Hypertension and non insulin-dependent diabetes mellitus (NIDDM) are well-known risk factors for atherosclerotic disease. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may exert a relevant role in the pathogenesis of atherosclerosis; their prognostic relevance has been recently demonstrated. The aim of the study was to investigate possible inter-relation between circulating adhesion molecule levels, carotid artery structure and endothelial function in 15 patients with NIDDM, as well as in 15 patients with both NIDDM and essential hypertension (NIDDM+EH) compared with 15 normal subjects (NS) and 15 euglycaemic patients with EH, matched for age, sex and body weight. All subjects were submitted to a biopsy of the gluteal subcutaneous fat. Small arteries were dissected and mounted on a micromyograph, and the media-to-lumen (M/L) ratio was then calculated. Carotid artery structure was investigated by Doppler ultrasound. Endothelial function was evaluated by investigation of the flow-mediated dilatation (FMD) of the brachial artery. ICAM-1 and VCAM-1 plasma levels were measured by ELISA. ICAM-1 and VCAM-1 plasma levels were significantly greater and FMD smaller in EH, NIDDM and NIDDM+EH than in NS, but no difference was observed among the three pathological groups. Carotid artery structural changes were more pronounced in NIDDM+EH. No significant difference was observed among NIDDM, EH and NS. The M/L ratio of subcutaneous small resistance arteries was significantly greater in NIDDM+EH than in NIDDM or EH. NS had a smaller M/L ratio than the other groups. Significant correlations were observed between ICAM-1 plasma levels and indices of carotid artery structure in diabetic patients. However, the relations were close only in NIDDM+EH. In conclusion, our data suggest that NIDDM+EH may present more pronounced vascular structural alterations than NIDDM, and that adhesion molecules plasma levels are closely inter-related with carotid artery structural alterations, at least in NIDDM+EH, but not with M/L ratio of small resistance arteries.
The adhesion of leucocytes to vascular endothelial cells is a critical early step in the initiation of athero-sclerosis. This process is partly mediated by cellular adhesion molecules, expressed on the endothelial membrane.1,2,3 While a transient rolling of leucocytes along endothelium is mediated by selectins, including L and P selectin, stronger attachment of white cells to endothelium is mediated by intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In particular, ICAM-1 (and ICAM-2) bind to the β2 subfamily of integrins (CD 18), expressed on leucocytes,4 and may contribute to the trapping white cells on local vascular walls.5 Increased levels of adhesion molecules have been found both in human hypertension6,7 and in diabetes mellitus.8,9,10,11 It was suggested that adhesion molecule plasma levels may have a prognostic significance in ischaemic heart disease12,13,14,15 as well as in healthy men.16 However, in a study such a prognostic relevance was not confirmed.17 Therefore, this issue remains, at least in part, controversial.18
An impairment of the endothelial function has been observed to be detected in the vasculature of patients with essential hypertension (EH)19,20,21 as well as of patients with non insulin-dependent diabetes mellitus (NIDDM).11,22,23,24 It was also demonstrated that, using a noninvasive, Echo-Doppler technique of assessment of endothelial function (flow-mediated dilatation (FMD) of the brachial artery), the presence of more than one risk factor for cardiovascular diseases (up to five or more) progressively impairs endothelial function.25 However, it is not presently known whether the circulating levels of adhesion molecules are associated with early changes in carotid artery structure in patients with both diabetes and hypertension.
Therefore, the aim of our study was to investigate the possible inter-relations between circulating adhesion molecule levels (ICAM-1 and VCAM-1), carotid artery structure and endothelial function in patients with NIDDM, as well as in patients with both NIDDM and EH (NIDDM+EH).
Patients and methods
A total of 15 patients with NIDDM, 15 NIDDM+EH, together with 15 normal subjects (NS) and 15 euglycaemic patients with EH, matched for age, sex and body weight were included in the study. Their age range was 50–70 years. The presence of hypertension was established according to ISH/WHO Guidelines (average of three different sphygmomanometric measurements, each performed on three separate days, after a wash-out period of at least 2 weeks if previously treated with antihypertensive drugs, >140/90 mmHg and <220/120 mmHg).26 The presence of NIDDM was established according to the Guidelines of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.27 The exclusion criteria were: a duration of NIDDM longer than 10 years, previous antihypertensive therapy with ACE inhibitors, calcium entry blockers or angiotensin II type 1 receptor antagonists for more than 6 months, previous or present administration of insulin, severe ocular complications (fourth stage retinopathy), severe neuropathy (orthostatic hypotension, paralysis of a peripheral nerve), serum creatinine greater than 177 μmol/l or proteinuria greater than 350 mg/24 h, previous myocardial infarction, peripheral arterial disease with claudication, trophic lesions or ulcers. Patients were recruited by the local Diabetologic Unit, screened and sent to our Hypertension Unit. Priority was given to newly diagnosed patients.
Venous blood samples were taken with the participants in the supine position, after a wash-out period of at least 2 weeks, for standard haematology and serum biochemistry tests, including triglycerides and total cholesterol and glycated haemoglobin (HbA1c), In addition, ICAM-1 and VCAM-1 plasma concentrations (ELISA)28 were evaluated.
B-mode imaging of carotid arteries was obtained using a Hewlett-Packard Sonos 5000 echocardiographic unit (Hewlett-Packard, Andover, MA, USA) equipped with a 7.5 MHz. imaging transducer. Subjects were investigated lying in supine position, with slight hyperextension of the neck, and the common carotid artery, the carotid bifurcation and the extracranial portions of internal and external carotid arteries were identified. The average duration of the scanning was 30 min and the entire scanning procedure was recorded on a 1/2 in super VHS videotape. All carotid measurements were subsequently performed by two independent readers, unaware of the subject's identity, echocardiographic measurements and risk factors, and average values were considered; VCR recordings of the entire scanning were analysed using the measure morphometry software of the echo unit.
Measurements included end-diastolic (minimum diameter) intima–media thickness of the far walls (the distance from the leading edge of the first echogenic line to the leading edge of the second echogenic line) as described previously by Pignoli et al.29 Several measures were obtained in each arterial segment6,7,8,9,10,11,12 according to a previously described protocol,30 and the mean value of all measurements on the far wall for each segment was calculated. The thickness of the intima–media layers was measured at end diastole and the mean maximum value was calculated in at least six points, in left and right common carotid artery, carotid bifurcation and internal carotid artery. Wall thickness in the carotid artery was never measured at the level of a discrete plaque.31
FMD of the brachial artery
High-resolution ultrasound was used to measure changes in brachial artery diameter, according to the previously described technique.25,32,33 Ultrasound studies were performed in the morning, after the patients had rested in the supine position for 30 min in a quiet room. It was possible to record good-quality scans using a 7.5 MHz linear array ultrasound probe (HP Sonos 1500 echocardiographic unit; Hewlett-Packard Andover, MA, USA) by a single dedicated physician. Scans of the brachial artery approximately 5 cm above the elbow were obtained in longitudinal section and the transducer was maintained in a fixed position relative to the patient's arm. Arterial flow velocity was measured by means of a pulsed Doppler signal, with the sample volume placed in the centre of the artery. Flow increase was induced by inflation of a blood pressure cuff placed around the arm up to 300 mmHg; after 5 min of arterial occlusion the cuff was deflated. An interval of 20 min was allowed for vessel recovery and sublingual glyceril trinitrate (GTN spray, 400 μg) was administered. Scans were recorded twice at baseline, from 30 s before to 120 s after the release of occlusion (including a flow velocity recording 15 s after cuff release), and from 2 to 4 min after the administration of sublingual GTN. Vessel diameter was measured at end diastole from S_VHS recordings by two observers unaware of the patient's clinical characteristics and treatment. Measurements were taken from the anterior to the posterior ‘m’ line. For the reactive hyperaemia scans diameter measurements were taken from 30 to 90 s after cuff deflation and the greatest diameter was used; four cardiac cycles were averaged for resting scans, reactive hyperaemia and GNT administration. FMD and GTN-induced dilation were determined as the percent diameter change relative to baseline measurements. Brachial blood flow was calculated from Doppler flow velocity measurements. Interobserver and intraobserver coefficient of variation for measurements of FMD were reported elsewhere.33
All participants underwent a biopsy of subcutaneous fat from the gluteal region (3 cm long, 0.5 cm wide and 1.5 cm deep).34
Small arteries (about 100–280 μm of average diameter in relaxed conditions, 2 mm long) were dissected from the subcutaneous fat of the biopsies and mounted as a ring preparation on an isometric myograph (410 A, JP Trading, Aarhus, Denmark), by threading onto two stainless-steel wires (40 μm diameter). The wires were attached to a force transducer and micrometer, respectively, as previously described by Aalkjaer et al34 and Mulvany et al.35 The media-to-lumen (M/L) ratio of the small artery was measured and taken as an index of vascular structure. Details about the micromyographic technique of evaluation of small artery morphology were previously reported.19,24,30,34,35,36
Evaluation of circulating ICAM-1 and VCAM-1
Plasma levels of ICAM-1 and VCAM-1 were quantified by a immunoenzymatic method (Soluble ICAM-1 and VCAM-1 immunoassays, R&D Systems, Minneapolis, MN, USA).28 The assay involves the simultaneous reaction of ICAM-1 or VCAM-1 present in the sample to two antibodies directed against different epitopes on the molecules. One antibody is coated onto the walls of the microtitre wells and the other is conjugated to the enzyme horseradish peroxidase. Any ICAM-1 or VCAM-1 present forms a bridge between the two antibodies. After removal of unbound material by aspiration and washing, the amount of conjugated bound to the well is detected by reaction with a substrate specific for the enzyme which yields a coloured product proportional to the amount of conjugated (and thus ICAM-1 or VCAM-1 in the sample). The coloured product was quantified photometrically. Typical sensitivity of these assays was less than 1 ng/ml.
The protocol of the study was approved by the ethics committee of our institution (Medical School, University of Brescia), and informed consent was obtained from each participant.
All data are expressed as mean±s.e.m., unless otherwise stated. One-way analysis of variance (ANOVA) and Bonferroni's correction for multiple comparisons were used to evaluate differences among groups. The relation between continuous variables was evaluated by linear regression (Pearson's correlation coefficients) and by nonparametric statistics (Spearman's rank correlation coefficients). All analyses were carried out with the BMDP statistical package (BMDP software programs 7D, 8D, IV, 2V 3S, BMDP Statistical Software Inc., Los Angeles, CA, USA).
The demographic, haemodynamic and humoral data are reported in Table 1. As expected, systolic and diastolic blood pressure was significantly higher in EH and in NIDDM+EH than in NIDDM or NS. Fasting glucose, body weight, body surface area, duration of the diseases, serum cholesterol or triglycerides were similar among groups. No signs of renal impairment were observed in any group.
Plasma levels of ICAM-1 and VCAM-1
No significant differences between, respectively, EH, NIDDM and NIDDM+EH were observed in ICAM-1 or VCAM-1 plasma levels (Figure 1). Both ICAM-1 and VCAM-1 plasma levels were significantly greater in EH, NIDDM and NIDDM+EH than in NS.
No difference among groups was observed in the FMD of the brachial artery among EH, NIDDM and NIDDM+EH (Figure 1). FMD of the brachial artery was significantly greater in NS than in the other groups.
Carotid artery structure
Small resistance artery structure
The M/L ratio of subcutaneous small resistance arteries was significantly greater in NIDDM+EH than in NIDDM or EH (Figure 1), thus suggesting the presence of more pronounced structural alterations. NS had a smaller M/L ratio than EH, NIDDM and NIDDM+EH. Additional morphological data were previously reported.11,24
Significant correlations were observed between ICAM-1 plasma levels and indices of carotid artery structure (Figure 3, Table 2). However, the relations were close only in NIDDM+EH (Figure 3, Table 2) and it remained statistically significant even eliminating a single data point on the right side of the graphic. No statistically significant correlation was observed between VCAM-1 plasma levels and indices of carotid artery structure in any group (data not shown). No correlations were observed between M/L ratio of subcutaneous small resistance arteries and plasma levels of adhesion molecules, and between FMD of the brachial artery and indices of carotid artery structure or plasma levels of adhesion molecules.
For the first time, this study has simultaneously evaluated indices of carotid artery structure and circulating levels of adhesion molecules in NIDDM+EH. Significant correlations between ICAM-1 plasma levels and carotid artery intima–media thickness were observed, thus suggesting the presence of inter-relations between adhesion molecules and early structural alterations in the carotid artery, with possible relevant clinical consequences in terms of evolution into overt atherosclerotic lesions.
Carotid artery structure and adhesion molecules
In previous studies, a direct link between carotid artery structure and circulating levels of adhesion molecules was observed. In the ARIC study,15 higher circulating levels of ICAM-1 were observed in patients with carotid artery atherosclerosis, compared with control subjects. Similarly, Mocco et al37 has observed increased levels of ICAM-1 in patients with carotid artery stenosis, compared with control subjects. Very recently, in a study of van der Meer I et al38 performed in a general population, ICAM-1 levels were strongly associated with carotid plaques, while VCAM-1 was not significantly associated with any measure of atherosclerosis. However, Blann et al39 were unable to observe any correlation between ICAM-1 and percent stenosis of the carotid artery in patients either with transient ischaemic attack or intermittent claudication. Otsuki et al40 could observe a positive correlation between plasma VCAM-1 concentrations and intima–media thickness of the carotid arteries in NIDDM. In addition, no correlation between VCAM-1 levels and carotid artery structure was observed in nondiabetic patients with atherosclerotic lesions.40 Higher levels of VCAM-1 were present in NIDDM with atherosclerotic lesions compared with NIDDM with normal carotid arteries.40 These studies therefore generally suggest a possible link between adhesion molecules and carotid artery structural alterations in several pathological conditions.
Diabetes, carotid artery structure and adhesion molecules
In our study, a significant correlation between indices of carotid artery structure was present only in NIDDM+EH, thus suggesting that the simultaneous presence of the two risk factors is more important than the presence of NIDDM alone in this regard. In fact, the cohorts with just one risk factor have a nearly normal carotid artery structure, while those patients in which both risk factors are present, have a more pronounced vascular disease. It is possible that the observed correlation merely reflects a more advanced atherosclerotic disease in NIDDM+EH. This may be linked to the synergistic deleterious effects of diabetes mellitus and hypertension on vascular structure, as evidenced by the presence of more pronounced structural alterations of the carotid artery and of subcutaneous small resistance arteries in this group. It cannot be completely excluded that NIDDM+EH may have had a longer duration of hyperglycaemia and/or a poorer diabetes of blood pressure control, albeit no difference in blood pressure or in HbA1c among the groups was observed.
Small artery structure and adhesion molecules
No significant correlation was observed between ICAM-1 and M/L ratio of subcutaneous small arteries, thus suggesting that the determinants of large or small artery structure are different. In fact, atherosclerotic lesions are present only in large- and mid-sized arteries, while small arteries may experience eutrophic or hypertrophic remodelling.
Diabetes and endothelial dysfunction
In our study, no additive effect of the simultaneous presence of diabetes and hypertension on endothelial dysfunction was observed. It was previously demonstrated that hypertensive patients33 and NIDDM22,23 separately show the presence of an impairment of endothelial function as evaluated with FMD in the brachial artery. In another study, the presence of more than one cardiovascular risk factor induced a progressive reduction of FMD in the brachial artery, suggesting a synergistic effect of the different risk factors;25 however, no good explanation of these conflicting results may be directly derived from our data.
In our study, no significant correlation was observed between FMD of the brachial artery and indices of carotid artery structure or between FMD of the brachial artery and circulating adhesion molecules. We have previously demonstrated that no significant correlation is present between indices of endothelial function obtained in vitro (maximum relaxation to acetylcholine of bradykinin in subcutaneous small arteries) and circulating levels of ICAM-1 and VCAM-1.11 The pathophysiological functions of the vascular endothelium are diverse and complex, and the different endothelial functions (vasomotion, cell adhesion, platelet aggregation, etc) may not be simultaneously and equally impaired. Evaluation of endothelial production of ICAM-1 gives therefore important information about a critical early step in the development of an inflammatory response, possibly leading to vascular damage, while endothelium-dependent vasodilator responses seem to be less important in this regard.
In conclusion, our data suggest that NIDDM+EH may present more pronounced vascular structural alterations than NIDDM, and that adhesion molecules plasma levels are closely inter-related with carotid artery structural alterations, at least in NIDDM+EH, but not with the M/L ratio of small resistance arteries.
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Rizzoni, D., Muiesan, M., Porteri, E. et al. Circulating adhesion molecules and carotid artery structural changes in patients with noninsulin-dependent diabetes mellitus. J Hum Hypertens 17, 463–470 (2003). https://doi.org/10.1038/sj.jhh.1001570
- diabetes mellitus
- carotid artery
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