(Hypertension. 2000;36:245.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Close Relationship of Abnormal Glucose Tolerance With Endothelial Dysfunction in Hypertension
From the Department of Internal Medicine, Divisions of Cardiology (H. Tomiyama, M.A., H. Yoshida, N.D.) and Endocrinology (R.O.), and Department of Central Laboratory (Y. Kimura, S.K., T. Kinouchi), Teikyo University School of Medicine, Ichihara Hospital; Department of Cardiology, Surugadai Nihon University Hospital (T. Kushiro); and Third Department of Internal Medicine, Chiba University School of Medicine (Y. Kuwabara), Chiba, Japan.
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Abstract |
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Abstract—Hypertension is frequently accompanied by left ventricular hypertrophy, endothelial dysfunction, and abnormal glucose metabolism. However, no study has examined the relative pathological significance of left ventricular hypertrophy and abnormal glucose metabolism on endothelial dysfunction in hypertension. This study was conducted to evaluate whether abnormal glucose tolerance assessed by 75-g oral glucose tolerance test or left ventricular hypertrophy is more closely associated with endothelial dysfunction in never-treated hypertensive patients without elevated fasting blood glucose. We studied 107 unmedicated hypertensive patients (mean age, 54±10 years) whose fasting blood glucose was <7.0 mmol/L. Endothelial function was assessed by change in brachial artery diameter in response to reactive hyperemia, and left ventricular mass index was determined by ultrasonography. Simple linear regression analysis demonstrated that endothelial function significantly correlated with left ventricular mass index and 2-hour blood glucose in 75-g oral glucose tolerance test, but not with fasting blood glucose. Multiple linear regression analysis revealed that endothelial function significantly correlated with 2-hour blood glucose (ß=-2.68, P<0.05) after we controlled for other clinical variables. Patients were divided into 3 groups according to 2-hour blood glucose levels. Endothelial function was more impaired in patients with diabetes (n=12; 4.7±1.8%) and in those with impaired glucose tolerance (n=31; 6.3±2.9%) than in those with normal glucose tolerance (n=64; 8.4±4.5%) (P<0.05), but left ventricular mass index was similar in these 3 groups. Abnormal glucose tolerance assessed by 75-g oral glucose tolerance test, rather than left ventricular hypertrophy, may have direct pathophysiological relevance to endothelial dysfunction in borderline to moderate hypertensive patients.
Key Words: hyperglycemia • hypertrophy, left ventricular • endothelium • glucose
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Introduction |
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Endothelial dysfunction is a feature of early stage atherosclerosis1 and is associated with cardiovascular risk.2 Recently, the probability of this abnormality as a risk marker or surrogate end point in the management of cardiovascular disease has been discussed.3 In hypertension, an association between left ventricular hypertrophy, which is an independent predictor of cardiovascular morbidity and mortality,4 and endothelial dysfunction has been reported in patients with hypertension.5 On the other hand, abnormal glucose metabolism (especially the early stage of abnormal glucose metabolism) frequently accompanies hypertension, and this association is well documented as the insulin resistance syndrome.6 Endothelial dysfunction is recognized even in the early stage of abnormal glucose metabolism.7 Except in cases of overt hyperglycemia, the 75-g oral glucose tolerance test (OGTT) is a standard method to assess abnormalities of glucose metabolism, and recent reports reinforced the clinical importance of the 75-g OGTT for detecting the attributable risks for cardiovascular events.8 While hypertension is linked pathophysiologically with left ventricular hypertrophy and abnormal glucose metabolism in different manners,4 9 no study has ever examined the clinical significance of hypertension-associated early-stage abnormal glucose tolerance assessed by 75-g OGTT on endothelial dysfunction.
We evaluated endothelial function, left ventricular mass, and glucose metabolism in patients with borderline to moderate hypertension without diabetic fasting plasma glucose and determined the relationships of abnormal glucose tolerance assessed by 75-g OGTT and left ventricular hypertrophy with endothelial dysfunction.
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Methods |
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Patients
We studied 107 consecutive ambulatory Japanese patients with borderline to mild hypertension (59 men, 48 women; mean age, 54±10 years) who visited Teikyo University School of Medicine, Ichihara Hospital, between April 1997 and June 1999. Inclusion criteria were as follows: no history of treatment with antihypertensive medications; evaluable ultrasonographic recordings of the heart, carotid artery, and brachial artery; and an average systolic blood pressure between 140 and 180 mm Hg and an average diastolic pressure between 90 and 105 mm Hg during 3 consecutive visits before the study. Patients with secondary hypertension, other serious medical problems requiring specific treatments, or fasting plasma glucose
7.0 mmol/L were excluded
from the study.
Study Protocol
The study protocol was approved by the Ethics Committee of
Teikyo University School of Medicine, Ichihara Hospital. Written
informed consent was obtained from all patients. Each patient underwent
echocardiography, ultrasonographic examination of
the carotid arteries, assessment of brachial
endothelial function, and 75-g OGTT. The procedures
were in accordance with institutional guidelines.
Ultrasonographic Examinations of the Heart and the Carotid
Arteries
Guided by 2-dimensional echocardiography,
M-mode echocardiograms were obtained with the use of a Sonolayer system
(SSH-160A, Toshiba Co) equipped with a 2.5-MHz or a 3.75-MHz
transducer. Data were printed on a strip-chart recorder at a speed
of 50 mm/s. The mean of 2 M-mode measurements determined by 2
investigators (H.T. and Y. Kimura) was used. The left
ventricular mass index (LVMI) was calculated by the method
of Devereux and Reicheck,10 which is the left
ventricular mass divided by the body surface area.
After the echocardiographic examination, imaging of both carotid arteries was performed with the use of an ultrasonographic system (SSH-160A, Toshiba) equipped with a 7.5-MHz transducer. Guided by 2-dimensional ultrasonography, end-diastolic far wall thickness and end-diastolic and peak-systolic internal dimensions were obtained on the basis of the means from 3 cardiac cycles of measurements from M-mode images of the right and the left common carotid arteries. Carotid arterial distensibility was calculated as previously described.11 Plaque was measured in B-mode images, and the plaque score was determined.12
Brachial Endothelial Function Test
The brachial endothelial function test, a
modified version of the method of Celermajer et al,13 14
has been described previously. Briefly, an ultrasonographic system
(SSH-160A, Toshiba) equipped with a 7.5-MHz transducer was used to
image the brachial artery of the dominant arm. In the long-axis view, a
straight segment (1 cm) of the brachial artery immediately above the
antecubital fossa was used in the study. M-mode tracings were obtained
together with simultaneous electrocardiographic
recordings with the use of a strip-chart recorder. After
baseline recordings were obtained, the percent change in the
diameter of the brachial artery in response to reactive
hyperemia (the cuff was inflated at the upper arm to 20
mm Hg above systolic blood pressure for 5 minutes) or to the
administration of glyceryl trinitrate was determined. For each patient,
the internal diameter of the brachial artery was measured by 2
observers (H.T. and Y. Kimura).
Oral Glucose Tolerance Test
An OGTT was performed in the morning after a 12-hour overnight
fast. Blood samples were drawn before and 30, 60, and 120 minutes after
ingestion of a solution containing 75 g of glucose, and blood
glucose and plasma insulin levels were determined.
Laboratory Measurements
Blood glucose levels were determined with the use of a
Glucoroder SX Analyzer (A & T). Plasma
triglycerides, total cholesterol, and HDL
cholesterol levels were measured enzymatically with a
Hitachi 731 Analyzer. Plasma insulin level was determined by
radioimmunoassay (SRL).
Statistical Analysis
Data are expressed as the mean±SD. Statistical analysis
was performed with the SPSS software package (SPSS Inc).
Univariate linear regression analysis and standard
t test were used to evaluate the relationships between
endothelial function and other clinical variables.
Multiple linear regression analysis was performed to evaluate
interaction and independent correlation between these variables. To
test interaction effect, a product term was introduced among the
independent variables. For example, if the interaction involving
gender and LVMI was of interest, one model to consider was the
following:
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The hypothesis ß12=0 was tested by partial F test. If it was rejected, we considered that there was no interaction effect between LVMI and gender.
In 2-group comparisons, the independent sample t test with
Levene’s test for equality of variance was used. In 3-group
comparisons, 1-way ANOVA or cross-table 
2 test
was performed. For multiple comparisons, Scheffé’s method or
Bonferroni’s method was performed to identify the individual
difference. A value for 2-tailed P<0.05 was accepted as
statistically significant.
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Results |
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Of the 107 patients, 43 had borderline hypertension and 64 had mild or moderate hypertension. Table 1 summarizes the clinical characteristics of all the patients.
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Table 2 depicts the association of the percent change in diameter of the brachial artery in response to reactive hyperemia or administration of glyceryl trinitrate with other continuous clinical variables tested by univariate linear regression analysis. Age, LVMI, and 2-hour blood glucose in 75-g OGTT (2-hour BG) significantly correlated with the percent change in diameter of the brachial artery in response to reactive hyperemia. Student’s t test for dichotomous variables demonstrated that the percent change in diameter of the brachial artery in response to reactive hyperemia was similar irrespective of gender or smoking habit (male [n=59], 7.3±4.1% and female [n=48], 7.4±4.1%; with smoking [n=35], 7.1±4.8% and without smoking [n=72], 7.6±3.7%).
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The regression coefficient between the percent change in the diameter of the brachial artery in response to reactive hyperemia and LVMI was -0.24 for male and -0.17 for female. The interaction effect of gender on the correlation was tested with a regression model by introducing a product term, such as genderxLVMI. The statistical test showed no interaction effect by gender. Similarly, smoking habit or gender had no significant interaction effect on the relation between the percent change in diameter of the brachial artery in response to reactive hyperemia and 2-hour BG or LVMI.
Independent association of LVMI and 2-hour BG with the percent change in diameter of the brachial artery in response to reactive hyperemia was assessed by multiple regression analysis after we controlled for age, blood pressure, total cholesterol and triglycerides, and smoking habits (Table 3). Multivariate analysis revealed that 2-hour BG independently correlated with the percent change in diameter of the brachial artery in response to reactive hyperemia. In contrast, LVMI was no more associated with the percent change in diameter of the brachial artery in response to reactive hyperemia. Furthermore, in a multiple regression analysis with a model containing both 2-hour BG and LVMI as independent variables for the percent change in diameter of the brachial artery in response to reactive hyperemia, only 2-hour BG was a significant variable (ß=-0.26, P=0.03).
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When the hypertensive patients were divided into a group with normal
fasting blood glucose (<6.0 mmol/L; n=89) and a group with
impaired fasting blood glucose (6.0 mmol/L) (n=18), the change
in diameter of the brachial artery in response to reactive
hyperemia was 7.5±3.8% in the former and 7.1±5.2% in the
latter. Thus, endothelial function was similar in both
groups. Then, the patients were classified by 75-g OGTT into a normal
glucose tolerance group (2-hour BG <7.8 mmol/L), an impaired
glucose tolerance group (7.8
2-hour BG <11.1 mmol/L), and a
diabetes group (2-hour BG 11.1 mmol/L).8 Table 4 shows the results of comparison of
clinical variables among hypertensive subjects with normal glucose
tolerance, impaired tolerance, and diabetes. The percent change in
diameter of the brachial artery in response to reactive
hyperemia was significantly impaired in hypertensive subjects
with impaired glucose tolerance compared with those with normal glucose
tolerance, and this impairment was significantly more prominent in
hypertensive subjects with diabetes than in those with impaired glucose
tolerance. In addition, in 1-way ANOVA with Scheffé’s method,
plaque score was higher in patients with diabetes (1.5±1.6) than in
those with impaired glucose tolerance (0.5±1.0) (P<0.05).
LVMI and age were similar in the 3 hypertensive subgroups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In hypertension, an elevated blood pressure induces left ventricular hypertrophy to compensate for increased wall stress4 and also impairs endothelial function by increasing shear stress.15 In this context, an association between these 2 pathophysiological abnormalities has been reported.5 In subjects with abnormal glucose metabolism, hyperglycemia also impairs endothelial function.16 Thus, either elevation of blood pressure or impaired glucose metabolism can directly affect endothelial function. To our knowledge, this is the first study to examine whether left ventricular hypertrophy or abnormal glucose metabolism is more closely associated with endothelial dysfunction in hypertensive patients.
In the present study, multiple linear regression analysis demonstrated a significant relationship between endothelial dysfunction and 2-hour BG but no significant correlation between endothelial function and elevated blood pressure level or increased left ventricular mass. Hypertensive patients were divided into 3 groups according to the 75-g OGTT values. Endothelial function was significantly more impaired in patients with glucose intolerance or diabetes than in those with normal glucose metabolism. Age, blood pressure, and LVMI were similar in these 3 subgroups. Therefore, in the setting of untreated borderline to moderate hypertension without elevated fasting blood glucose, the accompanying early-stage abnormal glucose metabolism assessed by 75-g OGTT, rather than left ventricular hypertrophy, may have a close pathophysiological relation with the impairment of endothelial function.
The American Diabetes Association dismissed the use of OGTT and recommended using impaired fasting glucose instead of impaired glucose tolerance as the diagnostic criterion of diabetes.17 However, the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study demonstrated that 75-g OGTT provides additional information for the prognosis of diabetes.8 The results in the present study demonstrated that 2-hour BG is a better index than fasting blood glucose for evaluating endothelial dysfunction in cases complicated with hypertension. Recently, Kawano et al18 demonstrated that acute postprandial hyperglycemia suppresses endothelium-dependent vasodilatation, and our results support their notion that prolonged and repeated postprandial hyperglycemia may contribute to the development and progression of atherosclerosis.
In addition to the role in controlling high blood pressure, left ventricular mass is a risk marker or a surrogate end point in the management of hypertension.4 On the other hand, interventions to correct abnormal glucose metabolism or endothelial dysfunction have not been regarded as additional surrogate end points in the management of hypertension. Although all the patients in the present study had either normal or early-stage abnormal glucose metabolism (because patients with overt diabetes mellitus were excluded from the study), endothelial dysfunction was prominent in patients with either glucose intolerance or diabetes, and atherosclerotic plaques in carotid artery were already evident in patients with diabetes. Suzuki et al19 reported that insulin resistance is an independent risk factor for carotid arterial sclerosis in hypertension. In addition to confirming their results, the present study also demonstrated that vascular functional damage, which is a key factor for the progression of atherosclerosis, is evident in hypertensive patients with even early-stage abnormal glucose metabolism. Therefore, the present study proposes the importance of conducting further studies to clarify whether interventions for early-stage abnormal glucose metabolism or endothelial dysfunction are beneficial in preventing progression of cardiovascular abnormalities.
Limitations
The impairment of endothelial function has been
demonstrated in patients with either hypertension or abnormal glucose
metabolism.2 18 20 On the other hand, some
studies have demonstrated that insulin resistance is associated with
endothelial dysfunction independent of blood pressure
level.21 22 These findings lead to a hypothesis that
elevated blood pressure and abnormal glucose level synergistically
contribute to endothelial dysfunction. According to our
previous report,14 the percent change in diameter of the
brachial artery in response to reactive hyperemia in
hypertensive patients with normal glucose tolerance (8.4±4.5%) was
significantly lower than that in 25 age-matched healthy volunteers
(11.6±2.3%) (14 men and 11 women; mean age, 52±12 years)
(P<0.01). While we did not perform 75-g OGTT for these
healthy volunteers, this result agrees with a synergetic contribution
of elevated blood pressure and abnormal glucose metabolism
to endothelial dysfunction. Further studies are needed
to determine whether elevated blood pressure and abnormal glucose
metabolism synergistically contribute to
endothelial dysfunction.
Conclusion
In patients with borderline to moderate hypertension, hypertension
associated with impaired glucose tolerance assessed by 75-g OGTT is
closely related to endothelial dysfunction,
irrespective of the presence or absence of left ventricular
hypertrophy. This close relation may play some roles in the
progression of cardiovascular abnormalities in
untreated hypertensive patients.
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Acknowledgments |
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We appreciate Chikako Koide for assistance in data collection and also appreciate Dr Teresa Nakatani for assistance in English translation.
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Footnotes |
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Reprint requests to Hirofumi Tomiyama, MD, Division of Cardiology, Department of Internal Medicine, Teikyo University School of Medicine, Ichihara Hospital, 3426-3 Anezaki, Ichihara, Chiba, Japan 299-0111.
Received October 29, 1999; first decision November 26, 1999; accepted March 6, 2000.
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References |
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|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Quyyumi AA. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med. 1998;105:32S–39S.[Medline] [Order article via Infotrieve]
2. Pinkney JH, Stehouwer CDA, Coppack SW, Yudkin JS. Endothelial dysfunction: cause of insulin resistance syndrome. Diabetes. 1997;46:S9–S13.
3. Elliot HL. Endothelial dysfunction in cardiovascular disease: risk factor, risk marker, or surrogate end point? J Cardiovasc Pharmacol.. 1998;32:S74–S77.
4. Frohlich ED, Apstein C, Chobanian AV, Devereux RB, Dustan HP, Dzau V, Fauad-Tarazi F, Horan MJ, Marcus M, Massie B. The heart in hypertension. N Engl J Med. 1992;327:998–1008.[Medline] [Order article via Infotrieve]
5.
Perticone F, Maio R, Ceravolo R, Cosco C, Cloro C,
Mattioli PL. Relationship between left ventricular mass and
endothelium-dependent vasodilation in never-treated
hypertensive patients. Circulation. 1999;99:1991–1996.
6. Ferrannini E, Buzzigoli G, Bonnadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350–357.[Abstract]
7. Guzman CB, Sowers JR. Special considerations in the therapy of diabetic hypertension. Prog Cardiovasc Dis. 1999;41:461–470.[Medline] [Order article via Infotrieve]
8. The DECODE Study Group on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet. 1999;354:617–621.[Medline] [Order article via Infotrieve]
9. Fagan TC, Deedwania PC. The cardiovascular dysmetabolic syndrome. Am J Med. 1998;105:77S–82S.[Medline] [Order article via Infotrieve]
10.
Devereux RB, Reicheck N.
Echocardiographic determination of left
ventricular mass in man: anatomic validation of the method.
Circulation. 1977;55:613–618.
11. Tomiyama H, Kimura Y, Sakuma H, Shiojima K, Yamamoto A, Saito I, Ishikawa Y, Yoshida H, Dona N. Effects of an ACE inhibitor and a calcium channel blocker on cardiovascular autonomic nervous system and carotid distensibility in patients with mild to moderate hypertension. Am J Hypertens. 1998;11:682–689.[Medline] [Order article via Infotrieve]
12.
Handa N, Matsumoto M, Maeda H, Hougaku H, Ogawa S,
Fukunaga R, Yoneda S, Kimura K, Kamada T. Ultrasonic evaluation of
early carotid atherosclerosis. Stroke. 1990;21:1567–1572.
13. Celemajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE, Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.[Medline] [Order article via Infotrieve]
14.
Tomiyama H, Kimura Y, Mitsuhashi H, Kinouchi T, Yoshida
H, Kushiro T, Doba N. Relationship between endothelial
function and fibrinolysis in early hypertension.
Hypertension. 1998;31:321–327.
15.
Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JY.
Mechanotransduction in response to shear stress: roles of receptor
tyrosine kinases, integrins, and Shc. J Biol Chem. 1999;274:18393–18400.
16.
Makimattila S, Virkamaki A, Groop PH, Cockroft J,
Utriainen T, Fagerudd J, Yki-Jarvinen H. Chronic hyperglycemia impairs
endothelial function and insulin sensitivity via
different mechanisms in insulin-dependent diabetes mellitus.
Circulation. 1996;94:1276–1282.
17. American Diabetes Association. Report of expert committees on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20:1183–1197.[Medline] [Order article via Infotrieve]
18.
Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y,
Sakamoto T, Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly
suppresses flow-mediated endothelium-dependent
vasodilation of brachial artery. J Am Coll Cardiol. 1999;34:146–154.
19.
Suzuki M, Shinozaki K, Kanazawa A, Hara Y, Hattori Y,
Tsushima M, Harano Y. Insulin resistance as an independent risk factor
for carotid wall thickening. Hypertension. 1996;28:593–598.
20. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level. J Am Coll Cardiol. 1994;23:1610–1616.[Abstract]
21.
Petrie JR, Ueda S, Webb DJ, Elliott HL, Connell JM.
Endothelial nitric oxide production and insulin
sensitivity: a physiological link with implications
for pathogenesis of cardiovascular disease.
Circulation. 1996;93:1331–1333.
22. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest. 1996;97:2601–2610.[Medline] [Order article via Infotrieve]
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