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NEW INSIGHTS INTO THE MECHANISMS ANDTHERAPEUTIC APPROACHES IN ATHEROSCLEROSIS

3.E .1

3.E .2

Wednesday 8 October 1997 : Educational Lectures

New insights into the mechanisms of atherosclerosis

Russell Ross . University of Washington, Seattle WA, USA

The lesions of atherosclerosis represent a chronic inflammatory process in-volving monocytes and T lymphocytes, accompanied by a fibroproliferativeprocess within the intima of the artery. The initial lesion of atherosclerosis,the fatty streak, begins as a result of adhesion and migration of the monocytesand T lymphocytes into the intima, where the monocytes become activated asmacrophages and, in hyperlipidemic individuals, become foam cells . Smoothmuscle cells present in the intima, or which migrate from the media into theintima, replicate and form matrix, resulting in an intermediate lesion, whichcan progress to an advanced lesion covered by a fibrous cap of smooth musclecells surrounded by a matrix of varying density that covers accumulationsof inflammatory cells with or without a necrotic center . Monocyte-derivedmacrophages and T cells replicate due to production of cytokines and growthfactors. Oxidized and glycated lipoproteins and other free radicals may play arole in the endothelial insult that results in this inflammatory-fibroproliferativeprocess . Gene expression by each of the cells at various times during lesion for-mation and progression represents key events in determining whether lesionswill be stable, regress, or progress . Genetically modified and chimeric mice, inwhich genes have been altered for platelet-derived growth factor, apoproteinE, and other molecules associated with the immune and inflammatory systemshave provided insights into this process . Intracellular signaling pathways formitogenesis, and the roles and interactions of the signaling molecules withcell-surface integrins are key elements in determining whether the lesionsremain quiescent or proliferate and expand . Magnetic resonance imaging hasbeen successfully used in experimental animals as well as in humans to followlesion formation and progression noninvasively in peripheral arteries .

This work was supported in part by NHLBI grant HL 18645 .

The role of endothelial function in the pathogenesis ofatherosclerosis

Thomas F. Luscher. Cardiology University Hospital Zurich, Switzerland

The coronary circulation is controlled by the central nervous system,circulating hormones and local vascular mechanisms . The importance of localregulatory mechanisms has only recently been recognized . The endotheliumis in a strategical anatomical position within the blood vessel wall locatedbetween the circulating blood and vascular smooth muscle cells . It canrespond to mechanical and hormonal signals from the blood ; of particularimportance is the fact that it is a source of mediators which can modulatethe contractile state and proliferative responses of vascular smooth musclecells, platelet function, coagulation as well as monocyte adhesion. Importantrelaxing factors are nitric oxide (NO) and prostacyclin and a putative hyper-polarizing factor. NO also inhibits smooth muscle proliferation and together-

with prostacyclin platelet adhesion and aggregation . Bradykinin induced NOproduction is regulated by angiotensin converting enzyme located on theendothelial cell membrane; indeed, the enzyme not only activates angiotensinI into angiotensin II, but also inactivates bradykinin . Endothelin (ET)-l andthromboxane A2 and prostaglandin H2 are contracting factors produced bythe endothelium. In contrast to thromboxane A2 and prostaglandin H2 whichactivate platelets, ET has no direct effects on these cells, but has proliferativeproperties in vascular smooth muscle . Under physiological conditions, theendothelium plays a protective role as it prevents adhesion of circulatingblood cells, keeps the vasculature in a vasodilated state d inhibits vascularsmooth muscle proliferation . In disease states such as atherosclerosis, on theother hand, endothelial dysfunction contributes to enhanced vasoconstrictorresponses, adhesion of platelets and monocytes and proliferation of vascularsmooth muscle cells, all events known to occur in coronary artery disease .Nitrates substitute in part for deficient endogenous NO, while angiotensinconverting enzyme inhibitors increase the bradykinin induced NO and prosta-cyclin production. The newly developed ET antagonists allow to specificallyblock the effects of ET. Pharmacological correction of endothelial dysfunctioncan also be achieved by calcium antagonists . These effects of various drugclasses may be important to treat coronary artery disease and its complications .

3 .E.3

11th International Symposium on Atherosclerosis, Paris, October 1997

Preventive and therapeutic approaches in atherosclerosis -current evidence and future prospects

W.W. Parmley. University of California San Francisco, USA

Prevention of disease is always better than treatment of established disease .Data suggest that reduction of risk factors is the major factor leading toreduced coronary heart disease mortality in the United States . Reduction ofrisk factors improves endothelial function and both limits plaque development,and stabilizes plaques - thus reducing myocardial infarction rate . Smokingplus exposure to environmental tobacco smoke (ETS) are the most correctablecause of mortality in the United States. Experimentally, ETS enhances thedevelopment of lipid lesions in the cholesterol fed rabbit, and adversely affectsvascular reactivity - an effect partially reversed by dietary administration ofL-arginine. ETS also increases the size of experimental myocardial infarction- an effect which can be attenuated by L-arginine . Lipid lowering and ACE-inhibitors improve vascular reactivity and reduce clinical events . Even thoughthe regressive effects of lipid lowering on plaques is relatively minimal, themyocardial infarction rate is reduced substantially . This plaque stabilizationmay occur by reducing the subplaque pool of lipid and/or by reducing foamcells at the plaque margins. The ability of ACE-inhibitors to reduce myocardialinfarction rate may be due to a reduction of Antiotensin 2 and an increase innitric oxide production by endothelial cells . Control of hypertension reducesstroke rate with a lesser effect on myocardial infarction rate. Aggressive lipidlowering is beneficial in both primary and secondary prevention . The additiveadverse effects of risk factors, requires a concerted effort to simultaneouslyreduce all risk factors. Newer genetic and molecular biology approaches maygreatly reduce existing risk factors .