O22	IMT or atherosclerotic plaque : Same or different disease? Pierre-Jean Touboul Hopital Bichat &Lariboisiere Paris, E-mail : pjtw@noos.fr IMT corresponds to the intima media complex, comprising endothelial cells, connective tissue and smooth muscle cells. This complex measured by ultrasonography on the wall of the common carotid artery where it generates a double line pattern has been positively correlated with the two anatomic first layers of the arterial wall. Association between intima media thickness and the major atherosclerotic risk factors has been demonstrated in a large number of epidemiologic studies. We know from cross-sectional epidemiologic studies that IMT of the common carotid artery comes before plaque plaque development. As age is the most powerful non-modifiable determinant of IMT, there is a need to know the normal values in the different countries and to adjust to this factor the values of IMT in interventional studies. Plaque is definitely atherosclerosclerotic disease as IMT may be the only anatomic remodelling at the early stage of hypertension. Many conditions may lead to variations of IMT without atherosclerotic disease. According to recent studies, IMT of the common carotid artery seems to be strongly associated with risk factors for stroke and prevalent stroke whereas increased thickening of the bifurcation including plaque is more directly associated with ischemic heart disease risk factors and prevalent ischemic heart disease. Will try during the presentation to clarify the relationship between carotid intima media thickening and plaque at the bifurcation as they may show different patterns of association with risk factors and prevalent disease.
O23	Carotid wall function, cholesterol and statins Henrik Sillesen, MD DMSc Chairman, Dept of Vascular Surgery, Gentofte Hospital, University of Copenhagen Atherosclerosis affects arteries througout the body and may results in various manifestations. The most common clinically is coronary artery disease causing angina, myocardial infarction and death. For many years, the pathogenetic mechanism was considered of obstructive nature and indeed, functional related chest pain, angina pectoris, results from rescricted blood supply to cardiac muscles. However, the risk of acute myocardial infarction and/or sudden death more often results from acute thrombosis of an atherosclerotic coronary artery -- not necessarily a severely stenotic. The mechanism in case of ischemic stroke is probably very similar, at least when thought to be related to an ipsilateral carotid stenosis. Thrombosis resulting from plaque rupture may cause either embolisation to the cerebral arteries or acute occlusion of the internal carotid artery itself. Atherosclerosis results from lipid accumulation in the arterial vessel wall. With increasing amounts being deposited in the vessel wall the plaque is formed. Plaque rupture results from thinning of the fibrous cap covering the lipid core, probably caused by inflammatory processes within the plaque. Lipid rich plaques appear more prone to rupture as compared to plaques composed mainly from fibrous tissue. Lowering cholesterol by statins have proven effective in preventing myocardial infarction and death, both in primary and as well as in secondary prevention trials. Whether statins work simply by the lipid lowering effect (reducing the passive diffusion form vessel lumen into the vessel wall, or statins also have other effects remains to be proven. However, anti-inflammatory actions have been suggested. Treating atherosclerotic patients with statins results in lower inflammatory markers in the blood. Also, removed atherosclerotic lesions from statin treated patients reveals less inflammation as compared to lesions from patients not treated by statins. Can plaques at risk of rupture (vulnerable plaques) be identified efficiently? In case of coronary atherosclerosis the answer is no -- at least when considering methods applicable to the general population. Concerning carotid atherosclerosis things are somewhat different. The carotid arteries have a much better topical anatomy, being located quite superficial in the neck without bone covering the most important parts. Thus, the carotid arteries, which are those who most often become affected by atherosclerotic lesions, may be investigated thoroughly by ultrasound in almost every patient. In addition, trying to validate a method for atherosclerotic plaque characterisation, hundreds of thousands of carotid plaques are removed annually, providing a means for comparison of ultrasound technology to histological assessment of the removed specimen. During the last decade many studies have indicated that ultrasound B-mode imaging may in fact give an estimate of plaque composition -- plaque type. The echo poor lesion -- sometimes termed echolucent-- has s higher content of fat and other "soft" tissue, compared to the highly reflective stenosis -- the echogenic lesion. Calcified lesions also reflect ultrasound strongly and may result in acustic shadows obstructing the further penetration of the sound beam. Also, the lipid-rich, echolucent lesions apparently are associated with increased lipid levels. However, a considerable variation within the mentioned groups remains to be dealt with. Recent longitudinal studies have shown that the echolucent plaque carries a much higher risk of stroke compared to the echogenic type, regardless of degree of carotid stenosis. It may be speculated if numbers needed to treat could be reduced dramatically if plaque type was taken into consideration when choice of therapy was made and it may also be discussed if lipid lowering would be beneficial for all patients with carotid atherosclerosis.
O24	A promoter polymorphism of the Interleukin-6 gene modulates the effects of alcohol and smoking on early carotid atherosclerosis. Sitzer M, Jerrard-Dunne P*, Risley P*, Steckel DA, Buehler A, von Kegler S, Markus HS*. Dept. Neurology, J.W. Goethe-University Frankfurt/Main, Germany; *Div. Clin. Neurosciences, St. Georges Hospital. Medical. School, London, UK Background: Smoking, obesity and heavy alcohol consumption are associated with increased inflammatory markers. The pro-inflammatory cytokine interleukin-6 IL-6 is thought to play an important role in atherogenesis. Previous studies have associated a functional gÕ c-174 IL-6 promoter polymorphism with cardiovascular disease. Methods : In a community population (n=942; aged 50-65 yrs), we examined the influence of this polymorphism and gene-environment interactions on both common carotid artery intima-media-thickness (CCA-IMT) and carotid plaque. Results: There was a strong interaction between IL-6 genotype, CCA-IMT, and alcohol intake (p=0.002). For drinkers of >30g/day, cc homozygotes had both greater age- and sex-adjusted mean± SD CCA-IMT (0.89± 0.22 vs. 0.78± 0.14mm, p=0.001), and IL-6 serum levels (p=0.03) than those with the gg/gc genotypes. A J-shaped relationship between alcohol and IMT was seen only in cc homozygotes. In heavy-drinkers, the age- and sex-adjusted odds ratio (95% confidence interval) for cc homozygotes having an IMT above the 90^th percentile was 5.3(1.9-14.6), and 10.2(3.0-35.0) additionally adjusted for conventional vascular risk factors. The cc genotype was also associated with an increased risk of carotid plaque in heavy drinkers: odds-ratio 3.6(1.2-11.5), p=0.025. An interaction was also found for smoking (p=0.009) but this could be partly explained by an interaction with alcohol (p=0.019 when alcohol interaction-term was included). No interaction was found with body mass index. Conclusion: The IL-6-174 polymorphism modulates the effects of heavy alcohol consumption, and to a lesser extent of smoking, on early carotid artery wall damage and is associated with atherosclerosis in heavy-drinkers.
O25	COLOUR-CODED DUPLEXSONOGRAPHY AS A DIAGNOSTIC TOOL IN PATIENTS WITH SUSPECTED TEMPORAL ARTERITIS M. Reinhard, D. Schmidt*, C. Auw-Haedrich*, and A. Hetzel Department of Neurology and Clinical Neurophysiology, University of Freiburg, Germany *Department of Ophthalmology, University of Freiburg, Germany Background: Biopsy of the temporal artery is usually required to confirm the diagnosis of Horton´s temporal arteritis. Recently, colour-coded duplexsonography has been reported to be a valuable additional tool in the diagnostic process of temporal arteritis. We aimed to evaluate this method in patients suspected of having temporal arteritis. Methods: 70 patients (69± 10 yrs, 46 women) with typical clinical symptoms and elevated ESR were studied using a compact linear array scanner (5-10 MHz). The main stem, frontal and parietal rami of the superficial temporal artery were examined on both sides in a longitudinal and transverse plane. In case of occipital headache the occipital artery was examined as well. A dark halo around the vessel wall (representing inflammatory edema), reduced vessel wall pulsations (preferably demonstrated by M-mode) and vessel occlusions were used as diagnostic criteria. 35 patients underwent biopsy of the temporal artery following the ultrasound examination. Results: 25 patients had positive ultrasound findings (84% halo, 68% reduced vessel wall pulsations, 25% occlusion of temporal artery branches). Comparing the ultrasound findings with biopsy results, ultrasonography had a sensitivity of 74%, specifity of 92%, a positive predictive value of 94% and a negative predictive value of 65%. In the one patient with a false positive result thickening of the adventitia but no inflammatory cells were found. The main differential diagnosis on ultrasound were atherosclerotic vessel wall thickenings, which were usually less hypoechogenic. Conclusions: Active vasculitis of the temporal artery can be detected by typical ultrasound findings, mainly a dark halo around the vessel wall. Negative findings, however, do not exclude the presence of arteritis. The lower negative predictive value is probably due to the absence of vessel wall edema in subacute stages and difficulties in reliably detecting distal segmental manifestations by ultrasound. On the other hand, positive ultrasound findings are highly predictive of temporal arteritis, and biopsy may not be necessary in the presence of typical clinical symptoms.
O26	b -Fibrinogen Gene Polymorphism (-455G/A) Is Mediated Inflammation Degree and Is Associated With Asymptomatic Carotid Artery Atherosclerosis E Ben-Assayag¹, I Bova², D Zeltser³, S Berliner³,T Nissel², S Lorenz M Levkovski², I Shapira³, N Bornstein² ¹Dpt. of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel-Aviv Universisty, Dpt. of ²Neurology and ³Internal "D", Tel-Aviv Sourasky Medical Center, Israel. Background: The -455G/A polymorphism at the promoter region of the b -fibrinogen gene has been related to plasma fibrinogen concentration and to the severity of coronary artery disease, the progression of atheroma, thrombosis risk and was associated with stroke in Japanese. Since fibrinogen is an acute-phase protein, an increased plasma fibrinogen level may reflect the inflammatory state of the vascular wall. Inflammatory processes may facilitate the transition of clinically stable to unstable atherosclerotic plaques. Methods: We investigated the relation of this polymorphism with carotid atherosclerosis and inflammation in 162 neurologically asymptomatic individuals. Atherosclerosis was quantified as intima-media thickness (IMT) measured in the common carotid artery and degree of stenosis measured in the internal and external carotid arteries by high-resolution ultrasonography. Inflammation examined using common inflammatory markers and erythrocyte aggregation test by a simple slide technique and image analysis. Results: The b -fibrinogen -455G/A polymorphism was significantly associated with elevated inflammatory degree and atherosclerosis: elevated plasma fibrinogen level (p=0.033), high-sensitive CRP (p=0.011), WBC (p=0.004), erythrocyte sedimentation rate (ESR), plasma interleukin-6 and increased degree of stenosis in the right carotid artery and slightly increase in mean IMT in the right common carotid artery. Individuals homozygous for the A allele had very high correlation between plasma fibrinogen and ESR (r=0.91, p=0.001) versus individuals homozygous to the G allele (r=0.62, p=0.000). The homozygous AA individuals presented also very high correlation between their other inflammatory markers, erythrocyte aggregation and with their IMT. Conclusions: These data suggest that the A^-455 allele of the b -fibrinogen promoter is associated with elevated inflammation and increased susceptibility for atherosclerosis in the carotid artery. The data suggest that their fibrinogen is more adhesive, and therefore they have such high correlation between their fibrinogen and ESR. Due to their baseline inflammatory degree, individuals homozygous for the fibrinogen –455A allele may be at particular risk for thrombotic event following an acute phase stimulus. Once identified, they may benefit from risk factor reduction and early therapy with statins or anti-inflammatory agents.
O27	CLOSE ASSOCIATION OF CAROTID AND AORTIC ATHERO-SCLEROSIS IN 210 PATIENTS WITH ISCHEMIC STROKE A. Harloff, M. Handke*, A. Hetzel Department of Neurology and Neurophysiology, University of Freiburg, Germany *Department of Cardiology and Angiology, University of Freiburg, Germany Background: Increased carotid intima-media-thickness (IMT) is closely related to cardiovascular risk factors and generalized atherosclerosis. However, little is known about the precise relation to aortic atherosclerosis, which represents a potential source of emboli in stroke patients. We aimed (1) to determine the correlation of IMT and carotid plaques with aortic atherosclerosis, and (2) to evaluate the necessity of transesophageal echocardiography (TEE) in the diagnostic management of stroke patients. Methods: Up to now 210 consecutive patients (62± 12 yrs) with ischemic stroke were investigated in an ongoing study. Carotid IMT of the far wall of the common carotid artery was measured bilaterally on four sites using a compact linear array scanner (5 MHz). Plaque size (PS) was determined bilaterally by multiplicating plaque length by plaque thickness of common and internal carotid artery. PS and mean IMT were compared with aortic arch plaque thickness (APT) in TEE (5 MHz TEE probe). IMT, PS and APT were correlated with age. Results: Increased IMT correlated with rising APT (r=0.44, p<0.001) as well as did PS with APT (r=0.63, p<0.001). Only 4 of 86 patients with IMT <0.9 mm had an APT ³ 4 mm (negative predictive value: 95%). In all of these 4 patients APT was <4.5 mm. Positive predictive value of IMT ³ 0.9 mm for APT ³ 4 mm was 29 %. Age correlated with IMT (r=0.45, p<0.001), PS (r=0.38, p<0.001) and APT (r=0.51, p<0.001). Conclusions: Given the high negative predictive value of IMT performance of TEE in the judgement of aortic atherosclerosis as a source of cerebral embolism seems dispensable in stroke patients with IMT <0.9 mm. On the other hand, increasing age, IMT and PS augment the probability of relevant atherosclerosis of the aortic arch. The low positive predictive value of IMT underlines the necessity of TEE in patients with embolic stroke of undetermined etiology.
O28	ARTERIAL WALL REMODELING IN INDIVIDUALS AT RISK FOR CARDIOVASCULAR DISEASE AND CONTROLS DESCRIBED BY INTIMA-MEDIA THICKNESS FREQUENCY DISTRIBUTION CURVES Eric de Groot, Andries Smit, John Kastelein Vascular Medicine, Academic Medical Centre, Amsterdam; Internal Medicine University Hospital,Groningen Introduction Atherosclerosis is a process of arterial walls with a slow onset of decades prior to manifestation of vascular disease. Lifelong follow-up data may contribute to identification and understanding of mechanisms, prevention and treatment of atherosclerotic disease. These data are currently not available. However, atherosclerosis may be illustrated in a model in which cross-sectional data of arterial wall thickness of different anatomic sites in populations in different extents exposed to cardiovascular risk are obtained in a standardized fashion. Methods B-mode ultrasound intima-media thickness (IMT) data were acquired in healthy controls: 46 young adolescents (15(SD3)yrs), 26 adults 34(10)yrs and 40 seniors (67(5)yrs), as well as in individuals at cardiovascular risk: 43 young adolescents with familial hypercholesterolemia (FH;15(3)yrs), 184 patients with coronary artery disease (CAD; 56(8)years) and 248 FH patients (48(8)yrs). IMT frequency distribution curves were created for each of the six populations. IMT’s that deviated from the IMT normal distribution of a given population were defined as lesions. Results Average IMT(SD) and % lesions in controls were: 0.52(0.09), 0.0%; 0.59(0.12), 0.0%; and 0.78(0.25)mm, 8.3% respectively. In the at risk populations these values were 0.54(0.10), 0.3%; 0.90(0.36), 17.4%; and 0.85(0.41)mm, 14.5%. Of all segments, the far wall of the common femoral artery of the FH population showed the highest absolute IMT (1.12(0.61)mm), the highest estimated relative IMT increase since young adolescence (+0.58mm) and the highest percentage of lesions (38%). Conclusions The studies show atherosclerosis as a generalized process of vascular walls with local differences in increase in wall thickness and increase in lesion formation with age and cardiovascular risk. Preferential lesion formation in populations and arterial wall segments with the highest estimated increase in IMT and therefore the highest atherosclerosis progression, indicate an intima-media complex thickness dependent threshold value for lesion formation.