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JOURNAL OF ATHEROSCLEROSIS RESEARCH

CONFERENCE R E P O R T

METABOLISM OF T H E A R T E R I A L WALL (Prague Congress, 4th 9th September 1961) F. P. WOODFORD

Department of Physical Chemistry, University of Leiden (The Netherlands) (Received September 22rid, 1961)

Of the papers presented at the Fourth International Angiological Congress, organized at Prague under the auspices of the International Union of Angiology, many were concerned with vessels other than those commonly studied in atherosclerosis research, and some with metabolic questions not directly bearing on atherosclerosis. The bulk of the contributions were, however, relevant to the disease, and aimed at uncovering one or more aspects of its pathogenesis, if not its aetiology. Because of the subject chosen for the congress, these papers tended to stress the importance of local factors in the vascular wall in the development of atherosclerosis, rather than the perhaps too frequently emphasized changes in serum lipid composition often associated with it. Lively interest was shown, for instance, in the mucopolysaccharides of the aortic wall. H. MUIR (London) reported the occurrence in human aortic intima and media of a hitherto unknown acid mucopolysaccharide which could not be detected in liver, lung, spleen, or subcutaneous tissue. The substance has only slight antithrombin activity and no fat clearing activity. The lipolytic activity of the arterial wall was reported by S. GER~ and associates (Budapest) to be inhibited by the crude mixture of mucopolysaccharides extracted from human aorta, an effect they considered to be a possible factor in the deposition of unlysed thrombi on the wall as mucopolysaccharides accumulate with age and in the vicinity of atherosclerotic lesions. These observations may be related to the decreased lipolytic activity of the arterial wall with age in experimental animals (T. ZEMPLI~NYI, D. GRAFNETTER, X. LOJDA AND O. MRHOVA, Prague). Findings apparently in complete disagreement were reported by I. GORE (West Roxbury), who had found that mucopolysaccharides from an elderly aorta had significant anticoagulant activity and stimulated the release of clearing factor in rats. His preparation had elastase activity and was possibly not protein-free. Dr. GORE also opposed a prevailing theory that an accumulation of mucopolysaccharides initiates the atherosclerotic lesion since he had been unable to find such accumulations in young aortas in areas where lesions were not already present; and indeed fatty streaks appeared to be associated with a local depletion of mucopolysaccharides (in agreement with earlier results of MOVATAND MOREl). A temporary change in circulating lipoproteins leading to their deposition in the wall in small amounts was considered by A. LAZZARINI-ROBERTSON (New York) to be a possible initiating factor in atherosclerosis. One of two types of cells obtained J. Atheroscler. Res., 1 (1961) 362-365

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from organ cultures of atherosclerotic aortas incorporates lipoproteins rapidly, and when the lipid-laden cells are isolated and incubated with cells from normal aortas some degenerate and release lipids which are incorporated into normal cells. Local vascular changes induced by the initial deposition could therefore be self-perpetuating and would not require permanent alterations of the blood lipids for their further development. N. T. WERTHESSEN (San Antonio) stressed the importance of local tissue factors in determining the degree of unsaturation of cholesterol esters which accumulate during atherosclerosis, pointing out that those in atherosclerotic tissue are more highly unsaturated than those in undiseased parts of the same arterial wall. V. FELT, S. R6HLING, J. HLADOVEC AND S. VOHNOUT (Prague) described the isolation of an "intercellular cement substance" from the aortic intima of rabbits which they had found to take up more labelled cholesterol from injected serum lipoproteins in atherosclerotic (cholesterol-fed) rabbits than in the controls. This intercellular substance, rather than the endothelial cells, was considered by J. ROSKAM and co-workers (Liege) to be the source of factors involved in blood coagulation. The activity of several enzymes had been examined by G. W. KITTINGER, B. C. WEXLER AND B. F. MILLER (Cincinnati) in the aortas of normal and atherosclerotic rats. Lactic dehydrogenase and phosphoglucomutase activity were lower and uridinediphosphoglucose pyrophosphorylase activity was higher in the diseased aortas, while T P N H production by the combined action of glucose 6-phosphate dehydrogenase and 6-phosphogluconic acid dehydrogenase was depressed. The importance of histochemical examination of enzyme activities to detect differences at various points of the vessel wall was emphasized by Z. LOJDA (Prague), though this point of view was contested by P. MANDEL (Strasbourg), who believed that local differences in the permeability of the wall could lead to apparent quantitative differences in the substrate which could be misleading. Both P. BEACONSFIELD (Rome) and P. MANDEL (Strasbourg) showed that glycolytic enzyme activity is high in arteries. Metabolism of glucose by this route, as opposed to its oxidative consumption, leads to a low rate of synthesis of the sources of energy bound to polyphosphate nucleotides (adenosine triphosphate, guanosine triphosphate, and uridine triphosphate). Depletion of these energy sources, in which the arterial wall is already poor, during the ageing process leads to decreased protein synthesis and disharmony of protein and mucopolysaccharide synthesis, which may result in the formation of free acids of high affinity to lipoproteins. The effects of hormones on arterial metabolism were discussed by M. R. MALINOW (Buenos Aires) and B. F. MILLER AND B. C. WEXLER (Cincinnati). The latter authors had succeeded in inducing a type of atherosclerosis as well as thrombosis, myocardial infarction and aneurysms in rats by injecting adrenocorticotrophic hormone into animals which had been repeatedly and frequently bred. They advocated paying more attention to the stress factor in the disease. MALINOW had demonstrated gonadal control of aortic endogenous oxygen uptake (in rats), the direct action of oestrogens on arterial oxygen consumption in vitro, and the fact that the arterial wall (of chickens) is capable of taking up oestradiol. J. Atheroscler. Res., 1 (1961) 362-36S

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The effect of other local changes on the development of atheroclerosis which were discussed included that of vasoconstrictor stresses, induced by W. H. GUTSTEIN (New York) with the help of a minute radio receiver attached to the vasomotor nerves of the aorta, and by S. RODBARD and collaborators (Buffalo) by enclosing part of the carotid artery in a polyethylene sleeve. J. C. PATERSON (London, Ontario) outlined the evidence for intimal capillary haemorrhage as the initiating event. R. ALTSCHUL (Saskatoon) had succeeded in inducing a form of atherosclerosis in the resistant species prairie gopher only by feeding cholesterol in conjunction with Sudan IV, and attributed the effect of the dye to a modification of endothelial permeability. C. J. SCHWARTZAND J. R. A. MITCHELL (Oxford) produced a challenging paper opposing the view held by some that the fatty streak is the precursor of the atherosclerotic plaque. They maintained that there is no positive evidence to support the view (quoting the lack of publications describing lesions intermediate in nature between fatty streaks and plaques) and much evidence against it, including the different topographical distribution of the two types of lesion in the artery and the lack of correlation between occurrence rates of fatty streaks and raised plaques in various populations. P. CONSTANTINIDES(Vancouver) pointed out that in rabbits subjected to waves of hyperlipidaemia over protracted periods animals sacrificed at an early stage showed fatty streaks while those examined after a further period showed typical plaques, but SCHWARTZ insisted that such evidence necessarily remained indirect. Regarding the possible influence of the arterial wall on thrombosis, both E. PERLICK (Leipzig) and L. DONNER (Prague) had determined the thromboplastic activity of human aorta; DONNERhad also examined other arteries. Both workers had established that aortas bearing ulcerated plaques had lower thromboplastic activity than nonatherosclerotic vessels, but DONNER could find no difference between the latter and mildly atherosclerotic aortas in this respect, while PERLICK found a regular decrease in the activity with increase in degree of atherosclerosis, which could be attributed in part to a decrease in the anti-heparin activity detectable in aqueous extracts of both intima and media. Modifications of components of the "extrinsic" coagulation system took place chiefly in the intimal layer. In the field of experimental atherosclerosis, the trend is to abandon traditional methods leading to foam-cell proliferation of the intima and to search for techniques which will produce lesions more closely resembling the spontaneous disease in man. G. A. GRESHAM AND A. N. HOWARD (Cambridge) showed, for instance, the lesions produced by feeding large quantities of butter and beef fat, without cholesterol, to rabbits and their microscopical and histochemical similarity to the fibro-elastic plaque of human atherosclerosis. T. B. CLARKSON AND H. B. LOFLAND (WinstonSalem) pointed out the possible use of a hitherto unused species for the study of atherosclerosis: the White Carneau pigeon, which develops atherosclerosis spontaneously on a grain diet. P. CONSTANTINIDES AND R. N. CHAKRAVARTI (Vancouver) were amongst those modern investigators endeavouring to produce not only atherosclerosis but thrombosis and myocardial infarction in animals. They had investigated J. Atheroscler. Res., 1 (1961) 362 365

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the effects of three types of agents, namely those causing vascular-wall injury (Viosterol), blood hypercoagulability (low dosage of RUSSELL'S viper venom) and blood pressure changes (adrenaline, chlorisondramine), on rabbits made atherosclerotic by a previously described technique (long-term exposure to waves of hyperlipidaemia). Only a combination of all three agents was effective in producing mural aortic thrombi, coronary thromboses and myocardial infarction. Thrombosis occurred for the most part in severely atherosclerotic arteries (though non-atherosclerotic arteries could also be affected) and most thrombi developed over necrotic, ruptured or haemorrhagic atheromatous plaques. A connection between atherosclerosis and thrombosis was thus in this study clearly indicated. In general, the impression gained concerning animal "atherosclerosis" is that it is likely to become a more useful tool for studying the spontaneous human disease than it has been in the past. REFERENCE 1 H. Z. MOVATAND 1~. H. MORE, Circulation, 12 (1955) 484. J. Atheroscler. Res., 1 (1961) 362-365