Carotid Atherosclerosis Arterial Stiffness and Stroke Events

Enrico Agabiti-Rosei Maria Lorenza Muiesan

Internal Medicine, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy

Abstract

Assessment of intima-media thickness or of measures of large arteries compliance may identify patients at increased risk for stroke. In fact, carotid atherosclerosis and arterial stiffness are both related to risk factors associated with the occurrence of stroke. In addition, several cross-sectional studies have shown that risk factors associated with the occurrence of stroke have been correlated with carotid atherosclerosis development and progression and with increased arterial stiffness. Some studies have also shown that aortic stiffness is associated with the extent of atherosclerosis in the carotid and in other vascular beds. More importantly, longitudinal studies have demonstrated that carotid atherosclerosis and arterial stiffness are independent predictors of stroke (and other cardiovascular events). Interventional studies have demonstrated that treatment with statins, calcium antagonists, ACE inhibitors, and insulin sensitizers may be particularly effective on slowing the progression or favoring the regression of atherosclerotic changes, and may reduce large artery stiffness. It remains to be proven, in large prospective studies, whether the regression of increased arterial stiffness or of carotid intima-media thickness and plaque have a prognostic significance, i.e. are associated with a reduction of the risk of cerebrovascular events.

Copyright © 2007 S. Karger AG, Basel

Introduction

Several cross-sectional studies have shown that risk factors associated with the occurrence of stroke have been correlated with carotid atherosclerosis development and progression and with increased arterial stiffness [1, 2]. Some studies have also shown that aortic stiffness is associated with the extent of atherosclerosis in the carotid and in other vascular beds.

More importantly, longitudinal studies have demonstrated that carotid atherosclerosis and arterial stiffness are independent predictors of stroke (and other cardiovascular events) [1-4]. Based on these important results, current research is focused on markers of subclinical arterial disease that may be measured by non-invasive investigation, i.e. arterial stiffness, carotid intima-media thickness (IMT) and plaque.

Carotid Atherosclerosis (IMT and Plaque)

Methodological Aspects

Carotid ultrasound is routinely used for the evaluation of patients with clinical signs (carotid bruits) or symptoms of cerebrovascular ischemia. Direct visualization of carotid and vertebral arteries is accurate and reproducible, and may allow the identification of plaques; in addition, duplex ultrasound is used to evaluate alterations in the Doppler peak systolic velocities and waveform, in order to measure degree of stenosis, and changes of flow direction in the vertebral arteries. Ultrasonic plaque morphology may add useful information on plaque stability and may correlate with symptoms. Definition of plaques is based on either arbitrary cutpoint of IMT, or on visual inspection and presence of acoustic shadows, or on changes in flow; these different methods can make difficult the evaluation of changes in plaque during interventional studies.

Values of carotid IMT measured at autopsy by ultrasound are similar to those calculated by direct measurement. In patients with preclinical disease, high-resolution ultrasound of the carotid arteries has been widely used for the measurement of intima-media complex (combined thickness of intima and media) in the arterial wall, in order to assess the prevalence, the main determinants and the progression of early vascular lesions [5, 6].

Quantitative analysis of IMT is reliable when sonographers are trained rigorously and reproducibility of scan measurements is evaluated over time; when these aspects are taken into account, measurement of IMT can be used in clinical trials and in routine clinical practice for cardiovascular risk assessment [7, 8].

There are different protocols and methods for measuring IMT [2, 7]. Measurements may be obtained by manual cursor placement or by automated computerized edge detection.

The most frequently used measurements in epidemiological and interventional clinical trials are: (1) mean maximum thickness (Mmax) of up to 12 dif ferent sites (right and left, near and far walls, distal common, bifurcation and proximal internal carotid); (2) overall single maximum IMT (Tmax), and (3) mean of the maximum IMT of the 4 far walls in the common, bifurcation or internal carotid segment, considered separately or pooled together for the carotid bifurcations and distal common carotid arteries (CBMmax).

Measurement of IMT at multiple sites frequently includes plaque thickness.

Some concern still exists regarding the clinical significance of these measures, since far wall common carotid thickness analysis by computerized edge detection may imply the risk of missing important information on other segments of the carotid tree. In addition, a diffuse thickening of the arterial wall may be observed in some patients and several focal plaques in others, so that multiple site IMT measurements could detect both alterations.

Intima-media thickening could represent an early phase in the development of atherosclerotic plaque: according to the results of the EVA (Etude du Vieillissement Artériel) study, in a sample of 1,010 subjects (age range 59-71 years), the higher IMT was a strong predictor of the occurrence of a new plaque during a mean follow-up of 4.4 years [9].

Clinical and epidemiological studies have given useful information on the reproducibility of IMT measured by ultrasound. Salonen et al. [10] have indicated that between-observers and intra-observers variation coefficients resulted in 10.5 and 8.3%, respectively. In the ACAPS study [11] mean replicate difference was 0.11 mm and in the MIDAS [12] 0.12 mm. More recently, in the ELSA (European Lacidipine Study of Atherosclerosis) that included more than 2,000 patients, the cross-sectional reproducibility of ultrasound measurements at baseline was calculated: the overall coefficient of reliability (R) was 0.859 for CBMmax, 0.872 for Mmax and 0.794 for Tmax; intra- and inter-reader reliability were 0.915 and 0.872, respectively [13].

The normal IMT values are influenced by age, gender and race. Normal values of IMT may be defined in terms of statistical distribution within a healthy population; however, it may be better defined in terms of increased risk. Available data indicate that the relation between carotid IMT and cardiovascular events is continuous; a threshold of 0.9 mm can be taken as a conservative estimate of a significant alteration.

Longitudinal Studies

Traditional risk factors, including male sex, aging, being overweight, elevated blood pressure, diabetes and smoking, are all positively associated with carotid IMT in observational and epidemiological studies [ 1, 2, 8]. Hypertension and particularly high systolic blood pressure values seem to have the greatest effect on IMT [5, 12-14]. Also, some new risk factors, including various lipoproteins, plasma viscosity, C-reactive protein and hyperhomocysteinemia, have demonstrated an association with increased IMT. Carotid IMT has also been found to be associated with preclini-cal structural changes in the heart [5], brain, kidney and lower limb arteries.

In the GENIC study that included 510 patients with brain infarction compared with 510 controls, it was observed that common carotid IMT, carotid plaques and the Framingham risk score all significantly correlated with the risk of stroke [15].

Several studies have demonstrated the important prognostic significance of asymptomatic plaque and IMT, as measured by ultrasound.

In patients with asymptomatic carotid atherosclerosis, the annual risk of stroke ranges from 1.3 to 3.3%. The highest risk is observed in patients with the most evident degree of stenosis; Norris et al. [16] observed, in patients with stenosis >75%, a combined annual transient ischemic attack and stroke rate of 10.5%, with 75% of events ipsilateral to the stenosed artery. In the Cardiovascular Health Study (CHS) population [17], 0.5% of subjects had high internal carotid peak velocity (approximately 2.5 m/s, suggesting a stenosis of >70%) and the 5-year risk of an ipsilateral fatal or non-fatal stroke was 5%.

The presence of increased IMT also confers risk for future stroke, as demonstrated by longitudinal prospective studies.

In a large sample of middle-aged (45-65 years) subjects (7,865 women and 6,349 men) enrolled into the ARIC (Atherosclerotic Risk In Communities) study, average IMT, measured by ultrasound at six sites of the carotid arteries, was associated with an increased incidence of stroke [18]. In Cox proportional hazard models, adjusting for age, race and community, the hazard ratio for highest IMT (= or >1 mm) to lowest IMT (<0.6 mm) was 8.5 (95% confidence interval (CI) 3.5-20.7) for women and 3.6 (95% CI 1.5-9.2) for men.

In the Rotterdam study [19] the common carotid IMT was measured in 1,373 control subjects who remained free of cardiovascular diseases, in 98 patients who had an acute myocardial infarction and in 95 patients with a stroke, during a mean follow-up period of 2.7 years. When cases and controls were compared, after adjustment for age and sex, the odds ratio (OR) for stroke per 1 standard deviation (SD) increase of IMT (0.163 mm) was 1.41 (95% CI 1.251.82). In men, the OR per SD increase (0.172 mm) was 1.81 (95% CI 1.30-2.51) and in women, an OR of 1.33 (95% CI 1.03-1.71) per 0.155-mm SD increase was observed. When subjects with a previous history of myocardial infarction or stroke were excluded, the ORs were 1.57 (1.27-1.94) for all subjects, 1.89 (95% CI 1.29-2.77) for men, and 1.37 (95% CI 1.02-1.83) for women. Additional adjustment for several cardiovascular risk factors attenuated these associations and the OR per 1 SD increase resulted: 1.34 (95% CI 1.08-1.67), 1.47

Table 1. Outline of the Rotterdam, ARIC and CHS studies

Study

Subjects

Age, years

Follow-up years

Events

Relative risk (95% CI)

Rotterdam study

(men & women)

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