus, supporting the notion of endothelial dependence.
In conclusion, our findings underscore the importance of impaired carbohydrate metabolism as reflected by high fasting glucose values on vascular function and structure. High fasting glucose values had an impact on both postischemic, endothelium-dependent vasodilatation and intima-media thickness and appeared to be a better indicator than were 2-hour postprandial glucose concentrations. Although we found numerous subjects who had impaired postischemic, endothelium-dependent vasodilatation but normal intima-media thickness, no subject who had normal postischemic, endothelium-dependent vasodilatation also had increased intima-media thickness. When simultaneously considering the fasting glucose values, we found that no subject with high fasting glucose had normal postischemic, endothelium-dependent vasodilatation, and most had a high intima-media thickness.
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Acknowledgments |
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This study was supported by an educational grant from Bayer, Wuppertal, Germany.
Received July 21, 1998; accepted September 7, 1998.
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