the role of nutrition atherosclerosis in

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THE ROLE OF NUTRITION IN ATHEROSCLEROSIS

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Ar-r-Ell B. Krnc .lNn JoHN W. FanquHAR LAncE AND GRowING pRopoRTroN oF MANKIND faces starvation because nutritional needs have outstripped food production.r These problems

of starvation and malnutrition have been discussed in another chapter (see Bergstrom, Food and PoTtulntion-a critical aypraisal). In modern and industrialized countries,however, starvation is overshadowedby problems created by the abundance of food, or by ingestion of types of foods that create ill health, Arising in parallel with this excessiveor altered food consumption has been the disease of atherosclerosis.This disease manifests itself primarily in the form of cardiovascular diseaseswhich now account for more than half the deaths in the United States and in many other countries. They are also responsible for a Iarge proportion of all premnture deaths in the age group thirty to sixty-five in both men and women. This chapter will be concerned with nutritional factors related to the development of atherosclerosisand with the control of those factors as a means of curbing the pandemic. I. Atheroscleroaie and ita Manifeetations Atherosclerosisis but one of many arterial diseases.The commonly used term lnrd,ened arteries includes not only atherosclerosisbut also thl much less common process termed Monckeberg's medinl calcific scbrosis which is characterized by calcification of the muscle wall of the arteries but no obstruction to blood flow. It also encompassesthe disease of arteriolosclerosiswhich is characterized by reactive changes in the smallest arteries as a result primarily of elevated blood pressure.2There are other arterial diseases such as inflammation of the arteries secondary to inThis investigationwas supported (in part) by a National Institute of Health Fellowshio I F03 AM 53722-01 from The National Institute of Arthritis. Metabohs; and DigestiveDiseases. "World hunger: Past, present, prospective "Thot there u;ould be greot l. lf3figier, famine." World Reo Nuh Diet,9: I ( 1968). 'S. L. Robbins, Pathology,3rd ed. (Philadelphia, W. B. SaundersCo., 1967), Vol. 1, pp. 753-602.

2A:7

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248

Enoironmental Problems in Medicine

fectious agents, e.g. syphilis, or altered immunity, e.g. polyarteritis nodosa.s However, because of its frequency and severity, atherosclerosisis by far the most important of the arterial diseases. The term atherosclerosis is derived from athero meaning soft mush or gruel, and sclerosrsmeaning hard. Properties of both softness and hardness are found in atheromatous lesions as a soft core of fat is encased in fibrous and calcium infiltrated tissue.3 Atherosclerosis is a silent disease until late in its development. It becomes known to the patient and his doctor through reduction of blood flow to a vital organ or through rupture of a diseased vessel. A partial reduction of the supply of oxygen and nutrients to tissues may manifest itself as periodic pain in the chest (angina pectoris), as transient alterationsin function of the brain (cerebral ischemia) or as leg pain follorving exercise (intermittent claudication). If the blood fow is not adequate to maintain cellular function, death of portions of the heart, brain or other tissues may occur. This can result in brain infarction; in gangrene if the process involves the extremities; or in myocardial infarction if the process involves the heart. Since the nutrient arteries to the heart are called the coronary arteries, myocardial infarction and angina pectoris are collectively termed coronary heart disease

(cHD). In the aorta,the invasiveatheromatousprocessmay result in a ballooning out of the weakenedarterial wall to form a so-calledaneurysmwhich may subsequentlyrupture into the surroundingtissuesor result in bleeding into the walls of the arterial lesion. A dissectionalong the arterial wall may subsequentlyoccur and result in blockage of branch arteries in its pathway. II. The Magnitude

of the Atheroscleroeie Problem

A. Illortality

One method of illustrating the gravity of the pandemic is through statistics of mortality resulting'from diseases directly or indirectly attributable to atherosclerosis.These data are collected by the United States Department of Health, Education, and Welfare from the death certificates listing the cause of death of each person dprg in the United States. Unfortunately these data are by no means complete. The sources of error include a) the inability of the physician to.accurately determine the cause of death in all caseswithout Iaboratory or autopsy assistance,b ) the need to identify a single cause of death despite the fact that the patient may have had multiple diseases contributing to death, and c ) the forced categorization of the cause of death into a list of diseasescoded to the ---Ua"siFca6o"

of atheroscleroticlesions. WHO: Techn Rep Ser, 143:4 (f958).

The RoIe of Nutrition in Atherosclerosis

2'4:9

lnternational Statistical Classification of Diseases, lniuries, and Causes of Death. Despite these inadequaciesthese statistics do represent the most complete and authoritative record of mortality causesin the United States. In Table XII-I are listed the eight most common causes of death in the United States for the year 1970.aMore than one half of all deaths in the United States result from cardiovasculardisease.This representsmore TABLE XII.I ESTIMATED DEATH RATES FOR THE EICHT LEADING CAUSESOF DEATH IN THE UNITED STATESDURING I97O Ronk

t, 2. 3. 4. 5. 6. 7. 8.

Co!.c

ol Deoth

All Causes CardiovascularDisease Malignant neoplasms,including neoplasmsof lymphatic and hematoporetic tissues Accidents Infuenza and Pneumonia Certain causesof mortality in early infancy Diabetes Mellitus Cirrhosis of liver Bronchitis, emphysema, and asthma

Death Rote

Percett ot Toto) Deetha

940.4 494.0

100.0 52.5

162.0 54.2 30.5 20.9 18.5

r5.8

r7.2 5.8 3.2 2.2 2.0 t.7

14.9

1.6

N of death are according to the Eighth Revision, Intemational Classificationof Diseases, Adopted, 1965. Data from Monthly Vital StatisticsReport ( 4 ).

than one million of the almost two million people who die every year. Deaths from cardiovascular disease are three times more numerous than those from cancer. Of these cardiovascular deaths, three-fourths were due to heart disease and about one-fourth to cerebrovascular disease.aOf those due to heart disease, almost all (over 90%) were secondary to coronary heart disease ( CHD ). In the case of cerebrovascular disease, atherosclerosisshares the major etiological role with hypertension.6 Heart disease is not confined to the United States. The United States sharesan exceedingly high heart diseaserate with Northern Ireland, Scotland, Australia and Finland.o In one study, the United States, Finland and the Netherlands were found to have approximately five times the death rate from CHD in men aged forty-five to fifty-nine as did such men in Italy, Greece and Japan.? Evidently, countries differ greatly in their death --'A";;is,rmmary

for the United States,1970. Monthly Vital StatisticsReport, I9:1 (1971). oC. M. Fisher, ]. P. Mohr, and R. D. Adams, "Cerebrovascular Diseases," in M. M. Wintrobe, et al., eds., Hartison's Prirwiplzs ol lnternal Medicine,6th ed. (New York, McGraw-Hill, 1970), pp. 1727-1763. oWorld Health Statistics Annual, 1966, "Vital Statistics and Causes of Death," WHO: Geneva,(i969), Vol. 1. ?A. Keys, ed., "Coronary Heart Diseasein Seven Countries," Amer Heart Ass Mottog, 529,

( re70).

250

EmsironmentalProblemsin Medicine

rates due to CHD. Further, the countries with high death rates, i.e. United States, Finland and Netherlands,are highly industrialized when compared to those countries,i.e. Italy and Greece,where coronary deaths in the forty to sixty-five age group are very rare. There are exceptions however since Finland is probably not as highly industrialized as is Japan. Heart diseaseis not confined to the elderly. It is the most common cause of death in males or females after the age of thirty-five in the United States and is exceeded onlv bv accidents as a cause of death in the twenty-five to thirty-fo,-rr gro"p (see footnote 4 ). Young adult men "g" are particularly susceptibleto heart diseaseand during middle age about one half of male deaths result from heart disease (Table XII-II). UnTABLE XII-II DEATHSDUE TO CARDIOVASCULAR DISEASEIN THE UNITED STATES DUNINC 1966 ACCORDING TO ACE AND SEX 'llmcn Agc Group

35-44 45-54 55-64 65-74 to+

4o of All Dcotha

34.r 48.4 54.6 59.6 67.4

Abtolute No. i^ t,o00.

15.7 5I.2 105.0 r57.4 224.7

m y'6

o! AII Deotha

25.1 33.1 46.r 60.6 73.r

No. in t,000t

7.2 19.2 46.6 109.0 269.8

Data from reference(6).

fortunately women rapidly catch up so that past sixty-five years of age their mortality is the same as the male rate. B. Preualence Studies Prevalence is defined as the amount of disease per unit of population found at any one time. It may give a misleading picture of the severity of a disorder since individuals who previously died from the problem are, of course, not included in the sample. Nevertheless,knowledge of prevalence can furnish some guide to the extent of the problem among the living population. 'artery The prevalence of coronary disease in the United States was determined in the National Health Suroey conducted from October, 1959 to December, 1962.8The survey was based on a nationwide probability sample of 7,710 adults between eighteen and seventy-nine drawn from the civilian noninstitutional population of the continental United States. Altogether 6,672 persons or 86.5 percent of the sample volunteered to ---T.

e;4"" ^nd C. C. Garst, Coronary Heart Disease in Adults, lJnited, States, 1960-1962, Data from the National Health Survey, National Center for Health Statistics, Public Health Survey Publication No. 1000, Series 11, No. I0, September 1965, US Department of Health, Education and Welfare.

The RoIe of Nutrition in Atherosclerosis rtes,i.e. United rhe^:ompared ths ,,.r the forty however sincl most common r in the United death in the rng adult men Idle age about : XII-II). Un-

examination during during which a brief history, hour examination histo{/, physical, physical, undergo a two hour electrocardiogram resting were and performed. Extrapolated tests blood

to the total United Statespopulationof 111.1million adults in the age group studied, the survey showed that 5.5 million, or approximately 5 iercent, had someevidenceof myocardial infarction or of angina pectoris. is in the mortality studies (Table II) young men showeda trend towards increasedheart disease(Table XII-III). Thus one out of every fffteen TABLE XII-III THE PREVALENCE OF CORONARYARTERY DISEASEIN ADULT MEN AND WOMEN ACCORDING TO AGE CROUP IN THE UNITED STATES Totcl

ED STATES 'tucn

---------76;ffi; No. in 1,0O0t

19.2 46.6 109.0 209.8

years of age

of population f the severity , problem are, dge of prevan among the ,d States was Jctober, 1959 te probability drawn from Inited States. rlunteered to tates, 1960-1962, rs, Public Health bment of Health,

25L

35-44 45-54 55-64 65-74 75-79

o.4 1.6 D.O

r 1.9 15,4 12.4

6

0.4 2.3 6.9 I4.r 16.8 13.0

0.3 1.0 4.1 9.9 14.3 11.9

Data from reference ( 8 )'

men between forty-five and fifty-four years of age has some evidence of coronary artery disease. C. Prospectioe Studies As previously mentioned prevalence studies may seriously underestimate the true incidence of a disease because prevalence data are derived only from the living. Since mortality rates from coronary disease are high, and are higher for men than women, the distortion in the true picture is great. For example, among men under the age of sixty-five during a fourteen year period approximately 50 percent of coronary disease episodes were in the form of myocardial infarction and approximately 50 percent of these were fatal within the first hour.e Sudden death among women was less common than in men and only 25 percent of all new episodes presented as myocardial infarctions.lo Although there has not been a prospective study based on a representative sample of the entire United States several studies of various populations within and without the flnited States have been reported since 1950. The best lcnown and Iongest study has been conducted under the auspices of the United States Public Health Service in Framingham, Massachusettslobeginning in 1950. A random sample of 4393 subjects (68.7% 'T. Gordon and W. B. Kannel, "Premature mortality from coronary heart disease," The Framingham Study, J Amer Med Ass, 2-15:1617 (197f ). 'qT. R. Dawber, W. B. Kannel and P. M. McNamara, "The prediction of coronary artery disease," Traru Ass Life Insur Med Dir Amer, 47:70 (f964).

2,52

Enpironmental Problemsin Medicine

responserate) '*'as taken, and combined with 734 volunteer subjects. All were free of coronary artery disease and between thirty to fifty-nine years of age. Subjects were followed for sixteen years through biennial examinations. Table XII-N gives the findings of the initial phases of the Framingham TASLEXII-IV THE PERCENTOF MEN OR WOMENOF A CERTAINAGE GROUPAT ENTRANCETO THE STUDYWHO DEVELOPEDCORONARY ARTERYDISEASEOVERA 10 YEARPERIOD Percent

?ypc ol Cotnary Attery Diacaae

All Forms Angina Pectoris Myocardial Infarction Sudden Death Data from reference 10.

Derelopiag

Coronory Agc

Irt-

3.8 0.6 t.7 0.6

30-39 W*

0.3 0.2 0.t 0

Diteoae

I0-t9

M"r,

9.6 2.6 4.2 L.2

Oocr

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t0

Pcrioil

at Entr!

w*

3.t 1.9 0.5 0.2

-

50-59

M;-----w;;;

16.0 J.l /.J

2.8

8.6 5.2 2,7 0.3

Study, which reinforces other mortality. and morbidity data in demonstrating that coronary artery disease is very prevalent in males. Thus a man forty to forty-nine years old has almost a 10 percent chance of demonstrating some manifestation of coronary artery disease within ten years. As noted above males not only are more inclined to have heart disease but that their heart disease is more severe, producing a higher rate of infarction and death than that found in women.

,i

III. The Proceea of Atheroecleroaierr,r2 Although many questions have yet to be answered and controversy still rages, most students of atherosclerosisaccept the following description of the evolution of this disease. The first visible lesion to appear on the arterial wall is the fatty streak. It begins when fat accumulates in the intima or inner lining of the artery. Cells in the arterial wall take up considerable amounts of fat creating a visible yellowish lump on the artery lining. This early lesion does not cause obstruction to blood fow because it is soft and easily compressed flat by the pressure within the arteries. Histologically, the fatty streak contains cells packed with fat globules and surrounded by extracellular fat. Probably because of the irritating properties of extracellular fats, an inflammatory reaction develops around the deposit. First, there is cellular 'Arteriosclerosis-A Report by the National Heart and Lung Institute Task Force on Arteriosclerosis,Vol 2. DHEW Publication No. ( NIH ) 72, (IS7L). uP. Constantirides, Experimental Atheroscbrosis (New York, Elsevier Publishing Co., 1 9 6 5) .


'!*l

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253

infiltration followed by fibrous encasement, At this stage the lesion is called the fibrous plaque, and by enlarging into the arterial lumen may seriously reduce blood flow' Fibrous plaques may further progress into what are called complicoted lesior*. First the roof of the abscesslike lesion may become thin and eroded, thus spilling its fatty contents into the blood stream. The fatty and connective tissue debris thereby released into the arterial tree may be swept into vital organs such as the brain or heart and cause damage. This process is known as embolism. and may result in cerebral damage or damage to muscle tissue. The fate of the fibrous plaque following erosion is variable. The most important consequence is that clots of blood elements may form on the surface and these clots may further occlude blood flow. The frequency of fatty streaks, ffbrous plaques and complicated lesions in various countries of the world has been studied by the International AtherosclerosisProject.tt By using standardized means of assessingthe Iesions in arteries removed at autopsy, they found that fatty streaks were common in all countries, even those with a low mortality from atherosclerotic vessel disease. These lesions were present even at birth and increased in numbers up until young adulthood. Fibrous plaques emerged around young adulthood, increasing in frequency throughout life. Complicated lesions were seen in middle life and also increased in number with age. In countries with higher incidences of heart disease the process was accelerated; that is, more lesions were found at an earlier age. For example, men of Guatemala were found to have only l0 percent of their coronary artery surface covered with fibrous plaques by sixty years of age. On the other hand, white citizens in New Orleans have 30 percent involvement and a correspondingly higher prevalence of coronary heart disease. IV. The Cauee of Atheroecleroeie Several theories of the cause of atherosclerosis have arisen over the past centuries. These three are most important: first, the lipid filtration theory, which states that the lesion is initiated in a high pressure system by blood lipids invading the arterial wall; second, the thrombogenic theory which suggests that the lesion arises from a clot on the vessel wall; and third, the lipid synthesis theory, which maintains that the increased synthesis of fats by the cells of the arterial wall is responsible for the increased lipid content. Although lacking final confirmation, most workers now believe that the ffrst theory is generally correct: that atherosclerosisis originally inoH. C. McGill, ed., "The geographic pathology of atherosclerosis," Lab Inoest, 18:463, ( 1 9 6 8) .

254


duced by blood lipids invading the areterial wall, but modified by many factors (see footnote 12). The difficulties in testing these theories is that atherosclerosisrequires years to develop and that results from animal experimentation may not be transferable to humans. However, animal models of atherosclerosis have been developed which show many similarities to the human disease.t{ Through such studies, Constantinides (see footnote 12) has developed a mathematical expression of the atherogenic forces at work on the arterial wall. The formula states that atherogenesisis related to the degree of elevationin blood lipids, degree of arterial wall injury, blood pressure,and the duration of these factors combined with the tendency toward clot formation. It would seem obvious that fats are involved in the atherosclerotic process. Analyses of atheromatous lesions have shown them to contain large amounts of cholesterol, primarily as the ester, and also small amounts of triglycerides, phospholipids and steroids.l6 Current studies reveal that these fats enter the arterial wall by simply percolating through the intima and linings of the wall.16'17This pathway also appears to be the main sourceof oxygen and nutrients for the inner wall of the artery (see footnote I2). Many workers have now been able to reproduce the fibrous plaque lesions in the space of months or of a few years in many speciesof animals, including primates, through high cholesterolor high saturatedfat diets (see footnote 12). However, to achieve this vastly acceleratedrate of development it is necessaryto raise the plasma cholesterollevel to levels that may be four times higher than normal. In addition to high plasma cholesterol levels, pressureand turbulence appear to be a necessary factor in the formation of lesions. Atheromas do not occur in low pressure veins; they are most common at branch sites of arteries,that is, areas of great turbulence (see footnote 13). Duncanls has "E. G. Hill, W. O. Lunberg and J. L. Titus, "Experimental atherosclerosisin swine. I. A comparisonof menhaden-oil supplementsin tallow and coconut oil diets," Moyo CIin Proc, 46:613 (1972\. -J. C. Geer, R. V. Panganamala,H. A. Newman, et aL, "Mtral Metabolism," in R. J. jones, ed., Atherosclerosis:Proceedingsof the Second Intemational Symposium ( New York, Springer-Verlag,1970), pp. 6-12. 'J. C. Geer, R. V. Panganamala, H. A. Newman, and D. G. Cornwell, "Arterial Wall Metabolism," in R. W. Wissler, J. C. Geer, and N. Kaufman, eds., The Pathogenesisof Atherosclerosis(Baltimore, Williams and Wilkins Co., 1972) pp. 200-2f3. '?S. Dayton and S. Hashimoto, "Recent advances in molecular pathology: a review of cholesterolfux and metabolism and arterial tissue and atheromata," Exp Molec Path, 73: 253, ( 1970). '8L. E. Duncan, J. Cornffeld and K. Buck, "Circulation of labeled albrrmin through the aortic wall of the dog," Circ Res,7:390 ( 1959).

The RoIe of Nutrition in Atherosclerosis suggested that arterial hypertension accelerates entry of lipids into the wall by stretching the wall and making it more porous. However, hypertension actually irrjures the arterial wall, causing microscopic disruption of its structure (see footnote 12). Atheromas will develop at minimally elevated Iipid levels if the artery is injured from arterial hypertension or from any of a myriad of other arterial wall irritants (see footnote 12 ). Y. Nutritional Factore Related to Atheroscleroeia Atherogenesis is promoted by hyperlipidemia, arterial wall injury, blood pressure and thrombogenesis. Dietary food stufis acting through these channels and in concert with non-nutritional factors, such as cigarette smoking, physical inactivity and psychologi'cal stress, are resPonsible for the pandemic of CHD in the world. In this section, dietary factors are considered. A. Excessine Calories When calories are ingested in excess of needs they are stored in the form of triglycerides within fat cells. In adults the additional fat is accomodated by increasing the size of existing fat cells rather than an actual increase in the number of cells.le Obesity app€ars greater in the United States than in Japan and certain European nations (see footnote 7) including England.2oThis health probIem has probably resulted from the abundance of calories that are available for consumption and very likely from reduced physical activity that results from the increased mechanization of our work.2l The gravity of this American problem is illustrated in the statistics reported by the Metropolitan Life Insurance Company; approximately 30 percent of men and 40 percent of women in the United States over the age of thirty are 20 percent or more above their desirable weight ( see Table XII-V.22 Chiang et aI23have placed the prevalence of significant obesity somewhere between 20 percent and 30 percent of the entire nation. One must recall that these figures are based on the percent deviation from a so-called desirable weight standard. Strictly speaking they reflect ttE. A. Sims and E. S. Horton, "Endocrine and metabolic adaption to obesity and starvation," Amer I Clin Nutr, 21:1455 (1968). .D. o. Reid, w. w. Holland and G. A. Rose, "An Anglo-Americai cardiovascular Comparison,"Loncet,2:L375 ( f 967). aR. B. Stuart and B. Davis, Slim Cl'tance in a Fat World, Behaoior Control of Obesity, (Champaign,ResearchPressCo., 1972). s'Frequency of overweight and underweight," Starm Bull Metrop Life ltuwr Co., 47:4

( re60). 8B. N, Chiang, L. V. Perlman and F. A. Epstein, "Overweight and hnrertension' a review," Circ, 39:403 (1969).

:5{ E

rI|


2,56

I !41

.4

TABLE XII-V DESIRABLEWEIGHTS FOR MEN AND WOMEN ACCORDINC TO HEIGHT AND FRAME FOR AGES 25 AND OVER Yleioht in Poundt Hcioht (I^ Sho..)

5'

2" ............. 3" ..............

Small

Frome

lr2-L20 rI5-123

Mediun

(Ir Fromc

rt8-129 t21-133 t24-136 127-r39 130-I43 r34-r47 138-152 t42-I56 146-I60 150-i65 r54-I70 r58-175 r62-180 167-i85 t72-190

126-141 129-144 t32-148 r35-I52 I38-156 142-I6I 147-166 I5r-170 l5s-174 159-179 164-184 168-189 173-194 178-199 182-204

llomen

4',

s',

1u

8 " . . . . . . . . ..... . o,

118-13I 12%r33 126-135 130-140 t34-r44 138-I48

96-107 98-I l0 i0l-113 I04-lt6 r9 107-1 tt0-I22 I r3-126 1l6-130 120-135 128-I43 128-r45 L32-147 136-151 140-155 r44-159

104-119 I06-r22 109-r25 I l2-128 115-l3I 1I8-134 121-r38 125-142 129-146 137-154 137-156 l4r-158 145-r63 149-I68 r53-I73

overweight and not necessarily obesity. The possible discrepancy may be illustratJd by the example of an athlete at the Peak of phylical training who may be overweight according to the desirable weight table, but have little adiposity. Because oi this possible discrepancy other methods of assessingobesity have been developed. One simple method has been to measure skin-fold The thickness of fat between a fold of skin has been found thickness.24''z5 proportional to the total body fat tissue as measured by more laborious methods (op. cit.). However, there has not yet been extensive exPerience with skin fold measnrements; for the general population, relative weight -----*-C.

C. TAt"er and J. Mayer, "Greater reliability of the triceps skin fold over the subskin fold as an index of obesity," Atner I Clin Nutr,20:950 (f967). scapular -tArrorrl,orroot, "Skin fold thickness and body fat," Nutr Reo,26:104 (f968)'

257

The Role of Nutrition in Atherosclerosis

(current weight/ideal weight for height, age, build and sex x 100%) remains the best general indicator for obesity.26 One of the most comprehensive studies to demonstrate the relationship between obesity and atherosclerotic heart disease has been the Framingham Study.2zAt the start of this study each individual was assigned a relative weigirt determined by the ratio (x100) of the individualls observed weight to the median weight for his sex-height group in the entire Framingham cross-section. From Table XII-VI, it can be seen that persons with a relative weight TABLE XII-VI HEARTDISEASEIN AVERAGEANNUALINCIDENCERATEFOR CORONARY MEN AGED 45-54FORFRAMINGHAMRELATIVEWEIGHT (PERCENT) NANGESDETERMINEDDURINCA SIXTEENYEARFOLLOW UP

r05-r09 110-114 I 15-tt9 L20-124

r08 100 L23 r61 equals 100 percent. Data from reference (27).

t, l

ii

I i

of 120 or more have a risk of contractingnew coronaryheart diseasethat is twice as great as that for those at ideal weight. As the relative weight decreasesso does the risk. From data gatheredfrom death certificatesof life insurance policy holders, a similir relationship between overweight and mortality was obFrom this information,tableswere constructedgiving the specific served.28 to height and sex that is associatedwith the lowest according weight, mortality rates.2e It has been suggestedthat obesity per se is not important in the development of CHD, but that some factor associatedwith obesity,is rerponlibl".to These obesity-relatedfactors include hypertension, hyperlipidemia, and diabetesmellitus' Hypertension is significantlymore comrironin obeseindividuals than nonobeseand converselyobesity is a commonfinding in the.hypertensive tG. Bray, M. Schwartz, R. Rozin et aI', "Relationship between oxygen consumption and body composition of obese patients," Metobolism' 19:418 (1970). -T. R.-Dawber, F. E. Moore and G. C. Mann, "Coronary heart disease in the Framingham study," Amer I Pubhc Health 17 ( suppl ) :4, ( 1957). sBuild.andBtoodPresxtre sruly, 1959, Chicago. society of Actuaries, (1959), Vol. I. ."New weight standards for men and women," Stotist Bull Metrop Lile lnslzr Co., 40tl

( 195e).

sA. Keys, C. Aravanis and H. Blackbum, "Coronary heart disease: overweight and obesity as risk factors," Ann Intern Med, 77:15 (1972).

258

Enpironmental Problems in M edicinc

population (see footnote 17 ). This relationship does not appear to be an artifact of the indirect auscultatory methods of measuring blood pressure, but appears to be independent of arm circumference. Further evidence of this relationship is demonstrated in studies showing that a fall in blood pressureoccurswith weight reduction (see footnote 23 ). It is not clear how obesity leads to hypertension. Dahl and his associates contend that the increasedsalt intake that parallels the excessiveconsumption of calories is responsible.srThe influence of salt on blood pressurewill be discussedmore fully in a subserluentsection. (see Section V-D ). The increased fat storage in the fat cells of the obese, and increased levels of fats in the blood of overweight people seem to be related phenomena. This association will be discussed in the section dealing with cholesteroland saturatedfats. ( seeSectionV-B ). There are ample clinical and laboratory data relating the problems of diabetes and obesity. Like hypertension and hyperlipidemia, diabetes is more common in overweight individuals. This diabetes may be produced by gaining weight, and reduced by weight loss.32Obesity-related diabetes is most commonly a mild form in which blood sugar levels are only modestly increased: in these patients one generally finds increased plasma insulin levels.:rsConcurrent elevation of plasma glucose in the presence of an abundance of insulin may be the result of a delayed insulin releasefrom a malfunctioning pancreas, a defective insulin molecule or a tissue resistance to insulin's action. It is not known how obesity is related to glucose intolerance. One mechanism that has been suggested concerns the increase in fat cell size associated with adult weight gain. These enlarged fat cells demonstrate a diminished sensitivity to insulin's action.3{Thus with enlargement of adipocytes, higher levels of insulin are required to do the same amount of work. It may be that in those individuals with limited capacity to produce and secrete insulin, insulin secretion rates will eventually fail to maintain normal blood sugar and thus hyperglycemia and glucosuria will ensue in the presenceof hyperinsulinemia.(see footnote 33 ) A considerable amount of evidence for an association between hyper"L. K. Dahl, L. Sjlver and R. W. Christie, "The role of salt in the fall of blood pressure accompanfng reductionin obesity," Neus Eng J Med,25B:1186 (1958). sE. L. Bierman and D. Porte, "Carbohydrate intolerance and lipemia," Ann Intem Med, 68:926(1968). sE. J. Dressick, A. S. Brickman and E. M. Gold, "Dissociation of the obesity-hyperinsulinism relationshipfollowing dietary restriction and hyperalin-rentation,"Amer J CIin Nutr, 25:746 (1972). "'L. B. Salans,J. L. Kittle and J. Hirsch, "The role of adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity," ] CIin lnrsest,4T:153 (1968),

r

l-

q


ZSg

Epstein glycemia and atherosclerotic heart diseasehas been reported.35,3? has reported that in diabetic males, aged fifteen to forty-four, the mortality from atherosclerotic heart diseaseis 4.6 times higher than in nondiabetic males, and in female diabetics the death ratJis 6.4 times that found in non-diabetic females,s6Thus not only do young male diabetics have high death rates from heart disease;diabetes removes the usual immunity from atherosclerosisin young women. Vascular disease in vessels of the brain and extremities is also markedly increasedin diabetics. Although it is not known how the hyperinsulinemic state of maturity onset diabetes leads to a higher incidence of atherosclerotic disease than in the nondiabetic state, hyperlipidemia may be the common link. Large amounts of insulin act upon the liver to increase the production and the secretion into plasma of lipoproteins, one of whose chief constituents is cholesterol.ssThe other major lipid of this lipoprotein, triglyceride, may also be responsiblefor the atherogenesisof hyperinsulinemic diabetes (see Section V-C). B. Cholesterol, saturated and unsaturated lats Fats or Iipids are our main sourceof energy during periods of prolonged physical exertion and also nocturnally some hours after the last meal.3e Triglycerides are the principal energy yielding lipids and are composed of half of a glucose molecule attached to three molecules of long carbon chain fatty acids. After absorption from the gut, fats are transported in blood, combined with a thin protein shield to make them soluble. These tiny fat globules, chylomicrons, are split into their constituent parts during removal from the plasma by an enzqe or groups of enzyrnes. The liberated fatty acids are resynthesized into triglycerides and stored for various lengths of time primarily in fat cells. During the fasting state this storage depot Iipid is transferred back into plasma as individual fatty acid molecules. These fatty acids may be burned for energy, principally in muscle, or may enter the liver. A portion of the transported fatty acids that enter the liver are combined with various liver proteins and with other lipids such as phospholipid and clolesterol. The package of lipid and $L. D. Ostrander, T. Francis, and N. S. Hayner, "The relationship of ca-rdjovascular diseaseto hyperglycemia," Ann Intern Med.,62: 1195 ( 1965). "'F. H. Epstein, "Some uses of prospective observations in the Tecumseh community Health Study," Proc Aog Soc Med, 60:56 (1967). "uF. H. Epstein, "Hyperglycemia, a risk factor in coronary heart disease," Circulotion, 3 6 : 6 0 9( 1 9 6 7 ) . "G. M. Reaven, R. L. Lerner, M. P. Stern, and J. W. Farquhar, "Role of insulin in endogenoushyperbiglyceridemia," J Clin Inoest, 46:1756 (1967). "'A. Frank, J. W. Farquhar and G. M. Reaven, "Response of hepatic alpha-glycerophosphate to changes in hepatic glucose formation," Metobolism, 17:716 (1963).

,! : 4 ; g:

260

Enuironmental Problems in Medicine

i I

protein is then secretedby the liver and is circulated in plasma as a complex molecule which is called oery lnto density lipoTnotein Very low density Iipoprotein is also called pre-beta lipoprotein, the latter term being derived from its electrophoretic behavior. The synthesis of this lipoprotein can be increasedby insulin (see Section V-A ) or by ingestion of carbohydratesor alcohol ( seeSectionV-C ). Cholesterol in the blood probably has no established function other than that of contributing to the lipoprotein structure.aoIts level is primarily. determined by dietary intake and endogenous synthesis from the liver, gastrointestinaltract and skin." Since cholesterol is not soluble it is carried in lipoproteins, primarily in low density lipoproteins or beta lipoprotein. The main excretory path of cholesterol is through its secretion into bile either unchanged orln the form of bile salts. Some of the bile salts are reabsorbed from the lower intestine to be reused. This excretory reabsorp tion pathway is utilized in the drug treatment of hypercholesterolemic states by use of resins which irreversibly bind with bile salts in the gut, thus creating a drain on the endogenous cholesterol pool. Cholesterol level in the plasma is also infuenced by the saturated: unsaturated fatty acid ratio of the diet.a2 Saturated fatty acids, that is, fatty acids without double bonds, will elevate cholesterol level in the plasma; a diet of mono-saturated fatty acids, with one double bond, causesno change; and polyunsaturatedfatty acids, which contain two or more double bonds, lower plasma cholesterol. The mechanism of hypcholesterolemic action of unsaturated fats is unclear. Spritz and Mishkel{3 have proposed that the configuration of the double bonds on the fatty acid molecules form a cis configuration, bending the molecule and increasing its width. Within the protein capsule of the lipoprotein the unsaturated fats then occupy more space-space normally occupied by cholesterol. Thus, unsaturated fats decreasethe cholesterol content of lipoprotein and reduce the plasma cholesterol level. Despite the apparent appeal of this theory, other workers have called attention to the increase in bile acid secretion 'oD. S. Frederickson, R. I. Levy and R. S. Lees, "Fat transport in lipoprotgins-xn integrated approach to mechanismsand disorders," Neui Eng I Med, 276:32, 94, 148, 215, and 273 ( 1967). '1J. M. Dietsch and J. D. Wilson, "Regulation of cholesterol metabolism," Neu Eng I Med,282:rI28, I179, r24l (1970). "D. M. Hegsted, R. B. McGandy, M. L. Myers and F. J. Stare, "Quantitative effects of dietary fat on serum cholesterol,"An-rI Clin Nutr,77:28I (1965). oN. Spritz and M. A. Mishkel, "Effect of dietary fats on plasma lipids and lipoproteins: and hypothesis for the lipidJowering effect of unsaturated fatty acids," I CIin Inaest, 48:78

( ls6e).

I

26r


causedby unsaturated acids.aaThis drain on bile acids could then create a situation similar to resins in depleting endogenouscholesterol. In summary, plasma cholesterol levels may be raised by increasing either dietary cholesterol intake or the dietary intake of saturated fat. Conversely plasma cholesterol levels may be lowered by an increased dietary intake oi polyunsaturated fat.a5Despite the effect of these dietary manipulations of plasma cholesterol, there are differences between individuals, largely unexplained differences in diet.ao However, in any individual the plasma cholesterol should decrease when the dietary content of cholesterol and saturated fats are lowered. The relationship of plasma cholesterolto CHD has been establishedin larger scale epidemiological studies of humans. Some of these data from United Statesand international studieswill be summarized below. Many prospective epidemiological studies have demonstrated a strong positive associationbetween plasma cholesterollevel and heart disease(see TABLE XII-VII SERUM CHOLESTEROL AND RELATIVE RISK OF DEVELOPING CORONARY HEART DISEASE IN SEVERAL STUDIES OF MIDDLE AGED AMERICAN MEN Stud.y ond rencc

No

Durotion oJ Follou Up (Yeon)

Relatito

Risk

Ouer

Choleeterol

tl

240 Framingham (27)

W. Elechic (48) Minneapolis (32) PeoplesGas (33)

I

260

)2AOmgA

t0

Albany (46) Los Angeles (47)

fr.ongea

r1 4.4

l5 .t..t

rooI

L75

loo I

I88

rooi

I

|

..u

346

216

rooi rro

| ','.o ^-.

lzss I

rooi 147

|

zss

ggz I |

saz ,uu

|

,'.

"\M. E. Connor, D. T. Witiak, D. B. Stone, et a-1.,"Cholesterol balance and fecal neutral steroid and bile acid excretion in normal hen fed dietary fats of djfferent fatty acid composition,"I CIin lnoest,48:1363 ( 1969)' 'W. B. Kannel and T. Gordon, "The Framingham Study: Section 24," NIH, U. S. DHEW (1970). 'J. T. Doyle, "Risk factors in coronaryheart disease,"Neulork I Med,63:1317 (1963).

262


(see Table XII-VII). In middle aged men higher levels footnote 27,ea1et'st of plasma cholesterol bring a continuously rising risk of heart disease.Thus, with a plasma cholesterol level of 250 mg percent men may expect about a three-fold increase in the risk of developing heart disease compared to those individuals with a plasma cholesterol less than 200 mg percent. High levels of cholesterol appear commonly. For example, in the Peoples Gas Company Study 36 percent of apparently normal men had plasma cholesterol levels of 250 mg percent or greater.s0'61 A similar relationship between cholesterol and coronary heart disease is demonstrated in Table XII-VIII. In a study of seven countries, the inTABLE XII-VIII CORONARYHEART DISEASE INCIDENCE/TO,OOO MEN 40-59 YEARS OF AGEAEAR DURING A FIVE YEAR FOLLOW-UP (CHD RATE) AND THE PERCENTAGEWITH SERUM CHOLESTENOLGREATER THAN 250 MC PERCENTIN SEVEN COUNTRIES Countrg

Japan Greece Yugoslavia Italy Netherlands

u.s.

Finland

CHD Botc

ls-20/IO,OOO/yt 32 DJ

t00

Cholcalerol >250 mg qo

T4 .| 13

IJV

JZ

r77

39 56

198

Data from reference (7).

cidence of serum cholesterol levels greater than 250 mg percent corresponded closely to rates of heart disease.A similar correlation was observed between the percent of diet calories provided by saturated fats and the incidence of coronary heart disease ( see footnote 7 ). Additional evidence was provided by a siudy of the saturated fat content of the diet, the semm cholesterol and the rate of coronary artery disease in people of Japanese ancestry living in Japan, Hawaii, and Los Angeles.62Keys has reported J. M. Chapman and F. J. Massey, "The inter-relationship of serum cholesterol, hypertension, body weight, and risk of coronary disease. Results of t}e ffrst ten years' follow up iu the Los Angelesheart study," J Chronit. Dis, 17:933 (f964). "O. Paul, M. H. Leper, W. H. Phelan et aI., "A longitudinal study of coronary heart disease,"Circulation, 28:20 ( 1963). '"A. Keys, H. L. Taylor, H. Blackburn et aI., "Coronary heart disease among Minnesota businessand professional men followed fffteen years," CircuLation,2S:381 (1963). oJ. Stamler, "Atherosclerotic coronary heart disease-the major challenge to contemporary public health and preventive medicine," Conn Med, 28:675 (1964). o'J. Stamler, Lectures on Prcoentioe Cordiobgy, ( New York, Grune and Stratton, Inc., 1967), p. 122. -A. Keys, N. Kimura and A. Kusukawa, "Lessons from serum cholesterol studies in Japau, Hawaii and Los Angeles," Ann Intem Med, 48:83 (1958).


263

an increasedamount of saturated fat in the diet, increased serum cholesterol level and increased severity of atherosclerotic disease as Japanesehave moved East, and assumedprogressively greater degrees of American customs and eating habits.

I

I

I I I

I I I

iI I

I

,l I

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I

Further evidence of the importance of dietary saturated fats and dietary cholesterol in producing coronary heart disease has accumulated from diet or drug trials where the serum cholesterol level was reduced and the incidence of heart diseasediminished. Most of these trials involved samples too small to be considered significant and also lacked certain important controls in their design. Further, some studies involved subjects with welladvanced and probably irreversible disease.ssHowever, Miettinen and his have recently reported results of a cholesterol lowering diet associates64 in men and women that was well controlled and of twelve years duration. The trial was conducted in cross-over design using two Finnish mental hospitals. For the first six years patients in one hospital were on a special diet, which primarily involved the substitution of skim for whole milk, and solt polyunsaturated margarine for butter and hard margarine: The other hospital served its normal diet. After six years the treatment was reversed. A lowering of both cholesterol and mortality due to ischemic heart diseaseand to all causeswas noted. However, only in men was mortality significantly reduced. Despite the evidence presented above, the majority opinion among cardiovascular epidemologists is that large scale, well controlled, double blind studies should be undertaken before the relationship between lowered plasma cholesterol and reduced coronary artery diseaseis finally confirmed. The mechanism of the atherogenic action of cholesterol appears obvious. The collection of cholesterol and fats within the arterial wall initiate a chronic inflammatory reaction (see Section IV ) . Hyperlipidemia may also accelerate atherogenesisby injuring the arterial wall66 or by influencing the clotting ability of blood.uu However an elevated level of cholesterol in plasma and a subsequent increased filtration into the arterial wall is undoubtedly the major means for cholesterol's atherogenic action.

{ { I

I t

(

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*S. Dayton, and M. L. Pearce, "Prevention of coronary heart disease and other comby modified diet," Arner I Med,46:75I (1969). plicationsof atherosclerosis 6'lr{. Miettinen, O. Turpienen, M. J. Karvonen et al., "Effect of cholesterol-loweringdiet on mortality from coronaryheart diseaseand other causes,"Lancet,2:835 (1912). *T. Shimamoto,"The relationship of edematous reaction in arteries to atherosclerosisand thrombosis,"I AtherosclerRes, 3:87 ( 1963) . *B. Kommerell, "Blood Coagulation," in Schettler and Body, eds., Atherosclerosis(New York, ElsevierPub. Co., 1969).

264

Enoironmental Problems in Medicirle

C. Carbohydrates arul Ethanol Carbohydrates and ethanol will be discussed together since they both have the effect of elevating the level of plasma triglyceride which may well be an important risk factor in coronary artery disease. Plasma triglyceride level may be influenced by many factors, including exercise(see footnote 19), obesity (see footnote 19 and 39),ut inheritance, the degree of glucose intolerance, the carbohydrate content of the diet68'68 alcohol, chronic renal disease and hypothyroidism. However, while. the resting level of triglycerides may vary between individuals, raising the carbohydrate content of the diet will invariably elevate that level, and lowering carbohydrate content will lower it. The mechanism of this action may be that carbohydrates stimulate insulin secretion which in turn accelerateshepatic triglyceride synthesis.60Or it may be that glucose provides abundant substrate for triglyceride synthesis. In addition to the efiect of quantity of carbohydrates, the specific types of carbohydrate may also play a role in triglyceride metabolism. Recent evidence suggests that sucrose, or simple table sugar which is composed of one molecule each of glucose and fructose, may have a more profound elevating effect on plasma lipids than do the more complex carbohydrates, e.g. starches.6l-65 Men and postmenopausal women appear especially predisposed to this sucrose effect,66 and this may explain the higher triglyceride levels found in these individuals compared to young and middle aged women.66Yudkin and othersoThave gone so far as to suggest that u'M. J. Albrink, J. W. Meigs and E. B. Mann, "Serum lipids, hypertension and coronary artery disease,"Amer I Med, 31:4 ( 1961). 68A.Chait, M. Mancini, A. W. February and B. Lewis, "Clinical and metabolic study of alcoholic hyperlipidemia," Lancet, 2 :62 ( I97 2) . tJ. W. Farquhar, A. Frank, R. C. Gross and G. M. Reaven, "Clucose, insulin and triglyceride responsesto high and low carbohydrate diets in man," I Clin lnaest, 45:1648 ( 1 9 6 6) . *G. M. Reaven, R. L. Lerner, M. P. Stem and J. W. Farquhar, "Role of insulin in endogenoushypertriglyceridemia,"J Clin inoest,46:1756 ( tS6Z1. t'E. H. Ahrens, Hirsch, K. Oette et al, "Carbohydrate-induced and fat-induced lipemia," J. Trarx Ass Amer Physicians,74:I34 ( 196l ). . u'I. Macdonald and D. M. Braithwaite, "The influence of dietary carbohydrateson the lipid pattern in serum and in adiposetissue,"CIin Sci, 72:23 (1964). cI. Macdonald, "The effects of various dietary carbohydrates in the serum lipids during a five day regimen,"Clin Sci,29:tg3 ( 1965). "'R. E. Hodges, and N. A. Rrehl, "The role of carbohydrates in lipid metabolism," Amer J CIin Nutr, 17 :334 ( 1965) . *I. Macdonald, "The lipid responseof postmenopausalwomen to dietary carbohydrates," Amer J Clin Nutr,lB:86 (1966). *P. D. Wood, M. P. Stern, A. Silvers et aJ, "Prevalence of plasma lipoprotein abnormaUties in a freeJiving population of the Central Valley, California," Circulation,45:f 14 (1973). -J. Yudkin and J. Morland, "Sugar intake and myocardial infarction," Amer J Clin Nutr, 2 0 : 5 0 3( 1 9 6 7 ) .

The Role of Nutrition in Atlrcrosclerosb

265

increased sucrose consumption is principally responsible for the CHD pandemic. They have shown that those patients who develop myocardial infarctions consumed more sucrose than a control population ( a finding that has been disputed by othersos),and that in several countries sucrose intake parallels plasma lipid levels.oeThe lipid elevating action of sucrose appears to reside in the fructose portion, since when glucose is substituted for sucrose lipid elevation is less marked. However other explanations for a difference between sucroseand starch effect may be that starches are more satiating and therefore diminish total caloric intake; or that starches are absorbed more slowly and cause lesser glucose and insulin rises in plasma; or that starchy foods are usually accompanied by plant sterols which nray independently decreaseplasma lipids (see Section V-F) (see footnote 64). Whatever the mechanism for this sucrose effect, it appears to lose effectivenesswhen dietary fat intake is increased.T0 Hypertriglyceridemiais also recognizedas a rather frequent consequence of moderate to marked alcohol consumption (see footnote 58).tt't' Alcohol apparently diverts fatty acids from energy yielding catabolic pathways to synthesis of triglycerides (see footnote 58 ). However, in severe casesof liver disease and cirrosis that accompanies chronic alcoholism the liver's capacity for synthesis is curtailed and hypertriglyceridemia disappears. Evidence for triglyceride's involvement in coronary artery disease arises from two sources.Albrink (see footnote 57) has reported significantly higher levels of serum triglycerides in individuals who have suffered an acute myocardial infarction than in men of similar age but without illness. However, it should be remembered that diet patterns may change after a seriousillness,and in these caseshypertriglyceridemia may not have been present prior to the incident. Carlson and BottigerTl have provided more conclusive evidence incriminating triglycerides in atherosclerotic heart disease.After a nine year followup of 3168 men in Stock*J. A. Little, H. M. Shanoff, A. Csima et aI, "Diet and senrm-lipids in male suryivors of myocardial infarction," Lancet, l:933 ( 1965). @A. Lopez, R. E. Hodges and N. A. Krehl, "Some interesting relationships between dietary carbohydrateand serumcholesterol,"Amer J Clin Nutr, -18:149( 1966). "oM. A. Antar, ]. A. Little, C. Lucas et aL, "Intercelationship befween the kinds of dietary carbohydrateand fat in hyperlipoproteinemic patients,"Atheroscl,ll:191 (1970). ^D. P. M. S. C. S. Davidson and C. S. Lieber, "Effects of ethanol in Losowsky, Jones, plasma lipids in man," .l Lab Clin Med, 62:675 ( 1963). ?'M. S. Losowsky, D. P. Jones, C. S. Davidson, and C. S. Lieber, "Studies of alcoholic hyperlipemia and its mechanism,"Amer I Med, 35:794 ( 1963). ^K. J. Isselbacher and N. J. Greenberger, "Metabolic effect of alcohol in liver," Neur Eng I Med, 270:35, and 402 ( tSea I. "L. A. Carlson and L. E. Bottiger, "Ischenic heart disease in relation to fasting values of plasma biglycerides and cholesterol,"Lancet, I :865 ( 1972) .

266

Enpironmental Problems in Medicine

holm they found that the initial plasma triglyceride level was a predictor of ischemic heart disease. It may be pointed out, however, that triglyceride is carried in the plasma aboard a protein and cholesterolcomplex (see footnote 40). Thus, any elevation in plasma triglyceride is accompanied by an elevation in cholesterol ( about 20%of the triglyceride elevation ) and this cholesterol elevation may be the atherogenic factor of the hypertriglyceridemia. D. SaIt Several lines of evidence support a direct relationship between dietary sodium chloride and hypertension. (a) Epidemiological and survey studies have demonstrated that hypertension tends to be rare in people whose intake of salt is habitually low and is frequently found in those with high salt intakes.?5'77 However, adiposity, the degree of physical activity and cultural factors may also have some bearing on the observed differences in blood pressure.TT(b) Certain strains of inbred rats appear to have a blood pressure that is unusually sensitive to changes in salt intake.?8The relationship of this phenomenon in small animals to hypertension in man remains to be established.(c) Severalworkers have shown that drastic sodium restriction or excessivesodium supplementation of the diet will be reflected by the appropriate blood pressure changes in hypertensive and non-hypertensive patients (see footnote 31).70'80 In addition diuretic therapy which produces a loss of sodium from the body is a well established and efiective antihypertensive modality. Although more definitive studies are needed, there is sufficient evidence to suggest that dietary sodium is operative in the cause of essential hypertension. The important role of hypertension in atherogenesishas been adequately illustrated in both animal and epidemiological studies. Almost all of the relevant epidemiological studies have demonstrated the relationship of blood pressure to the chance of developing CHD. For example, in the Framingham study (see footnote 27) systolic blood pres6L. K. Dahl and R. A. Love, "Etiological role of sodium chloride intake in essential hypertensionin humans," I Amer M ed Assoc,164:397 ( 1957). "tS. Kaneta, K. Ishiguro, S. Kobayashi and E. Takahashi, "An epidemiological study on nutrition and cerebrovascularlesions in Tohoku area of Japan," Tohoku J Exp lrLed,83:398 ( 1 9 6 4) . "I. Maddocks, "Blood pressurein Melanesians,"Med I Aust, 1:L123 ( f967). '"L. K. Dahl, "Effects of chronic excesssalt feeding: Induction of self-sustaininghypertension in rats," I Exp Med, 114:23I ( t96t ). dV. P. Dole, L. K. Dahl, C. C. Cotzias et aI, "Dietary treatment of hypertension. II Sodium depletion as related to the therapeutic efiect," J Clin Inoest,30:584 (fSSf1. &F. T. Hatch, A. R. Wertheim, C. H. Eurman et al, "Effects of diet in essential hypertension," Amer I Med,,17:499 ( f 954 ) .

The Role ol Nutrition in Atherosclerosis sure, as well as diastolic or mean blood pressure, was found to predict With each progressivelyhigher level of systolicblood future heart

pressurea correspondinglyhigher risk was noted. This relationship was even evident throughout the normal mnge of blood pressures.Thus both plasma cholesterol and systolic blood presst-rredemonstrate an increasing risk of developing CHD with higher levels within the rnrmal range. Although there have been no Iarge scale experimental attempts to lower blood pressure in a free living population by reduction in dietary salt, there have been excellent studies of the effect of antihypertensive drug therapy on the course of hypertension.8l The Veterans Administration Cooperative Study Group has made the most complete study of hypertension, utilizing over five hundred male subjects. Reduction in blood pressure by the use of diuretics in combination with alpha methyldopa or reserpine and hydralazine reduced the incidence of strokes to one-twelfth that of the control group. It should be pointed out, however, that the incidence of manifestations of coronary artery disease was not significantly different between the treated and non-treated goup. However, the duration of the treatment was short and perhaps inadequate to reveal such differences. This illustrates the need to view atherogenesis as being the product of many factors instead of any single factor. E. Vater hard.nessand d,ietary minerak Soff water differs from hard water in that it lacks many minerals, primarily calcium and magnesium. The consumption of soft water has been related to increased death rate due to atherosclerotic heart disease.s2*84 The evidence for this association has been the correlation between cardiovascu]ar mortality rates and water hardness or calcium concentration of geographical areas, where no significant.differences in such risk factors as degree of physical activity,ss social factors (see footnote 83), blood pressure, serum cholesterol, and blood sugar were found. A greater incidence of mortalityin light smokers (less than fifteen cigarettes/day) has been noted in the soft water areas than hard water areas.86Differences between the --EE.

D. Fteis, "Medical treatment of chronic hypertension," Mod Conc Cardiooasc Dis, 40:I7 (L971). *H. A. Schroeder,"Relation between mortality from cardiovascular disease and treated water suppUes,"I Amer Med Assn,172:1902 ( f 960 ). &M. D. Crawford, M. J. Gardner and J. N. Morris, "Mortality and hardness of local water supplies,"Lancet, I:827 ( 1968). *T. W. Anderson and W. H. le Riche, "Sudden death from ischemic heart disease in Ontario and its correlation with water hardnessand other factors," Canad.Med Assn J,705:

1 5 5( r 9 7 r ) .

eT. Crawford and M. D. Crawford: "Prevalence and pathological changes of ischemic heart diseasein a hard-water and soft-water area." Larwet 1:229 (1967 ). eP. C. Elwood, D. Bainton, F. Moore et aI, "Cardiovascular surveys in areas with different water supplies," Brit Meil J, I :362 ( f97f ).

268

Enoironmpntal Problems in Medicine

communities concerned only the rate of myocardial infarctions; atheromatous involvement of coronary arteries were indistinguishable between areasvarfng in water hardness (see footnote 85 ). Various factors including the absenceof calcium and magnesium, the presence of nitratessTand cadmiums8 have been suggested as the responsible factor, yet none is proven. In fact, to quote from a recent report of a National Heart and Lung Institute Task Force, "There is considerable uncertainty as to the validity of these correlations and much additional work remains to be done in the subject" ( seefootnote I I ) . Various trace elements contained in foods or water may influence cardiovascular mortality. Chromium, vanadium, zinc and manganese may be protective and fluorine, cadmium and copper harmful through their effects on blood pressure, arterial wall calcification or other means.seFor none of these elements, however, does sufficient evidence for their role exist for them to be considered important in atherosclerosis. F. Dietary Fiberso And Plant SreroJsel Dietary fibers, for example, cellulose, lignin, and pentosans,are normal undigestible ingredients of cereals and other plant products. These fibers appear to absorb bile salts in the intestinal tract, thus reducing the endogenous cholesterol level by increasing the rate of further breakdown of liver cholesterolto replenishthe bile saltslost from the intestine.e2 Proof of the effectivenessof dietary fibers in reducing semm cholesterol and in preventing ischemic heart diseaserests on (a ) the possibleexplanation for the hypocholesterolemic action of plant products in man and animals and (b) an explanation for the vastly different mortality rates from coronary artery disease in countries of high dietary fiber content, such as Africa, and countries where the diet is low in fiber content such as the United States.Despite this appealing theory of dietary fiber content relationship to heart disease,a final statement of its role may not be made until confirmatory data is collected from well controlled human studies. In addition to the various plant products that have been mentioned, (unsaturated fatty acids, starches and dietary fibers ), the plant sterols are another class of compounds that have a lowering effect on plasma lipids. e'W. E. Morton, "Hypertension and drinking water constituents in Colorado," Amer J Public Health, 6l: l37l ( 197f ). *H. A. Schroeder,"The water factor," New Eng Med, 280:836 ( 1969). I "R. Masironi, "Trace elements and cardiovascular disease," Bull WHO,40:305 (1969). 'H. Trowell, "Ischemic heart disease and dietary frber," Arner I Clin Nutr, 25:926 ( 1 9 7 2) . "M. Y. Subbiah, "Significance of dietary plant sterols in man and experimental animals," Mago Chn Proc,46:549 ( 197i ). "'M. A. Eastwood and D. Hamilton, "Studies on the absorption of bile salts to nonabsorbedcomponentsof diet," Biochim Biophys Acta, 152:165 ( I968).

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269

Sitosterolsare the main plant sterols that have this effect.o3(see footnote 91) These compounds exist in all plants and are analoguesto the cholesterol of animal tissues. They exert their action probably through blocking cholesterol absorption, and exert this action even in the absence of unsaturated fats.eaTheir significancein the amounts generally consumed remains in doubt, however, because of the large amount of vegetables necessary to provide an effective sitosterol intake. G. Vitamins and Caffeine It has been suggested that Vitamins A, E, Be, C and D a-ffect the atherosclerotic process through their effect of serum cholesterol or arterial connective tissue.e5'e0Large double blind studies, however, have not conffrmed these suspicions, and, therefore, there is no scientific basis for vitamin supplementation in the prevention or treatment of atherosclerosis in the patient on an adequate, well-balanced diet. As of yet there is no evidence of an effect of caffeine on atherogenesis.e? Epidemiological studies of coffee ingestion have not been large enough in scale, or have failed to separate coffee ingestion from other atherogenetic factors such as smoking. Animal studies have been inconclusive. One may state that cafteine may be contraindicated in persons with irritability of the myocardium or in individuals with hypertension. VI. Evidence for the Preventability of Atheroecleroeie Frorn epidemiological studies we have learned that in over 20 percent of patients, sudden death is the first manifestation of atherosclerosis.esOf those who survive a myocardial infarction, their prognosis is more related to their cardiovascular state and electrocardiographic findings than to the reversible nutritional condition of hypercholesterolemia.esThus nutritional modification is most effective in the primary prevention of heart disease. There is some suggestion that diet alterations may be useful in reversing non-clinical atheromatous disease. Many animal studies have demon*J. W. Farquhar, R. E. Smith and M. E. Dempsey, "The efiect of beta sitosterol on tlre serum lipids of young men with atlreroscleroticheart disease,"Circulntion, 14:77 (1956). 'J. W. Farquhar and M. Sokolow, "Response of serum lipids and lipoproteins of men to beta-sitosteroland sa-ffoweroil. A long term study," Circulation,I7:890 (1958). 5F. G. Schettler and R. Sanwald, "Vitamins," AtheroscLerosis(New York, Elsewier Pub. Co.,1969). 'C. F. Shaffer, "Ascorbic acid and atherosclerosis,"Amer J CIin Nutr,23:27 (1970). nS. Hayden, "Epiderniology," Atherosclerosis ( Ed: Schettler and Boyd ), ( New York, Elsevier Pub. Co., 1969). '"D. M. Spain, V. A. Bradess and C. Mohr, "Coronary atherosclerosisas a cause of unexpectedand unexplained death," 174:394 ( 1960). *The Coronary Drug Project Research Group, "The prognostic importance of the electrocardiogram after myocardial infarction," Ann Intern Med,77:677 (1572).

270

Enpironmental Problems in ltLedicine

strated reversibility of fatty streaksand fibrous plaque lesions (see footnote 12). One of the more impressive studies has been that of Armstrong and In a well-controlled study they fed thirty Rhesusmonkeys his associates.l00 an atherogenic diet for seventeenmonths at which time ten were sacrificed. The remainder were sacrificedafter an additional forty months of a cholesterol-free diet. In contrast to those on the atherogenic diet only, those on a regressiondiet demonstrated significantly less stenosisand a reduction of the fibrous plaques to a narrow scar, Complicated lesions, for example, ulcerated lesions,were not presentin adequatenumbers for study; however, even in severehuman lesions the cholesterolin the lesions is exchangeable with serum cholesterol and may tlierefore reduce in size.lol Evidence of the reversibility of the atherosclerotic process in humans is strong but not conclusive.The increasingincidence of atherosclerosisin Japanese residents in Japan, Hawaii and California suggest that environmental factors have a major role (see footnote 52). Studies of the primary prevention of heart disease through diet modification have usually been successful in lowering death rates related to ischemic heart disease, especially in men (see footnote 54). However, reduction in mortality does not necessarily equal a reduction in the degree of atheromatous disease,Although conclusive evidence of the reversibility of human atherosclerotic lesions has not yet been presented,the evidence is growing that reversibility as well as prevention can be reasonably expected if coronary risk factors are reduced to a lower level in humans, Further long-range, well controiled primary prevention trials in man are clearly indicated to assign relative weights to the various risk factors, and to test the hypothesis that reduction in those risk factors is beneficial. VII. Nutritional Approach to the Prevention of Atheroecleroeis A. Food Source In parallel with the rising incidence of coronary disease in man in recent decades has been the rise of atheromatous disease of animals in captivity (see footnote 12). The historical background for this development and its importance to man is illustrated in cattle. Cattle originally grazed on wide expanses of land and subsisted on a diet of both water-rich grass, which is poor in polyunsaturated fats, and forest vegetation of nuts and tree products, which are rich in polyunsafurated fats. Now they are restrained to feeding lots under crowded conditions, with little physical ac'*M. L. Armstrong, E. D. Wamer and W. E. Connor, "Regression of coronary atherosclerosisin Rhesusmonkeys," Circ Res,27:59 (L970). 'o'A. V. Chobanian and W. Hollander, "Body cholesterol meiabolism in man: I. The equilibration of serum and tissuecholesterol,"J CIin lnaest, 4I:I732 ( 1962).


27L

tivity and a diet solely of water-rich vegation.'o2Since a large portion of our diet consistsof cattle products,e.g. meat and milk, it is not surprising that that total fat content and proportionof saturatedto unsaturatedfat in cattle and man are now similar (seefootnote102). Reducingthe fat content of beef could be achieved by decreasingfeeding and increasingthe activity of cattle, and perhapsby developingstrainsof cattle that are high However, if this increasedthe cost of raising in polyunsafuratedfats.103 cattle, or alteredthe flavor and tendernessof meat, one wondershow well this changewould be acceptedby the consumers. To increase shelf life and retard spoilage, the fats in many food productsare hardened,that is, changedfrom polyunsaturatedto saturated fats. However, food producers have now made available unhardened fats, for example,soft margarine,milk with butter-fats removed (skim milk), and polyunsaturatedoils. These trends should be encouragedand enlarged.Unfortunately, general public acceptanceof these foods could also be a problem. B. Consutner Behaaior Change Although data are not available, one would surmise that the majority of Americans know that it is best to maintain ideal weight and avoid excessesof certain types of fats, of carbohydrates and of salt. What is lacking is a change in motivation and behavior toward eating habits. An evaluation should be made of the effectivenessof public health education including the role of the mass media. It seemslikely that a personal touch, for example, group sessions similar to those used in Weight Watchers, may be necessaryto effect any lasting changes. C. Legisl.ation If the food industry is insensitive to the needs of national health and people lack the ability to initiate or to sustain appropriate behavior change, Iegislation may then become a helpful adjunct in reducing wide spread use of harmful foods. For example, labeling practices could be enforced that would enable the consumer to select lower risk foods. A more radical move would be to influence the types of food produced by direct legislative action. VIII. Summary Atherosclerosis is a disease of arteries created by fat accumulating in the arterial walls and bv the associated inflammatorv reaction. These ro'M. A. Crawford, "Fatty acid ratios in freeJiving and domestic animals," Lancet, 7z 1329( 1968). tGP. Nestel, N. Havenstein, H. M. Whyte et al, "L,ower plasma cholesterol after eating |. polyunsaturated ruminants fats," Neus Eng I Med, 288:379 ( 1973 ).

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arterial lesions are important in that they may lead to occlusion of the nutrient vessel to an organ and cause death and disability due to coronary heart disease (CHD), cerebral thrombosis, and other related conditions, The magnitude of this disease problem is great not only in the United States but also in many other industrialized countries. It is three times as frequent as the seeond ranking cause of death, cancer. Five percent of Americans currently suffer from CHD and a middle-aged male has a 20 percent chance of developing CHD before sixty years of age. Atherosclerosis is a result of the prolonged effect of multiple factors including hyperlipidemia, hypertension, smoking, and others. It begins in childhood and progressesthroughout life. Various, nutritional factors have definitely been incriminated and include excesscalories, high levels of dietary cholesterol and saturated fats, normal or high intake of alcohol or carbohydrate in susceptible individuals, and increased amounts of salt in certain predisposed individuals. There is as yet insufficient evidence to support a role in atherosclerosis for water softness, dietary minerals, vitamins, caffeine, and dietary ffber, but all these dietary constituents have been implicated as being either harmful or beneficial. Evidence from animal and human studies shows that although atherosclerosis worsens with age, it is not an inevitable accompaniment of age and is strongly infuenced by environment. There is support for its being reversible. Nutritional modification of our diet could develop from voluntaly or government-initiated changes in cattle-raising practices and in production and processing of food stuffs. There is also a great need for change in the basic health habits of the population. It must be remembered that atherosclerosis results from many factors including non-nutritional ones such as cigarette smoking, physical inactivity and psychosocial stress. In addition there are other possible risk factors on which we need much more information. Thus, nutritional modification should be accompanied by * increased understanding of the role of these other factors and an attack bn those that are shown to be of importance. From the knowledge at hand, however, it would appear that in any solution of the atherosclerosis problem the central role of nutrition must be acknowledged.