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[ Scientific Activities - Actividades Científicas ]

Detection of preclinical atherosclerosis: methods and
interest for prevention

Pr  Alain Simon

Centre de Médecine Préventive Cardiovasculaire
Hôpital Broussais, PARIS

Methods of detection
Interest for prevention
Therapeutic value
Clinical perspectives

Preclinical atherosclerosis occurs several years or decades before the onset of the first clinical event. Silent, it is often unknown and therefore must be detected systematically in subjects with high risk for cardiovascular disease. Such a detection would allow to better stratify the cardiovascular risk and justify to treat more or less aggressively the modifiable risk factors of one individual in primary prevention (1).

Methods of detection

The methods of detection of preclinical atherosclerosis are necessarily non invasive. Four main markers are currently of interest: Thickening and stiffening of large artery walls, coronary artery calcification, and endothelium-dependent vasoactivity.

Arterial wall thickening

It can be detected by high-resolution ultrasonography in peripheral large arteries and realizes two different aspects: the focal plaque and the intima-media thickening. Plaque is a focal echogenic structure encroaching into the lumen of the artery and accurately detectable in carotid arteries, abdominal aorta and femoral arteries (2). As the reliable assessment of its volume is not currently possible, plaque is generally characterized in a dichotomous way by its presence (whatever the number and the precise location) or its absence in the arterial site investigated (2). The site of investigation can be (i): both carotids (ii), the abdominal aorta, and both (iii) femorals. So the number of diseased sites in one subject, (i.e arterial sites carriers of at least one plaque) may vary from 0, 1, 2 or 3 if the three above arterial sites are investigated. The reproducibility of such a procedure averages 95% (2).
Intima-media thickness (IMT) gives a characteristic echographic image constituted of two parallel echogenic lines representing the interfaces between the blood and the intima and between the media and the adventitia (3) (Figure 1). To achieve an optimal quality of measurement, IMT should be measured in the far wall of the common carotid artery, along a longitudinal vascular length of at least 1 cm, and with the assistance of an automated computerized program of image analysis (3). Then, the precision of IMT measurement is below one tenth of millimeter and its reproducibility averages 95% (3-4). A practical limitation to the IMT measurement is related to the absence of definition of its precise pathological value due to a lack of agreement between the various methodological procedures of measures used in the literature. However carotid IMT of >= 1 mm whatever the methodology of measurement, and age and gender of the patient, represents unquestionably a pathological thickening. Intima-media thickening is not necessarily of atherosclerotic nature in particular if it results from medial hypertrophy such as in hypertension (4). Unfortunately this pathological issue cannot be elucidated with current ultrasonic techniques which cannot measure separately intima thickness and media thickness because of their insufficient power of axial resolution (3).

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Figure 1. Common carotid far wall intima-media thickness measured by ultrasonography with automated computerized image analysis. The parallel right and green lines mark interfaces between blood and intima and between media and adventitia, respectively. The distance between the two lines is measured on at least 100 consecutive points inside the rectangle.

Arterial wall stiffening

Stiffening is a marker of vascular sclerosis. It can be detected in various vessels as carotid and femoral arteries, the abdominal aorta and brachial and radial arteries, principally by means of echotracking techniques which determine the local systolo-diastolic distension of the vessel in percentage of its diastolic lumen diameter (4). An index of wall stiffening can be calculated as the ratio between the logarithm of the {systolic pressure divided by the diastolic pressure} and the systolodiastolic distension of the artery (4). Arterial pressure used in this calculation should be ideally the local arterial pressure inside the artery investigated. Such a local pressure can be measured by applanation tonometry (4). However in clinical practice arterial pressure can approximate brachial artery pressure measured by the classical sphygmomanometric procedure. The normal and pathological values of arterial stiffness are difficult to define precisely because they vary considerably according to the type of artery investigated and the technique of measurement.

Coronary artery calcifications

Coronary calcifications are synonymous of coronary atheroma and can be detected rapidly and non-invasively by electrom beam computed tomography which visualizes the calcium deposit in epicardial coronary arteries with high precision (2) (Figure 2). The sum of calcium deposit area within the whole coronary tree is transformed into a global score of calcium in the coronary tree (2). However, the absence of coronary artery calcification does not absolutely eliminate the possibility of non-calcified atheroma plaque. A calcium score of > 0 can be subdivided into three grades: 0 to 9, low score; 10 to 99, moderate score; 100 or more, elevated score (2) but coronary calcium score must be interpreted according to age and gender of the subject because they strongly influence the coronary calcium process. The main limitation to use coronary artery calcification as a non-invasive marker of coronary atheroma results from the difficulty of access of patients to electrom beam computed tomography which is a technique rarely available in particular in Europe.

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Figure 2. Example of coronary artery calcifications on 4 transversal cardiac slices obtained with electrom beam computed tomography (IMATRON) Calcium deposit is seen inside circles on the epicardial coronary arteries, especially left .

 Endothelium-dependent vasomotion

It represents the capacity of one artery (brachial, femoral, or radial) to dilate (or to constrict) in response to transient increase (or decrease) in the endothelial NO secretion induced by hyperhemia reactive to 3-5 minutes ischemia (or by ischemia itself) (5-6). Ischemia is provoked by excluding the distal circulation of a limb with a cuff inflated at supra systolic pressure (5-6). The normal value of endothelium-dependent vasodilation induced by hyperhemia in the brachial or femoral artery approximates 10% of the baseline diameter of the artery (5). A decreased vasodilation of 3% or less was observed in the presence of cardiovascular risk factors as smoking, hypercholesterolemia and family history of premature cardiovascular disease. Such impaired high-flow vasodilatation is pathological and reflects the endothelial dysfunction (5). This endothelial dysfonction occurs in the absence of definite atheromatous lesion but it is likely that it is associated to very early atheromatous structural alteration such as intima-media thickening.

Interest for prevention

Predictive value

Preclinical atherosclerosis reflects the integrated effects of multiple risk factors over time. Most markers of preclinical atherosclerosis are associated with a number of traditional cardiovascular risk factors (age, male gender, central obesity, hypertension, dyslipidemia, diabetes mellitus) but also with new or emerging risk factors (fibrinogen, lipoprotein(a), homocystein, polymorphisms of gene candidates for hypertension and dyslipiemeia, psychosocial factors and socio-echonomic status) (1-2). Such associations may explain that markers of atherosclerosis and especially plaque, intima-media thickening, and coronary artery calcifications have shown a strong predictive value for subsequent clinical events. The presence of carotid plaque multiplyies by 4 the 3-year incidence of acute myocardial infarctus in a general population of finnish middle-aged men (7) (Table 1) (7). The simulation of coronary event risk with the Framingham model in a cross-sectional analysis of asymptomatic men at risk for cardiovascular disease has shown that the presence of echographic plaque at multiple extracoronary sites (carotid, abdominal aorta, femoral) multiplied by 2.5 the 10-year risk of coronary heart disease (2) (Table 1). Carotid intima-media thickening increases also considerably the risk of coronary and/or cardiovascular complications within various populations of asymptomatic subjects. The risk is multiplied by 1.5 to 5 according to the populations studied and the degree of thickening (7-11) (Table 1). Using the Framingham model for predicting the 10-year risk of coronary event we have shown that each 0.1 mm increase in carotid intima-media thickness was accompanied by a concomitant 20 % increase in risk of coronary complication in asymptomatic middle-aged men and women (12). The predictive value of carotid intima-media thickening is independent of the classical cardiovascular risk factors and stronger than each of them. Coronary artery calcifications, inespective of their quantity, multiply by 3 the 3-year risk of coronary event in asymptomatic middle-aged men (13) (Table 1). When coronary calcium deposit is major (coronary calcium score of > 100) the risk of coronary complication is multiplied by a factor of > 20 (14) (Table 1).

Table 1

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Therapeutic value

Quantitative markers of preclinical atherosclerosis allow to monitor the progression/regression of the arterial disease (2). Carotid IMT is widely used in therapeutic trials with lipid lowering drugs or antihypertensive agents because of its high precision and reproducibility rates (15-24) (Table 2). The drug capacity to retard the progression of carotid intima-media thickening is generally considered as an antiatherosclerotic property. Other markers of atherosclerosis such as wall stiffening, coronary artery calcifications, and endothelium-dependent vasomotion have an enormous potential for testing drug effects on the artery walls. However the complexity of their measurement coupled to problems of precision and reproducibility have considerably limited their use in long-term therapeutic trials. Concerning echographic plaque of peripheral arteries, the difficulty to measure their volume accurately is a major limitation to their use as marker of progression/regression of atherosclerosis.

Table 2

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Clinical perspectives

It is likely that the detection of preclinical atherosclerosis will represent an invaluable tool in preventive cardiovascular medicine in the next future (1). Preclinical atherosclerosis evidences the existence of high risk of cardiovascular disease and, unlike cardiovascular risk factors demonstrates the presence of silent arterial disease. Therefore it provides a strong argument to justify the decision to treat vigorously a subject. For a given level of risk factor, for example a moderate hypercholesterolemia, it would be logical to give a lipid lowering drug preferentially to the subject with evidence of preclinical atherosclerosis and to reserve non pharmacological treatment to the subject free from atherosclerosis (1). This preventive high-risk strategy based on the detection of preclinical atherosclerosis may be considered as "primary-secondary", ie intermediate between the primary prevention of a non diseased subject and the secondary prevention of a subject with established atherosclerotic disease. However before to recommend such a strategy in clinical practice, several issues should be solved (1). The first one is the choice of the marker to use for detecting preclinical atherosclerosis. This choice has not yet been the matter of agreement between different groups in the literature. However a marker whose the detection is non-invasive, safe, inexpensive, relatively simple, precise and reproducible, such as IMT will be necessarily promoted. A second problem is related to the diagnosis value of the marker as regards atherosclerotic disease and to its predictive value as regards subsequent clinical complications. Some markers such as echographic plaque of peripheral arteries or coronary artery calcifications clearly indicate the presence of atherosclerosis. Others, such as intima-media thickening, wall stiffening, or endothelial dysfunction are more equivocal markers of atherosclerosis. However the diagnosis value of a marker as regard atherosclerosis is not a necessary condition for a high predictive value as regards clinical complication. The typical example is carotid IMT which predicts clinical cardiovascular complications despite it is a non specific marker of atherosclerosis. A last obstacle is the definition of normal and pathological values for quantitative markers such as intima-media thickening, coronary artery calcium scores, wall stiffening, or endothelial dysfunction. These definitions would require a definite agreement on methodological procedures and epidemiological longitudinal studies in general populations of different countries for defining the threshold value of the marker above which the risk of complication increases substantially.
Finally the detection of preclinical atherosclerosis should induce additional health costs. However if atherosclerosis detection might help to better target costly treatments to high-risk subjects and to avoid to treat unnecessarily low-risks subjects, important saving could ensue. For example, the echographic detection of plaque in peripheral arteries approximates the cost of a few months treatment with new lipid lowering or antihypertensive drugs which are generally prescribed for life.



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