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Relationship Between Endothelial Dysfunction, Intima Media Thickness and Cardiovascular Risk Factors in Asymptomatic Subjects

Posted on: Wednesday, 10 August 2005, 03:01 CDT

Aim. The aim of the study was to evaluate endothelial function and intima media thickness (IMT) in relation to cardiovascular risk factors (RF).

Methods. We enrolled 113 patients, mean age 6212 years; patients underwent: anamnesis, physical examination, measurement of body weight and height and blood pressure. Biochemistry variables were also measured: total cholesterol, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), triglycerides and glycemia. Vascular echography was performed to analyze flow mediated vasodilatation (FMD) at the brachial artery and IMT of the carotid and femoral arteries.

Results. Compared with patients without RF, patients with cardiovascular RF showed an impaired FMD (p<0.05) and higher values of mean carotid IMT (p=0.03). Age (p<0.005) and diabetes (p<0.05) were directly correlated with carotid IMT, while femoral IMT is correlated with age (p<0.005) and male gender (p<0.02). Regarding the relationship between endothelial function cardiovascular RF, we showed an inverse linear correlation between systolic blood pressure (p<0.005), smoking (p<0.05) and FMD, and concerning biochemical parameters, we founded that total cholesterol (p<0.05) and LDL-C plasma levels (p<0.005) were inversely correlated with FMD. Finally, we showed a lower FMD in patients with carotid and femoral IMT in comparison with patients without peripheral atherosclerosis (p=0.01).

Conclusion. The present data indicate that cardiovascular RF are associated with impaired endothelial function and increased IMT, and that the presence of carotid and femoral IMT is significantly correlated with endothelial dysfunction.

[Int Angiol 2005;24:52-8]

Key words: Atherosclerosis - Risk factors - Ultrasonography, Doppler - Endothelium, physiology.

Endothelial dysfunction is considered an early event in the development of atherosclerosis, reflecting a functional change that occurs before the morphological changes.1, 2

In recent years, a variety of methods have been developed to assess endothelial function; some of these are based on invasive procedures such as strain-gauge plethysmography, and others are based on non invasive techniques such as vascular ultrasound.3 For measurement of endothelial function in a large population, the vascular ultrasound method, proposed by Celermajer et al.,3 appears practical because of its non invasive nature, its brief duration, its repeatability and its low variability. Major risk factors for atherosclerotic vascular disease (e.g., hypertension, diabetes, smoking, hypercholesterolemia, and obesity),4-7 have been associated with endothelial cell dysfunction, and it is now well established that coronary atherosclerosis is characterized by an early loss of endothelial-dependent vasodilation.

Several epidemiological studies and clinical trials have used the measurement of intima media thickness (IMT) at the common carotid artery (CCA), obtained by non invasive high-resolution B-mode ultrasonography, as an early marker of systemic atherosclerosis. The evaluation of the carotid artery wall with this methods is inexpensive, highly reproducible and without risks.8

An increased IMT of the carotid artery wall is thought to be an early marker of atherosclerosis. Several studies have suggested an association between extracranial carotid artery disease and the incidence of coronary heart disease (CHD): 1) patients with transient ischemic attack are most likely to die from CHD; 2) atherosclerosis of the extracranial carotid arteries is correlated with atherosclerosis of coronary arteries; 3) risk factors (RF) for extracranial carotid atherosclerosis are also risk factors for CHD;9 4) there is an association between IMT and CHD and/or stroke.10-12 Since endothelial dysfunction and increased IMT are interrelated, but indicative of different aspects of the atherosclerotic process, their early detection could have implications in highly directed and strong primary prevention. Some studies have related endothelial dysfunction and carotid IMT,13 in patients with demonstrated atherosclerosis or coronary disease. The aim of this study is to analyze whether peripheral endothelial function and carotid and femoral IMT are impaired in patients with coronary risk factors.

Materials and methods

We enrolled 113 subjects (89 male, 24 female), mean age 6212 years, admitted consecutively between 2001 and 2002 to the Department of Cardiovascular Diseases. At baseline, all patients were asymptomatic from cardiovascular and cerebrovascular events. All patients after giving a complete medical history underwent a clinical and physical examination with measurements of height, body weight, blood pressure in the sitting position, a fasting lipid profile and fasting blood glucose.

Body mass index (BMI) was obtained using the following formula: weight in kg/square of height in cm. Family history of coronary artery disease was also assessed. Patients were classified as either never or ever smokers. Hypertension was defined when the patient declared a history of high blood pressure and a resting blood pressure > 140/90 mmHg, or the use of antihypertensive medications. Dyslipidemic patients were defined as those with a diagnosis of dyslipidemia, documented by fasting serum cholesterol values above 200 mg/dL or low-density lipoprotein cholesterol (LDL-C) values above 160 mg/dL, or patients under treatment with lipid-lowering drugs. Diabetes was diagnosed if fasting blood sugar was >126 mg/dL or the patient was taking an oral hypoglycemic agent or insulin.

B-mode real-time ultrasound (Toshiba, model 270 SS) was used to evaluate IMT in the carotid arteries using a probe of 7.5-10.0 MHz. Based on the studies of Pignoli et al.14 patients were examined in the supine position, and each carotid wall and segment was examined to identify the thickest intimal-medial site. Each scan of the common carotid artery began just above the clavicle, and the transducer was moved cephalad past the bifurcation and along the internal carotid artery. Three segments were identified on each side: the most distal 1 cm of the common carotid being most proximal to the bifurcation, the bifurcation itself, and the proximal 1 cm of the internal carotid artery. The mean of the 3 measurements of IMT in each patient was calculated. The mean carotid maximal IMT in our patients was 1.20.2 mm. In case of missing data at any of the 3 measurements, the mean IMT of the available values was calculated. We have also evaluated the arterial wall thickness in the femoral arteries. The femoral artery was examined distally to the inguinal ligament, at the site where the artery divides into the superficial femoral artery and the profunda femoris artery. The mean carotid maximal IMT in our patients was 1.30.4 mm.

Endothelial function was evaluated according to recent guidelines by ultrasound using a 7.5-MHz linear-array transducer.15 Patients were asked not ingest substances that might affect flow mediated dilatation (FMD) such as caffeine, or use tobacco for at least 6 h before the study. All vasoactive medications were withdrawn for at least 4 half-lives, if possible. The subjects have been studied in a quiet, temperature-controlled room, in supine position. Patients remained in the supine position for at least 10 min before the study and were kept in this position during the procedure. The artery was scanned 3 to 5 cm above the elbow, the site where the clearest image can be obtained. The focus zone was set to the depth of the anterior vessel wall. Depth and gain settings were optimized to identify the lumen-vessel wall interface. The diameter of the brachial artery was measured from the anterior to the posterior interface.

We evaluated the variation of the diameter of the brachial artery at baseline, using high-resolution ultrasound, and after arterial occlusion for 5 min through cuff inflation to at least 50 mmHg above the systolic pressure. The flow-mediated vasodilator response to reactive hyperemia was continuously recorded from 30s before to 5 min after cuff deflation. Reactive hyperemia (change in flow velocity) was measured when compression was released, and the new arterial diameter and flow velocity were measured 1 min later. The percent change between the diameter at release of compression (D2) and the baseline diameter (D1) is the socalled endothelium dependent vasodilation (EDV).

TABLE I.-Clinical characteristics and laboratory in patient's male, female e total population.

Thus: EDV=[(D2-D1)/D1] . 100. Ten minutes later, when the artery returned to baseline, 300 mg of nitroglycerine was administered and 4 min later the arterial diameter was again measured. The percent change between the postnitroglycerine diameter (D3) and the baseline value (D1) is the so-called endothelium-independent vasodilation or nitroglycerine-mediated vasodilation (NitroMV). Thus: NitroMV=[(D3- D1)/D1] . 100.

Statistical analysis

Statistical analyses was performed using the Stat view Program (Abacus Concepts Inc.). Means and standard deviations were calculated and the differences were analyzed using the Student's ttest. The differences between nominal statistic variables were analyzed by the χ^sup 2^ test. Statistical significance was considered to be achieved when differences between groups had P values less than 0.05. Correlation between con\tinuous variables was analyzed using Pearson's correlation coefficient. A multivariate analysis was performed in order to determine which variables were associated with an improvement in endothelial function and carotid and femoral IMT. In the analysis plasma levels of cholesterol, LDL- C, triglycerides, age, BMI, presence of smoking habit or hypertension, diabetes, were entered as independent variables.

Results

A total of 19 patients (17%) did not have any coronary risk factor, 14 patients (12%) had one risk factor and 80 (70%) patients had more than one risk factor. Among the 68 hypertensive patients 83% were receiving treatment with antihypertensive drugs; the drug most frequently used were diuretics (45%), b-blockers (14%), angiotensin-converting enzyme (ACE) inhibitors (15%), angiotensin II receptor antagonists (ARA II) (19%) and calcium entry blockers (7%). In the subgroup of 33 dyslipidemic patients, 24% were receiving treatment with statins, 22% were under dietary control, and 54% were untreated (80% of these had been recently diagnosed).

Regarding the traditional cardiovascular risk factors, there was a higher prevalence of hypertension (64% vs 44%, p<0.05) and diabetes (18% vs 12%) in males in comparison to females. Concerning the laboratory patterns we found higher levels of glycemia in males in comparison to females (11561 mg/dL vs 8115 mg/dL, p<0.001) while HDL-C (4012 mg/dL vs 388 mg/dL, p<0.05) was significantly higher in females in comparison with males (Table I).

Males had larger baseline brachial artery diameter (BAD) than females (40.6 mm vs 3.60.6 mm, p<0.05) and the FMD in response to reactive hyperemia, was significantly higher in females than in males (124.4% in females vs 7.24.5%, p<0.005 in males respectively), (Table I). After nitroglycerin, endothelium-independent vasodilatation was not significantly different between the two groups (males vs female).

Figure 1.-Endothelial function and carotid IMT in relation to traditional risk factors.

Figure 2.-Relationship between carotid IMT and endothelial function.

Endothelial dysfunction and carotid atherosclerosis were related with coronary risk factors; in fact, a lower FMD was found in patients with cardiovascular risk in comparison to subject without RF (7.14.6% vs 9.84%, p<0.05) and higher values of mean carotid IMT (1.050.29 mm vs 1.370.19 mm, p=0.03), (Figure 1). After nitroglycerin, endothelial-independent vasodilatation was not significantly different between the two groups (subject with RF vs subject without).

Age (r=+0.32, p<0.005) and diabetes (r=+0.21, p<0.05) were positively and significantly correlated with carotid atherosclerosis (IMT), and inversely and significantly with FMD (age, r=-0.27, p<0.007; diabetes, r=-0.24, p<0.05). In addition, a statistically significant inverse linear correlation between systolic blood pressure (r=-0.17, p<0.005), smoking (r=-0.35, p<0.05), and FMD was found.

We have also demonstrated that femoral atherosclerosis has been correlated with age (r=+0.31, p<0.005) and male gender (r=+0.34, p<0.02).

Regarding biochemical parameters we found that total cholesterol (r=-0.08, p<0.05) and LDLC concentration (r=-0.09, p<0.005) had a poor inverse linear relationship with endothelial function, while HDL-C (r=+0.12, p<0.005) had a poor positive linear relationship with FMD; no correlation with carotid and femoral IMT has been demonstrated. There was a negative linear relationship between carotid IMT and endothelial function (r=-0.51, P=0.002, Figure 2), and a lower FMD in patients with carotid and femoral IMT in comparison with patients without peripheral atherosclerosis (6.93.4% vs 9.84%, P=0.01, Figure 3). After nitroglycerin, endothelium- independent vasodilatation was not significantly different between the two groups. The overall effect of coronary RF on the independent variables FMD and IMT was analyzed using a linear multiple regression model. To identify possible variables independently related with endothelial dysfunction and carotid and femoral IMT we build a statistical model of multivariate analysis (multiple regression), including the following clinical and biochemical variables evaluated on admission: age, BMI, presence of smoking habit or hypertension, history of coronary artery disease (CAD), glycemia, total cholesterol, LDL-C and HDL-C, triglycerides. The variables and their coefficients predicting endothelial dysfunction in the regression model were age (p=0.001), smoking (p=0.003), hypertension (p=0.04), and carotid IMT (p=0.05). The variables predicting carotid IMT were age (p=0.01), hyperglycemia (p=0.03), hypertension (p=0.05), and levels of HDL-C (p=0.007). The variables and their coefficients predicting femoral IMT were male gender (p=0.004) and hypertension (p=0.03). The final regression models are summarized in Table II.

Figure 3.-Endothelial function in patients with or without peripheral atherosclerosis.

TABLE II.-Multiple linear regression models of the variables: flow mediated dilation (FMD) and carotid and femoral intima media- thickness (IMT).

Discussion and conclusions

At the present time, B-mode ultrasonography is extensively used to detect early structural changes in carotid arteries because the thickening process in these areas is considered to be a prognostic marker for the development of atherosclerosis and appears to correlate with coronary lesions.16 In our study we tested the possible existence of a relation between early structural changes of carotid and femoral arteries and endothelial function evaluated by a non invasive technique, as vascular ultrasounds. Also, we investigated the relationship between these parameters and the risk factors present in our patients.

Endothelial dysfunction is defined as a functional deterioration of the endothelium characterized by vasospasm, vasoconstriction, alterations in coagulation mechanisms and fibrinolysis, and increased vascular proliferation.

The mechanism through which a dysfunctioning endothelium could promote atherosclerosis is caused by an alteration in the L- arginine-NO pathway, leading to a reduction of NO bioavailability.17 NO appears to be not only a potent vasodilator but also an endogenous inhibitor of platelet aggregation,18 vascular smooth muscle cell growth and migration, leukocyte adhesion, and adhesion molecule expression. It is clear that an alteration in the L- arginine-NO pathway may reduce this potentially antiatherosclerotic activity. In addition, a dysfunctional endothelium may attract platelets that produce and release prostanoids such as thromboxane A2, which causes vasoconstriction and further platelet aggregation, and/or oxygen free radicals, which can destroy NO and cause vascular damage.19

Several studies have demonstrated that endothelial dysfunction is related to coronary RF; in our study we showed, in according with the literature, a lower FMD in patients with cardiovascular RF in comparison with subject without RF (p<0.05). The results obtained in our patients have found that age (p<0.005) and diabetes (p<0.05) are positively and significantly correlated with carotid atherosclerosis, and inversely and significantly with FMD (age, p<0.007; diabetes, p<0.05).

In detail, we have found a statistically significant inverse linear correlation between systolic pressure (p<0.005), smoking (p<0.05), and endothelial function and regarding biochemical parameters we found that total cholesterol (p<0.05) and LDL-C concentration (p<0.005) were inversely related with endothelial function, while HDL-C (p<0.005) was positively and significantly correlated with FMD.

The present study provides additional information on the spectrum of endothelial function deterioration: the process can occur in healthy individuals, some degree is seen in persons with one or several risk factors, and finally, there is progression to clinical atherosclerosis. We have also demonstrated, according with previous studies, higher values of IMT in patients with coronary risk factors in comparison to patients without RF (p=0.03); moreover, carotid IMT has been shown to be related to age (p<0.005) and diabetes (p<0.05), while age (p<0.005) and male gender (p<0.02) were also related with femoral atherosclerosis.

Two studies have correlated carotid IMT with endothelial function; in one of them, coronary arteriography was used to investigate these two parameters in patients with clinically suspected coronary disease. A lower endothelial function was found in the group with angiographically significant lesions as compared to those without lesions. Moreover, an increased carotid IMT was found in patients with coronary disease.18

The other one compared FMD and IMT in 34 men with demonstrated atherosclerosis and 33 men without atherosclerosis, but with coronary risk factors; in this study higher IMT values and poorer endothelial function were found in the atherosclerotic group. Finally the authors also reported a negative con-elation between IMT and FMD.19-21

In our study we have demonstrated, according with these results, an inverse correlation between endothelial function and carotid IMT (P=0.002), as measured with non-invasive techniques, as vascular ultrasounds. We also showed a lower FMD in patients with multifocal atherosclerosis (carotid and femoral IMT) in comparison with patients with one localization (femoral or carotid), and in subject without peripheral atherosclerosis (p<0.01).

In conclusion, although further study is needed, our data suggest that non invasive measurement of endothelial function and IMT are interrelated techniques that probably assess the same atherosclerotic process from different points of view (functional and anatomic, respectively) allowing early, non-invasive assessment of cardiovascular risk in patients with asymptomatic risk factors. These finding appear to be important to attentionate these patients with endothelial dysfunction and/or IMT of carotid and/or f\emoral arteries, with a more precocious and aggressive correction of risk factors to avoid cerebral and cardiac fatal and non fatal events in the follow-up.

Received June 21, 2004; sent for revision July 16, 2004; revised August 30, 2004; accepted for publication September 20, 2004.

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E. CORRADO 1, I. MURATORI2, R. TANTILLO 1, F. CONTORNO 1, G. COPPOLA 1, A. STRANO 3 S. NOVO 1

1 Unit of Cardiovascular Diseases, Division of Cardiology, Post- graduate School of Cardiology, University of Palermo, Palermo, Italy

2 Department of Internal Medicine and Cardiovascular Diseases, University of Palermo, Palermo, Italy

3 Center for the Study of Atherosclerosis and Dismetabolic Diseases, University of Rome TorVergata, Rome, Italy

Address reprint requests to: Prof. S. Novo, MD, Unit of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular and Nephro-Urological Diseases, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", Via del Vespro 141, 90127 Palermo, Italy. E-mail: novosav@unipa.it

Copyright Edizioni Minerva Medica Mar 2005

Source: International Angiology

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