791

The Progression of AtherosclerosisIT is part of the folklore of atherosclerosis that the

condition takes decades to develop; this may be true ofthe total picture, but there is increasing evidence thatindividual lesions can develop at a rapid rate. In a largeseries of repeated angiograms DeBakeyl recognisedthree groups-mainly younger patients with individuallesions that appear and rapidly progress in the course ofone to three years, patients with gradual progression,and patients in whom the disease seems to be static overmany years. This is compatible with necropsyfindings; most aortas from subjects aged forty andabove have lesions of several different types and stageswithin a single segment, ranging from small, focalproliferations of smooth-muscle cells to large whitefibrous plaques, and from fatty spots to large fibro-fattylesions.Published reports on repeat angiograms after

coronary artery bypass grafting describe changes in thehomografts, the bypassed vessels, and vessels that havenot been bypassed. The main objective of most of thesereports is evaluation of surgical procedures, but as abyproduct they provide some new insights into

atherogenesis, which is a process that we still do notunderstand. Angiography cannot tell us about thenature of lesions, but it provides information on thetime-course of their growth in relation to other factors.

1. DeBakey ME. Patterns of atherosclerosis and rates of progression. In: Carlson LS,Paoletti R, Weber G, eds. International Conference on Atherosclerosis. New York:Raven Press, 1978: 45-48.

The most widely used autograft is the saphenousvein. In most series about 80% of grafts are patentabout one year after surgery, and thereafter the rate ofocclusion is slower, at 1-2% per annum.2-4 Most

saphenous vein grafts also undergo luminal narrowing;in 6-18 months nearly 70% showed diffuse or focalnarrowing of 20-4507o and in 12% narrowing reached50-80%. New occlusions were particularly associatedwith focal narrowing.3 Histological studies on

saphenous vein grafts recovered at reoperation ornecropsy suggest that occlusion results fromthrombosis rather than intimal proliferation. The ratioof intimal to medial thickness in grafts examined 0-30days (mean 14) after implantation was between 1 and 2,and the thickness fairly uniform; this was similar to theratio in native saphenous veins from random

necropsies in the same age group. After 12 months theratio had increased to 3 in 57% and to 4 in only 10% ofgrafts, and these thickenings were mainly focal. 5,6Focal mural thrombi were a feature of virtually all

segments of saphenous vein grafts and the amount offibrin increased with time. 7 Thrombi were not

specifically associated with valve sites, and they werepresent at all time intervals, so did not necessarilyresult from endothelial damage during harvesting andinsertion of the vein. The mural thrombi consisted ofthin, laminar deposits of fibrin, and the layeredappearance of the intima suggested a causal relationwith intimal thickening.6,7 "Fibrous plaques"containing loose, cellular conective tissue, foci of fibrinand, in one case, lipid-laden macrophages were alreadypresent in four grafts in place for 14-30 days, and>75% luminal narrowing was caused by concentricplaques in two grafts in place for 4 and 6 months. In adifferent series the time-course seemed longer, possiblyreflecting different definitions of atherosclerosis, but"true atherosclerosis" was seen after 12 months, andwas more frequent in patients with hyperlipidaemia.6Thus in the grafted vein an atherosclerotic plaque,probably initiated by mural thrombus, can developwithin a year.Reports on repeat angiograms of the coronary

arteries themselves fall into three groups-wholecoronary trees in non-operated patients who had towait a long time before surgery, or received medicaltreatment only; non-bypassed arteries in patients withgrafts to major stenoses; and the proximal bypassedsegments of grafted arteries. In unbypassed arteries

2 Robert EW, Guthaner DF, Wexler L, Alderman EL. Six-year clinical and angiographicfollow-up of patients with previously documented complete revasularization.Circulation 1978; 58 (suppl 1): 194-99.

3. Campeau L, Lespérance J, Corbara F, et al. Aortocoronary saphenous vein bypass graftchanges 5 to 7 years after surgery. Circulation 1978; 58 (suppl 1): 170-75.

4. Kouchoukos NT, Karp RB, Oberman A, et al Long-term patency of saphenous veinsfor coronary bypass grafting. Circulation 1978; 58 (suppl 1) 96-99.

5. Lawrie GM, Lie JT, Morris GC, Beazley HL. Vein graft patency and intimalproliferation after aortocoronary bypass: early and long term angiopathologiccorrelations. Am J Cardiol 1976, 38: 856-62

6. Lie JT, Lawrie GM, Morris GC. Aortocoronary bypass saphenous vein graftatherosclerosis. Am J Cardiol 1977; 40: 906-14.

7. Bulkley BH, Hutchins GM. Accelerated "atherosclerosis": a morphologic study of 97saphenous vein coronary artery bypass grafts. Circulation 1977; 55: 163-69.

792

new lesions appeared remarkably seldom in the

angiographically normal segments. In nearly 1500segments new lesions were seen in only 1% after oneyear, and 407o after_about five years; in one small series(26 segments) new lesions were reported in 2307o aftersix years.8-1O This slow rate of initiation is surprisingbecause the patients all had disabling cardiac ischaemiaalthough many were young. However, the results maybe distorted9 because repeat angiography is availableonly on survivors, and patients with rapidlyprogressive disease may have died or receivedadditional bypass surgery. In contrast to the normalsegments, existing lesions showed a high incidence ofprogression which related to type of lesion and initialdegree of stenosis." 11 Up to one year there was

progression in 12% of lesions initially producing<50% stenosis, and this increased to 40% in two to sixyears; half the lesions with >75% stenosis were totallyoccluded by six years.8,12 Most rapid progression(without occlusion) occurred in lesions with 25-50%initial stenosis. Larger lesions seemed to progress moreslowly; I 1,13 this might be an artifact resulting from theirhigh rate of total occlusion, or reflect loss of water asearly oedematous proliferative lesions mature intofibrous plaques.’4,1s

In the proximal segments of bypassed arteries

progression of stenosis and occlusion was accelerated,and this has led to debate on the wisdom of graftingarteries with <50% stenosis.16 After a year there was

progression in 45-58% of bypassed stenoses comparedwith 10-12% in unbypassed segments.8,12 As in nativearteries, lesions with <50% initial stenosis progressedmore frequently than larger lesions (85% versus 65% attwo to three-and-a-half years) and showed a greaterincrease in narrowing.12 After five years new lesionswere seen in 12% of previously normal segments inbypassed arteries compared with only 2% of the sameanatomical segments in medically managed patients. 10In a small series of bypassed arteries with <50%

stenosis, Cashin et all’ 17 reported a much higherincidence of progression and production of newlesions.

8. Bourassa MG, Lesp&eacute;rance J, Corbara F, Saltiel J, Campeau L. Progression ofobstructive coronary artery disease 5 to 7 years after aortocoronary bypass surgery.Circulation 1978; 58 (suppl 1): 100-06.

9. Bruschke AVG, Wijers TS, Kolsters W, Landmann J. The anatomic evolution ofcoronary artery disease demonstrated by coronary arteriography in 256 nonoperatedpatients. Circulation 1981, 63: 527-36

10. Prick MH, Valle M, Harjola P-T. Progression of coronary artery disease in randomizedmedical and surgical patients over a 5-year angiographic follow-up. Am J Cardiol1983; 52: 681-85.

11 R&ouml;sch J, Antonovic R, Trenouth RS, et al. The natural history of coronary arterystenosis. Radiology 1976; 119: 513-20.

12 Cosgrove DM, Loop FD, Saunders CL, Lytle BW, Kramer JR. Should coronaryarteries with less than fifty percent stenosis be bypassed? J Thorac Cardiovasc Surg1981, 82: 520-30.

13. Kramer JR, Kitazume H, Proudfit WL, et al. Segmental analysis of the rate ofprogression in patients with progressive atherosclerosis. Am Heart J 1983, 106:1427-31.

14. Haust MD. The morphogenesis and fate of potential and early atherosclerotic lesions inman. Human Pathol 1971; 2: 1-29

15 Smith EB, Ashall C Compartmentalization of water in human atherosclerotic lesions.Arteriosclerosis 1984; 4: 21-27.

16. Loop FD. Progression of coronary atherosclerosis. N Engl J Med 1984; 311: 851-53.17. Cashin WL, Sanmarco ME, Nessim SA, Blankenhorn DH. Accelerated progression of

atherosclerosis in coronary vessels with minimum lesions that are bypassed. N EnglJ Med 1984; 311: 824-28.

The acceleration in grafted arteries is presumed to berelated primarily to reduction in flow-relativehaemostasis leading to increased tendency to

thrombosis. In histological studies on patients whodied at various times after bypass surgery, thrombuswas found immediately distal to stenoses in 48% of 35bypassed coronary segments,18 and fibrin was presenton the walls of 27% of vein grafts and 24% of theassociated bypassed coronary arteries,19 thus

implicating a thrombic component in their increasedatherogenesis. (Forty years before these studies

Duguid20 proposed that deposition of fibrin thrombuswas a major factor in plaque growth.) The results alsoimply that proximal stenoses that reduce flow mayaccelerate atherogenesis in the distal segments of

unbypassed arteries. Reduced haemostatic pressure inthe bypassed segment could also change endothelialpermeability. In studies on the permeability of rataortas to circulating protein tracers Huttner et al2’found an increase in hypertension, but in acutelyhypotensive animals (20-30 mm Hg) much largeramounts of protein tracers appeared in the

subendothelium, suggesting a loss of endothelialbarrier function. In theory, this could also occur instenosing lesions in unbypassed arteries. As blood

passes through a constriction there is increase in

velocity and drop in pressure. Brown 22 calculated thatwhen blood at a flow rate of 1’ 1 ml/s passed through60%, 70%, and 80% stenoses in the left anterior

descending artery the minimum pressures at thenarrowest point would be 5, 14, and 72 mm Hg lessthan aortic pressure. This pressure drop might causean advanced atheroma to collapse and ulcerate. It

might also, as in the hypotensive rats, change thebarrier function of the endothelium and lead to

pathological insudation of plasma components into thestenosing lesion, thereby adding to its growth.

Surprisingly, progression of coronary artery stenosiswas not related to the conventional risk factors,hypercholesterolaemia, hypertension, and smoking.9,12This was so even in a group of relatively young patients(mean age forty-eight at the time of their first

angiogram) in whom the risk factors were monitored atboth first and second angiograms. However, increasedocclusion, presumably thrombotic, was significantlyassociated with smoking.23

It is clear that serial angiographic studies offer manypointers that may help us to understand the

development of atherosclerosis and that there are a

18. Vlodaver Z, Edwards JE Pathologic analysis in fatal cases following saphenous veincoronary arterial bypass Chest 1973, 64: 555-63

19. Spray TL, Roberts WC. Status of the grafts and the native coronary arteries proximaland distal to coronary anastomotic sites of aorto-coronary bypass grafts Circulation1977; 55: 741-49

20. Duguid JB Thrombosis as a factor in the pathogenesis of coronary atherosclerosis. JPathol Bacteriol 1946; 58: 207-12.

21. H&uuml;ttner I, Boutet M, Rona G, More RH. Studies on protein passage through arterialendothelium. Lab Invest 1973; 29: 536-46

22. Brown BG, Bolson EL, Dodge HT. Dynamic mechanisms in human coronary stenosis.Circulation 1984; 70: 917-22.

23. Moise A, Lesp&eacute;rance J, Theroux P, et al. Clinical and angiographic predictors of newtotal coronary occlusion in coronary artery disease: analysis of 313 nonoperatedpatients. Am J Cardiol 1984; 54: 1176-81.

793

wealth of data on file. Unfortunately, the natural

history of atherosclerosis was not the primary topic ofmany of the published papers, and the information thatcan be gleaned from them, particularly with respect tothe time factor, is often incomplete.

Food and PopulationTHE wellbeing and the numbers of each biological

species depend on food supply; and, for Homo sapiens,annual estimates of world populationl and world foodsupplies2 allow us to assess how we as a species aregetting on. The world population in 1983 was 4677million-an increase of 1770 million since 1960. Of the

present population 25% live in "more developed"countries, mostly in Europe and North America with afew in other continents. In these the rate of populationincrease is falling and the overall annual rate is now0.16%; in Austria, Belgium, Denmark, West and EastGermany, Hungary, Sweden, and the UK the popula-tions now seem to be in equilibrium. In the "lessdeveloped" parts of the world, population is increasingat an estimated overall annual rate of 2 .1% (in Chinaonly 1. 5% but in the whole of Africa 3 .0%).Over one-third of the world population live in China

and India and in each of these countries there are nowmore people than in the whole continents of America orEurope or Africa. Both the Chinese and Indian govern-ments actively support family planning, which is

becoming more and more acceptable to the people. As aresult birth rates, though still high (23 per thousand inChina and 36 per thousand in India), are beginning tofall and the growth of population to slow down. InChina, since the government began to encourageindividual enterprise among peasant farmers, foodproduction has increased and by over 7 - .5% in the pasttwo years. In India food production has increased overthe past 30 years, about as fast as population growth.This has been achieved more by increasing yields thanby bringing fresh land into cultivation. Thus the yieldof food grains rose from 605 kg/hectare in 1955-56 to944 kg/hectare in 1975-76 and to 1032 kg/hectare in1981-82,3 a year the monsoon rains were good. Indiahas much good soil and everywhere there is abundantsunlight, which provides the energy for cereal produc-tion. (Blaxter4 has calculated that the maximum yieldof cereal with the sunlight available in the UK is 13tonnes per hectare and that this has been achieved byone Lothian farmer.) Indian farmers have the sunlightthat could enable them to produce much more cereal ifthey continue to apply the new agricultural methodsmade available by the green revolution as they have

1 Population Reference Bureau. World population, 1984. 1337 Connecticut Avenue,Washington DC: PRB, 1984

2 Food and Agriculture Organisation of the United Nations. The state of food andagriculture. 1983. Rome: FAO, 1984

done in the past few years. If family planningprogrammes gain momentum, Indian agricultureshould be able to provide the food for the inevitablefurther increase in population. Cautious optimism ispermissible for China and India and also for most othercountries in Asia, where in general food supplycontinues to keep pace with population growth.2

It is difficult not to be pessimistic about Africa. Birthrates continue to be over 40 in most countries and the

population continues to grow at an undiminished rateof about 3% every year. Family planning programmesget little or no support from most governments and arenot yet effective. The FAO report2 has a special sectionon Sub-Saharan Africa, which consists of 46 countriesthat lie completely or partly south of the Sahara desert.In most of these the food supply has been barelykeeping pace with growth of population and in at least21 countries has been falling behind in the past decade.The situation is worst in the Sahel, the region thatborders the desert and stretches for over 3000 milesacross the continent.

The causes are manifold. Firstly, there is theweather. For several years rainfall in the Sahel has beenbelow average and the Sahara desert is slowly movingsouth. Secondly, the livestock population is falling.This is only partly because of lack of fodder. In manycountries there are large losses of cattle from disease,notably rinderpest: the veterinary services that couldtackle this disease are not available. However, themajor obstacles to development of agriculture are

human. The colonial powers (Belgian, British, French,and Portuguese) each encouraged the production ofcrops for export and paid less attention to the growth ofcrops required to feed the local populations. Afterindependence national governments, with the laudableintention of increasing their countries’ wealth, haveoften continued this policy. But the world markets forthese crops have declined and prices have fallen. Manyfarming families, unable to get a living from theircrops, have migrated to the large cities hoping to findwork. There, although governments have invested inindustries producing essential goods, much money hasbeen spent on prestige projects such as state airlinesand government buildings; arrangements for the 1977meeting of the Organisation of African Unity costGabon over$200 million. Back on the farms, peasantsin some countries have been confused and have becomeless productive following government schemes to takeover ownership of the land which, however wellmeaning in intent, have been planned inadequately.The FAO report describes the economic problems

besetting African countries dependent on internationaland overseas trade for support for their food supply.There are seven pages of tables giving economic andagricultural data for individual countries and over 30pages of text written in United Nations English, not

3 Gopalan C. Nutrition and health care: problems and policies 1984. Nutr Found IndiaSpec Publ Ser 1984, no 1, 29

4 Blaxter K. Food and power Yearbook of the Royal Society of Edinburgh. Edinburgh.RSE, 1982: 5-11.