International Journal of Angiology 13:27–30 (2004) DOI: 10.1007/s00547-004-1062-2
Common Carotid Intima-media Thickness in Peripheral Arterial Disease Bettina-Maria Taute, M.D.,1 Martin Schoenmetzler, M.D.,1 Ralf Taute, Math.,1 Klaus Haensgen, M.D.,1 Gernot Keyszer, M.D.,2 Christine Tiroch, M.D.,2 Hubert Podhaisky, M.D.1 1 Department of Internal Medicine III/Angiology, and 2Department of Internal Medicine I/Rheumatology, Martin Luther University, Halle-Wittenberg, Germany
Abstract. The common carotid intima-media thickness (IMT) is regarded as a reliable predictor of cardiovascular morbidity. Patients with peripheral arterial disease (PAD) have an increased risk of cardiovascular morbidity and mortality, and PAD is associated with increases in IMT. The aim of this study was to establish whether IMT would be a suitable parameter for predicting cardiovascular risk in individual patients with PAD and the factors involved in determining IMT in these patients. This prospective study included 314 subjects: 112 patients with isolated PAD, 85 patients with PAD and additional coronary and/or cerebrovascular atherosclerosis, and 117 subjects without atherosclerotic disease. Maximum IMT (mIMT) was measured using high-resolution B-mode ultrasonography. Patients with isolated PAD were examined for influencing factors on mIMT. The mIMT in patients with isolated PAD (1.01 ± 0.2 mm) was not significantly different from that of patients with PAD and additional systemic atherosclerosis (1.01 ± 0.17 mm). Controls showed a significantly lower mIMT (0.71 ± 0.15 mm). In multivariate stepwise regression analysis, the chief influencing factors on mIMT in patients with isolated PAD included age as well as fasting insulin and plasminogen activator inhibitor-1 (PAI-1). We found significant correlations between mIMT and the presence of microalbuminuria in nondiabetics with PAD. The highly increased mIMT values of patients with isolated PAD reflect the elevated cardiovascular risk which is already present in the early clinical stages of PAD. The links between fasting insulin, PAI-1, microalbuminuria, and older age with mIMT in isolated PAD are at the same time important predictors of the development of systemic atherosclerosis in PAD.
Introduction The common carotid IMT detected by ultrasound reflects the effect of multiple exogenous, endogenous, and genetic risk factors on the arterial vascular wall. Since the pioneering investigations by Pignoli et al. [1], numerous studies have indicated that IMT is associated with increased cardiovascular risk. This applies to coronary and cerebrovascular morbidity to the same extent [2–7]. IMT is regarded to be a surrogate marker of generalized atherosclerosis and therefore a reliable indicator of cardiovascular risk [8]. High IMT values have been reported in patients with PAD [9–13]. This patient group has a very high risk of experiencing a future coronary or cerebrovascular event (fatal or nonfatal) [14]. This study therefore investigated whether IMT would be a suitable marker for predicting individual cardiovascular risk in patients with PAD. Our investigation also examined the factors that correlate with IMT in patients with PAD.
Materials and Methods Study Design IMT measurements were carried out in patients with isolated PAD at the initial symptomatic stage and in patients with more severe PAD as well as existing systemic atherosclerosis in coronary and/or cerebral vascular regions. IMT measurements from an age-matched group with no atherosclerotic vascular disease were used as controls in order to be able to estimate the extent of the IMT increase in PAD. In patients with isolated PAD, the correlation of several epidemiological, clinical, and laboratory parameters with IMT was determined as well.
Patients and Controls Correspondence to: Bettina-Maria Taute, M.D., Martin Luther University of Halle-Wittenberg, Department of Internal Medicine III/ Angiology, Ernst-Grube-Str. 40, D-06097 Halle/Saale, Germany, E-mail:
[email protected]
This prospective study included 314 subjects who were divided into three groups. These comprised 112 patients with isolated PAD at the stage of mild intermittent claudication (male/female: 88/24), 85
28 patients with PAD and existing coronary and/or cerebrovascular atherosclerosis at the stage of severe intermittent claudication or critical limb ischemia (male/female: 57/28), and 117 controls (male/female: 27/ 90). Controls, with a resting ankle-brachial blood pressure index (ABPI) > 0.9, and patients with isolated PAD (ABPI < 0.9) were included in the study, provided they showed no detectable signs of symptomatic or 1 asymptomatic cerebrovascular atherosclerosis (CVD) or coronary artery disease (CAD). Patients were classified as having PAD and systemic atherosclerosis on the basis of evidence of CVD and/or CAD (previous cerebrovascular and/or coronary events, existing coronary artery disease and/or carotid artery disease). Patients with impaired renal function were excluded from the study.
Maximum Common Carotid Intima-media Thickness (mIMT) The mIMT of the common carotid artery was assessed using highresolution ultrasonography. A color-coded duplex scanning system with a 7–10 MHz linear-array probe was used. Measurement of mIMT in the common carotid artery was carried out in longitudinal sections, on both sides, at approximately 1–1.5 cm proximal to the bifurcation, and only on the far wall of the artery. Measurements were made in a plaque-free area. The measuring calipers were positioned manually on 2 the enddiastolically frozen image. The largest measured values taken from the right or the left side were used for further analysis.
Taute et al.: Intima-media Thickness in Peripheral Arterial Disease lipoprotein (a), and triglyceride were correlated with mIMT. Hemostatic variables (hematocrit, ADP-induced and collagen-induced platelet aggregation, platelet retention, PAI-1, von Willebrand factor) and other biohumoral variables such as fibrinogen, total plasma homocysteine (tHcy), and microalbuminuria were included in the analysis as well. Microalbuminuria was defined by immunonephelometry as an albumin excretion rate of > 30mg/L.
Statistical Analysis Statistical analysis was performed using the German version of the SPSS 10.0 program. Values of p < 0.05 were considered statistically significant. Dichotomous variables were specified numerically in terms of prevalence (percentage), and continuous data were expressed as mean ± standard deviation. Univariate comparisons of risk factors and other dichotomous variables between the groups were calculated with contingency tables and evaluated using Pearson’s chi-square statistics. Continuous variables were evaluated with one-factorial ANOVA and the Scheffe´ tests. Stepwise multiple regression was used to analyze the combined effect of candidate variables on mIMT values in patients with isolated PAD.
Results Characterization of Study Patients (197 Patients with PAD)
Assessment of PAD, CVD, and CAD Doppler-sonographic measurement of systolic blood pressure and calculation of the ABPI were used to define PAD (ABPI < 0.9) and its severity. The leg with the most severe circulation problems determined the assignment of the PAD stage. The localization of PAD in the lower limbs was based upon the results of clinical angiological examinations, 3 CW-Doppler sonography and the use of diagnosis-based preinterventional angiography. A color duplex sonographic examination of the common and internal carotid arteries was carried out in all patients to detect atherosclerotic plaques, stenoses or occlusions. Previous cerebrovascular events were recorded. The presence of CAD was determined using anamnestic data and by evaluating 12-channel resting electrocardiograms. Symptomatic patients underwent coronary angiography.
Risk-Factor Assessment Diabetic patients were classified according to World Health Organization guidelines. Patients taking antihypertensive therapy were considered as hypertensive. Nicotine abuse was defined as current or previous smoking. The latter term was applied in patients with more than 20 pack years who did not give up smoking more than five years previous to this study. Nicotine exposure was quantified by pack years. Patients were diagnosed as having hyperlipoproteinemia if they were undergoing treatment with lipid-lowering drugs or if their fasting total cholesterol values exceeded 6.2 mmol/L, or their fasting triglyceride 4 values exceeded 1.7 mmol/L, respectively.
In the 85 patients with PAD and systemic atherosclerosis, additional CVD was found in 96.4%. Additional CAD was seen in 49.3%, and 45.8% showed an overlap of PAD, CVD, and CAD. Patients with isolated PAD displayed the following features: The average parameter values for lipometabolic HDL and LDL cholesterol (Table 1), lipoprotein (a) (0.26 ± 0.33 g/L), and PAI-1 (3.7 ± 2.9 U/mL) were above the respective reference ranges. A total of 23.4% of patients were treated for hyperlipoproteinemia, whereas 39.6% had not yet been diagnosed. Microalbuminuria was found in 57.1% of diabetics (Type II only) and in 69.7% of nondiabetics with PAD. THcy concentrations of over 15 lmol/L were detected in 6.2% of patients only; 38.5% had levels of 9–15 lmol/L. THcy levels were significantly higher in women (11.9 ± 6.9 lmol/L) than in men (9.6 ± 3.2lmol/L, p < 0.05). The average value for systolic blood pressure was 153 ± 21 5 mm Hg, 26.2 ± 3.8 kg/m2 for the BMI, and 170 ± 8 cm for height. An iliaco-femoral localized PAD was found in 40% of patients, 26% had a femoral, 14% an iliaco-femoro-crural, 11% a femoro-crural, 5% a crural, and 4% an isolated aorto-iliacal localization. Maximal IMT in PAD and Controls
Correlation of mIMT with Clinical and Laboratory Variables in Patients with Isolated PAD A variety of epidemiological and clinical factors were examined in relation to PAD. These included age, height, gender, body-mass index, systolic blood pressure, pack years of smoking, and the severity (ABPI) and localization of PAD. In addition, factors reflecting the extent of metabolic syndrome such as fasting levels of blood glucose, insulin, high- and low-density lipoprotein cholesterol, HDL/LDL quotient,
The mIMT in patients with isolated PAD at the stage of mild intermittent claudication (1.01 ± 0.2 mm) was not significantly different from the mIMT in patients having PAD with additional systemic atherosclerosis at higher stages of disease (1.01 ± 0.17 mm). In contrast, the controls displayed a significantly lower mIMT (0.71 ± 0.15 mm). Significantly lower mIMT values for women were seen in the control group but not in the
Taute et al.: Intima-media Thickness in Peripheral Arterial Disease
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Table 1. General characteristics of the study population Controls
Parameter
PAD, Isolated
PAD and Systemic Atherosclerosis
mIMT (mm) Male Female
0.71 ± 0.15 0.78 ± 0.22 0.69 ± 0.11à
1.01 ± 0.20 1.00 ± 0.20 1.02 ± 0.23
1.01 ± 0.18 1.04 ± 0.18 0.99 ± 0.16
Age (years) Male Female
60.85 ± 10.3 60.78 ± 9.26 60.88 ± 10.63
60.96 ± 8.81 60.26 ± 8.96 63.54 ± 7.85
65.74 ± 9.2 63.81 ± 9.15 69.82 ± 8.04à
1.09 ± 0.12 1.8 ± 0.9 1.4 ± 0.4 3.4 ± 0.9 13.7 41 38.5
0.67 ± 0.16 2.1 ± 2.1 1.2 ± 0.4 4.4 ± 0.9 18.8 42.3 97.3
0.47 ± 0.18 2.3 ± 1.6 1.1 ± 0.3 3.5 ± 1.3 43.8 70.5 65.8
ABPI 7 TG (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) 8 Diabetes (%) Hypertension (%) Smokers (%) à
p < 0.05 for male vs. female, p < 0.05 between the groups.
Table 2. Factors associated with mIMT in 112 patients with isolated PAD at the stage of mild intermittent claudication Dependent Variable
Independent Variables
Standardized Coefficient Beta
Significance p-value
mIMT
Age Insulin PAI-1
0.307 0.251 0.255
0.009 0.028 0.028
R2 = 0.22 (cumulative coefficient of contribution).
PAD patients. An overview of the characteristics of the study subjects is given in Table 1. Potential Effects on mIMT in Patients with Isolated PAD (n = 112) Univariate examination of the correlations between mIMT and potential influencing factors revealed significant links to age (p = 0.001), PAI-1 (p = 0.012), and fasting insulin (p = 0.002). A significant correlation between mIMT and fasting insulin (p = 0.001) was detected in nondiabetics. A link with microalbuminuria was found as well (p = 0.016). Table 2 displays the correlations of potential influencing factors with mIMT in isolated PAD derived from multivariate regression analysis. Discussion As expected, the comparison of mIMT between 117 persons with no apparent vascular abnormalities and 197 patients with PAD reveal significant differences. Higher values in PAD patients are associated with manifest atherosclerosis [9,13]. Within the PAD group, the mIMT in patients with isolated PAD at the stage of mild intermittent claudication (mean ABPI 0.67) is not different from the mIMT in PAD patients with systemic atherosclerosis at the stage of severe intermittent claudication or critical limb ischemia (mean ABPI 0.47).
These results indicate that mIMT already displays generalized atherosclerosis in the early symptomatic stages of PAD, i.e., at the stage of mild intermittent claudication. This supports the clinical observation that patients with early PAD have a considerable risk of cardiovascular disease and stresses the importance of secondary prevention in PAD. It can be assumed that in patients with PAD, a reduced ABPI is an indicator of a higher risk for the systemic progression of atherosclerosis, and the mIMT shows the cardiovascular risk increased generally and for all patients similarly. This means that the mIMT in PAD, together with the ABPI and the vascular risk-factor profile, contribute to individual risk prediction. The mIMT cannot, however, be used as the sole parameter for risk assessment in PAD. It is interesting to note that the well-established gender differences found in IMT of healthy individuals [15,16] are not seen in patients with PAD, where even a tendency toward higher values is found in women. Although the group of 52 female subjects was relatively small, our finding supports previous research demonstrating that the development of extracoronary atherosclerosis is not gender-related [17]. Our observation cannot be explained by the distribution of risk factors, a higher average age of the women, or the tendency toward higher homocysteine levels in women. It can, however, be concluded that postmenopausal women with PAD are exposed to an equal, if not higher, cardiovascular risk than men. In patients with isolated PAD, age, fasting insulin, and PAI-1 showed the strongest correlations with mIMT. Microalbuminuria is associated with the mIMT in nondiabetics with PAD only. Insulin resistance and hyperinsulinemia contribute to the atherosclerotic process [18–20]. Even small concentrations of insulin can exert a stimulating effect on smooth-muscle cell proliferation of the arterial wall [21]. IMT is associated with fasting insulin levels and with impaired insulin-sensitivity in nondiabetics and subjects who are free of atherosclerotic disease [22,23]. In addition, impaired regulation of fibrinolytic activity due to elevated PAI-1 levels, which are known to correlate with
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Taute et al.: Intima-media Thickness in Peripheral Arterial Disease
the IMT in CAD [24], could contribute to the atherosclerotic process. The high incidence of microalbuminuria, in both nondiabetics and in diabetics with PAD observed in this study, reflects a generalized abnormality of vascular function and is associated with two- to four-fold increases in cardiovascular and general mortality [25,26]. Microalbuminuria is already related to atherosclerosis in the early stages of the disease process [27]. The association of microalbuminuria with mIMT in our study confirms that this parameter is a valid marker of generalized atherosclerosis.
10.
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Conclusion The study indicates that mIMT does not discriminate between patients with isolated PAD in the early clinical stage and patients with PAD and systemic atherosclerosis in severe clinical stages. The highly increased mIMT values of patients with isolated PAD reflect the elevated cardiovascular risk which is already present in the early clinical stages of PAD. The absence of a gender-related difference in mIMT in PAD possibly indicates a specific cardiovascular risk in postmenopausal women with PAD. The described links between fasting insulin, PAI-1, microalbuminuria, and older age with mIMT in isolated PAD are at the same time important predictors of the development of systemic atherosclerosis in PAD.
14. 6 15.
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