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Diet and Atherosclerosis: :Past, Present and .Future CHARLES J. GLUECK, MD Cincinnati WILLIAM E. CONNOR, MD Portland, Oregon
IGNATOWSKI in 1901 and Anitschkow in 1913 induced atherosclerosis in experimental animals by feeding cholesterol ennched diets, thereby initiating more than six decades of work focused on the relationship of diet to atherosclerosis and diet to plasma lipids and lipoproteins." 2 As indicated by several recent reviews of the relationship of diet to atherosclerosis and serum lipids, many investigators3-6 believe that appreciable reduction in the levels of plasma cholesterol and low density lipoprotein cholesterol would ameliorate atherosclerosis or prevent its inception. However, the degrees of certitude relative to these conclusions may differ widely.3-6 Irrespective of the controversy about the limitations of the diet-coronary heart disease (cHD) relationship,3-6 there have been appreciable secular changes in nutritional intake patterns, plasma cholesterol levels and cHD mortality in the last decade. Since 1970 overall dietary intake of cholesterol has' fallen and the polyunsaturate/ saturate (P/s) ratio of dietary fat has increased.7-9 Referto: Glueck CJ, Connor WE: Diet and atherosclerosis: Past, present and future (Clinical Nutrition Symposium). West J Med 130:117-122, Feb 1979 From the Lipid Research and General Research Center, University of Cincinnati Medical Center, College of Medicine, Cincinnati, Ohio (Dr. Glueck) and from the General Clinical Research Center and the Department of Medicine, University of Oregon Health Sciences Center, Portland, Oregon (Dr. Connor). Supported by U.S. Public Health Service Research Grants HL14230; HL-19130, and HL-06336 from the National Heart and Lung Institute; and by the General Clinical Research Centers Program (RR-334, RR-68, and RR-59) of the Divisiozf of Research Resources of the National Institutes of Health. Partially supported by the Lipid Research Clinic Contract NIH NHLBI N01-HV 2-2914 L. Reprint requests to: Charles J. Glueck, MD, Lipid Research and General Research Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
Dietary cholesterol intake in children, as well as in adults, appears to be lower than had previously been estimated.10 Also, within the last decade there has been a downward trend in plasma cholesterol levels.1' Finally, and perhaps most important, there has been an equitemporal downward trend in cHD mortality.'2"3 In 1975 the reduction in CHD mortality was more than 20 percent overall for persons in the age groups 36 to 74.12,13 A causal relationship among these aggregate changes' in nutritional intake, plasma cholesterol and coronary heart disease has not been unequivocally proven in man. Nevertheless, their equitemporal occurrence leads to speculation'2 that community changes in nutrition might lead to lower plasma cholesterol levels (as shown in the National Diet-Heart Study and- in the California three-community studies)14"5 and, consequently, over time might lead to a reduction in coronary heart disease event rate. This review will examine data for pediatric and adult populations relevant to the relationship of diet to plasma lipids or atherosclerosis, or both, with the emphasis that a reasoned, data-based, unequivocal resolution of the current controversy "can nutritional diet modification prevent or ameliorate atherosclerosis" is not possible at present.3-6 Nevertheless, physicians and scientists often must make working decisions in the absence of absolutely conclusive scientific proof.4 Moreover, after careful assessment of currently available data, three scientific national and representative nutrition councils in the United States have THE WESTERN JOURNAL OF MEDICINE
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ABBREVIATIONS USED IN TEXT CHD=coronary heart disease C-HDL=-cholesterol carried by high density
lipoproteins C-LDL=cholesterol carried by low density lipoproteins
HDL=high density lipoprotein LDL=low density lipoprotein P/S ratio=polyunsaturate/saturate ratio
stressed that reasonable means should be followed to modify the nutritional conditions which contribute to elevated plasma cholesterol and triglyceride levels.'6-'8
In addition, nutritional advisory groups from five other nations have advised that their citizens modify their dietary habits in the direction of lessened intakes of animal and saturated fats.'9 These recommendations have not been made quickly but rather cautiously and over a considerable period (since the early 1960's). Some of the expert committees have been reformed from time to time and yet, after further review of the coptinually developing evidence, they have reached similar or even firmer conclusions. Where legitimate differences of opinion still yet remain is in the realm of how universally prudent dietary practices should be applied. Should the entire population be advised about dietary change, or only those deemed at risk for the development of coronary heart disease? In the judgments of the American Heart Association and the Intersociety Commission for Heart Disease, dietary prudence is recommended for all.'6"18 However, the Food and Nutrition Board of the National Research Council suggests that only those persons with hyperlipidemia (that is, with plasma cholesterol levels above 220 mg per dl) should change their dietary practices.'7 The surprising degree of agreement is that those with mild to severe hyperlipidemia should restrict saturated fat and cholesterol intakes and observe caloric restriction if overweight. No responsible group of physicians anywhere in this country or elsewhere has advocated no dietary treatment for hyperlipidemia in an attempt to prevent atherosclerosis. Because hyperlipidemia is such a common condition in this country (a third of adults), it is clear that dietary change at minimum would involve a very large segment of the population and
probably millions of families. A nutritional principle which has been applied to the mass fortifi118
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cation of foods with vitamins and minerals is that if the nutritional problem is widely distributed (or could be if not prevented), then it is quite appropriate to recommend that the fortified food be given to all. We suggest that our current epidemic of atherosclerotic coronary heart disease warrants similar consideration. This view receives further emphasis from the next section which deals with atherosclerosis in children.
Diet, Plasma Lipids and Atherosclerosis in Childhood It is now generally accepted that the genesis of atherosclerosis is in childhood.20 Coronary and aortic atherosclerosis was reported in a third of soldiers autopsied by Enos and co-workers2' and McNamara and co-workers22 and in the youthful years. There is considerable pathologic evidence that the mature fibrocalcific plaque found in middle adult life evolves during the first 20 years.20-23 There is suggestive, but not unequivocal, evidence that the fatty streak of childhood is a precursor of the mature atherosclerotic lesions.20-23 Symptomatic CHD iS usually present by the age of 10 and is always manifested in the second decade in children homozygous for familial hypercholesterolemia.24 In approximately 30 percent of adolescent boys (average age 13), heterozygous for familial hypercholesterolemia, there are abnormal maximum exercise electrocardiographic findings, compared to 7 percent of agematched normal boys, suggesting the potential of physiologic myocardial ischemia.25 Also, in young adult men heterozygous for familial hypercholesterolemia, morbidity and mortality from coronary artery disease appears between ages 20 and 30, suggesting that development and progression of the mature atherosclerotic lesions are well accelerated by the end of the second decade.26 The aggregate data from pathologic anatomical studies,20-23 and from the most severe manifestations of hypercholesterolemia in children and young adults,24-26 provide the background that persuades many physicians and scientists that to be effective, prevention of CHD must begin in the teenage years and possibly earlier.5'20 Children in the United States have higher plasma cholesterol levels than do children of other populations in which adult atherosclerotic disease is much less frequent.27-30 Approximately 5 percent of United States children, ages 5 to 18, have plasma cholesterol levels greater than 200 to 220
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C mg per dl.27-29 Those children with elevated plasma cholesterol levels in childhood are likely to maintain a similar elevated rank order throughout childhood, into adulthood.529 In addition, children with genetic hyperlipidemia, particularly familial hypercholesterolemia, can be identified in childhood.29'31
Childhood Diet and Hyperlipoproteinemia As summarized by Glueck and Stein,29 "it is estimated that approximately 1 percent of unselected children have monogenic familial hypercholesterolemia, familial hypertriglyceridemia, or familial combined hyperlipidemia." However, studies in population groups show that most hypercholesterolemia is not due to the "monogenic" familial hyperlipoproteinemias,31 but is likely related to the intake of dietary cholesterol, saturated fat and total calories.3-5 31-33 Plasma cholesterol levels in children having low total cholesterol and low saturated fat intake and in vegetarian children are 30 to 40 mg per dl below those of children receiving conventional Western diets.2932 Moreover, nutrition modification in small cohorts of children has been shown to produce significant reduction in plasma cholesterol levels. McGandy and associates34 studied a boarding school population. The calories provided from fat were reduced from 39 to 34 percent. Cholesterol consumption was decreased from 720 to 380 mg per day, and the dietary P/s ratio was increased from 0.2 to approximately 1.2. In 200 schoolchildren, ages 13 to 18, the mean plasma cholesterol level fell approximately 10 percent on this dietary regimen.34 Using a shortterm outpatient protocol in families with adolescent children, Witchi and associates35 reduced dietary cholesterol and saturated fat, and increased polyunsaturated fat. An average reduction in serum cholesterol approximating 10 percent was produced in adolescents over three weeks.35 There was a high degree of dietary cooperation among the free living families in this study. In a longer-term study in younger children, Friedman and co-workers36 provided low cholesterol, low saturated fat diets to normal infants from birth. At age 3, their mean cholesterol levels were 145±4 mg per dl, significantly lower than in 422 controls whose mean values were 154 + 1, having had no dietary intervention. Stein and associates37 evaluated 229 adolescent males in a South African boarding school. The
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type of dietary fatty acids was altered, but not the amount of total fat or cholesterol. Using polyunsaturate-rich, saturate-poor diets, a 14 percent reduction in total and low density lipoprotein plasma cholesterol was achieved. The final ratio of polyunsaturate to monounsaturates to saturated fats was approximately 1:1:1. The above findings34-37 suggest that prudent, and rdlatively easy-to-achieve dietary changes, similar to those suggested by various nutritional councils,'6"17 would be successful in lowering plasma cholesterol levels in American children. Such diets would be particularly effective in that majority of children whose hypercholesterolemia was secondary to excessive ingestion of cholesterol and saturated fat.29'37 Dietary modification also has considerable utility in children who have familial hypercholesterolemia or hypertriglyceridemia, or both. Approximately a third of children with familial hypercholesterolemia will attain normal total plasma cholesterol and low density lipoprotein (LDL) cholesterol levels with dietary modification which reduces fat to 25 percent to 30 percent of total calories, substitutes polyunsaturates for saturates to reach a P/s ratio of 1:1 and limits dietary cholesterol to less than 200 mg per day, adjusted downward for younger children.5'29 Above age 10 in children heterozygous for familial hypercholesterolemia5'29 such a diet may reduce total and LDL cholesterol by 10 percent to 20 percent, but will not usually bring plasma cholesterol to normal levels. Therapy with bile acid binding resins is often necessary in such children to attain -adequate control.5 Elevated triglycerides in most children with familial hypertriglyceridemia can be brought to normal levels by weight reI
duction.5'29 Epidemiological3-5"6'32 and pathological20-23 evidence in humans and evidence from experimental animals suggests that maintenance of low plasma cholesterol levels beginning in childhood might be much more effective in retarding the progression of atherosclerosis than reducing levels beginning in the fourth or fifth decades.5 A controlled and blinded test to this hypothesis has not and probably never will be done due to overwhelmingly expensive logistics and the necessity for a four to' five decade follow-up if the study begins in the first decade of life.5 Although opinion is widely divided about the advisability of recommending a modified diet for all children,29 there is near unanimity that children falling in the THE WESTERN JOURNAL OF MEDICINE
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top decile of their age and sex distribution for plasma cholesterol and triglyceride levels should be treated.5'29,35
Diet-Atherosclerosis Relationships in Adults Three decades of detailed epidemiological studies have identified major risk factors for CHD including age, sex, hypercholesterolemia (elevations of LDL cholesterol), hypertension, cigarette smoking and diabetes.3-6'38-40 Obesity, personality type and lack of physicial activity are additional, but less well-established risk factors.3-6'38-40 These established risk factors "may be causal agents, intervening variables, or secondary indicators of a more fundamental disturbance."5 The amounts of cholesterol carried by the low density lipoproteins and by the high density lipoprotein (HDL) are more specific and have opposing risk factors for CHD (positive for C-LDL, inverse for C-HDL).41'42 Recommendations for dietary modification in population groups'6 blanket a heterogeneous group of subjects whose CHD risk status could be better gauged individually by measurement of fasting plasma cholesterol, C-HDL and triglyceride, allowing estimation of C-LDL.4'5 Specific lipoprotein sampling would facilitate identification of the approximately one out of 250 unselected Americans29 with familial hypercholesterolemia, who usually require individually determined diet and drug treatment.24-26 29 The approximate 30 percent of Americans having total plasma cholesterol levels of 250 mg per dl or greater would also be identified,43 a group of subjects shown to be at sharply increased CHD risk.43 Since CHD risk increases along with total plasma cholesterol throughout its entire distribution,39'40 (one basis for populationwide dietary modification recommendations),16 specific lipoprotein measurement would locate persons within the distribution. As is the case for children, hypercholesterolemia in adults is probably for the most part not due to the familial hyperlipoproteinemias,293'33 or to polygenic traits, but is most likely related to the intake of dietary cholesterol, saturated and polyunsaturated fat, and total calories. Moreover, in adults the development, progression and potential regression of the atherosclerotic lesion appears to be closely related to the plasma cholesterol level.6'43-47 Connor and associates and Mattson and associates have shown48'49 that dietary cholesterol has a close correlation with plasma cholesterol levels over a dietary range of 0 to 600 mg per day, but 120
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a further increase above 600 mg per day does not further substantially increase plasma cholesterol levels.48'49 Over a 20-year period of study, Keys and coworkers50'51 have shown that increments in dietary saturated fatty acids elevate serum cholesterol levels, whereas polyunsaturated fatty acids tend to diminish them. Mattson and associates52 found that sharp increments in trans fatty acids in the diet (present in partially hydrogenated vegetable oils) had no specific effect on plasma cholesterol and triglyceride. Studies in vegetarians and primitive people whose dietary cholesterol, saturated fat and total calorie intake is sharply lower than that in Westernized societies, have suggested overall a significant relationship among diet, plasma lipid levels and coronary heart disease.53-55 Keys and associates56 have shown, in Japanese migrants to Hawaii and California, a close and consistent relationship between dietary saturated fats, blood lipids and CHD event rates. Dietary modification in specific small cohorts can significantly lower serum cholesterol levels particularly when accompanied by a reduction of cholesterol and total saturated fat intake, and a relative increase in polyunsaturated fats.57 Weight reduction and modification of dietary lipids may well have a synergistic effect.58 Despite the incremental evidence relating dietary cholesterol and saturated fat to CHD there are clearly areas of discordance.6 Within culturally homogeneous groups, epidemiologic studies in children and adults may at times (as in the Tarahumara Indians) but not always show significant associations between nutrient intakes and serum lipids'0'32'59 or CHD risk.59 There are certain limitations to the interpretations of such studies.60 Random errors in the collection of dietary data would lead to the underestimation of any relationships between nutrients and CHD.60 Moreaver, recent diet habits do not represent lifetime patterns, and development of atherosclerosis over decades makes it misleading to relate recent dietary practices to the risk of CHD.3-5 A more serious challenge to believability of the diet-heart relationship has been the lack of unequivocal, uniform reduction in "hard" or "soft" end points in populations where diets have been modified44-46'6' or where lipid-lowering drugs have been given.62 In four dietary modification trials completed, there was significant lowering of plasma cholesterol, and suggestive but not un-
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equivocal reduction in "hard" and "soft" end points for CHD.44-46'61 The drug-heart study did not systematically utilize dietary modification.62 Using nicotinic acid and clofibrate (Atromid), there was no conclusive reduction in cHD morbidity and mortality after five years of followup.62 These small clinical trials may (speculatively) have failed to detect a substantial effect on CHD because they were carried out in adults whose atherosclerosis was advanced and potentially' irreversible.44-46 61'62 A controlled trial on the effect of dietary modification on CHD in young adults is probably not feasible,14 due to the requirement for an unmanageably large number of subjects in order to obtain statistically convincing results. There are, however, two very large intervention trials currently underway. It is hoped that the MRFIT trial (modification of diet, smoking and hypertension) and the Lipid Research Clinic (LRC) study (modified diet and cholestyramine resin) will provide incremental evidence relevant to amelioration and prevention of cH in adults. Results from the MRFIT and LRC studies probably will not become available until 1983 or later, and will necessarily be primarily applied generally to a truncated segment of the population distribution selected by virtue of high initial risk. Studies in the future might profitably focus on the essentially unexplored relationships of C-HDL to diet, and to other environmental factors. Since studies designed to lower total plasma cholesterol and C-LDL have provided only reduction in CHD in selected groups of the population44-46'61'62 or cases of total vascular disease,44-46'6162 safe and effective methods to elevate C-HDL might open up alternative avenues to amelioration of atherosclerosis. Careful epidemiological studies of the secular trends towards reduction in dietary cholesterol and saturated fats, plasma cholesterol and cHD event rates should be continued and expanded, perhaps to include prospective cohort follow-up, to identify, if possible, any etiological relationships between these variables. Further assessment and documentation of the possible CHD-sparing effects of balanced exercise programs,63 and their long-term relationship to plasma lipids and lipoproteins may be an exciting and -underevaluated area for future work. REFERENCES 1. Ignatowski A: Ueber die Wirkung des tierischen Eiweisses auf die Aorta und die Parenchymatosen Organe der Kaninchen. Virchow's Arch Pathol Anat Physiol 198:248-270, 1909 2. Anitschkow N, Chalatow S: Ueber experimentelle Cholesterinsteatase und ihre Bedeutung fur die Enstehung einiger patholigischer Prozesse. Centralbl Aug Pathol Anat 24:1-9, 1913
3. Glueck CJ, Connor WE: Diet-coronary heart disease relationships reconnoitered. Am J Clin Nutr 31:727-737, 1978 4. Glueck CJ, Mattson F, Bierman EL: Diet and coronary heart disease: Certitude, effectiveness, feasibility, safety. N Engl J Med 298:1471-1474, 1978 5. Glueck CJ, McGill HS, Shank R, et al: The value and safety of diet modification to control hyperlipidemia in childhood and adolescence. Circulation 58:A381-A385, 1978, 6. Connor WE, Connor SL: The key role of nutritional factors in the prevention of coronary heart disease. Prey Med 1:49-83, 1972 7. Agricultural Statistics. US Dept. of Agriculture, US Govt Print Off, 1975 8. Kromer GW: Fats and oils: Natural and processed foods, In White PL, Fletcher DC (Eds): Nutrients in Processed Foods, Fats, and Carbohydrates. Acton, MA, Publishing Sciences Group, Inc, 1975 9. Chandler CA, Marston RM: Fat in the U.S. diet. Nutrition Program News, US Dept of Agriculture, 1976, pp 1-8 10. Frank GC, Berenson GS, Webber LS: Dietary studies and the relationship of diet to cardiovascular disease risk factor variables in 10-year-old children: The Bogalusa Heart Study. Am J Clin Nutr 31:328-340, 1978 11. A comparison of levels of serum cholesterol of adults 18-74 years of age in the United States in 1960-1962 and 1971-1974Advance data. Vital and Health Statistics of the National Center for Health Statistics, US Dept. of Health, Education, and Welfare, Feb 5, 1977 12. Walker W: Changing United States life-style and declining vascular mortality: Cause or coincidence? (Editorial). N Engl J Med 297:163-165, 1977 13. National Heart, Blood Vessel, Lung and Blood ProgramFourth Report of the Direction of the National Heart, Lung, and Blood Institute, DHEW publication No. (NIH)77-1170, US Dept of Health, Education and Welfare, Public Health Service, Natl Institutes of Health, 1977 14. National Diet-Heart Study Research Group: National dietheart study final report. Circulation 37(Suppl I) :1-1-1-428, 1968 15. Meyer AJ, McAlister A, Nash J, et al: Maintenance of cardiovascular risk reduction: Results in high risk subjects. Circulation (Suppl II):11-226, 1976 16. Primary prevention of the atherosclerotic diseases-Report of the Inter-society Commission for Heart Disease Resources. Circulation 42:A55-A95, 1970 17. Diet and coronary heart disease: A joint policy statement of the AMA Council on Foods and Nutrition and the Food and Nutrition Board of the National Academy of Sciences-National Research Council. JAMA 22:1647, 1972 18. American Heart Association Committee on Nutrition: Diet and Heart Disease. Dailas, American Heart Association, 1978 19. Manning GW, Haust MD (Eds): Atherosclerosis: Metabolic, Morphologic, and Clinical Aspects. New York, Plenum Press, 1977 20. McGill NC, Jr: Atherosclerosis: Problems in pathogenesis, In Gotto AM, Paoletti R (Eds): Atherosclerosis Reviews. New York, Raven Press, 1977, pp 27-65 21. Enos WF, Beyer JC, Holmes RH: Pathogenesis of coronary disease in American soldiers killed in Korea. JAMA 158:912-914, 1955 22. McNamara JJ, Molot MA, Stremple JF, et al: Coronary artery disease in combat casualties in Vietnam. JAMA 216:11851187, 1971 23. Holman RL, McGill HS Jr, Strong JP, et al: The natural history of atherosclerosis-The early aortic lesions as seen in New Orleans in the middle of the 20th century. Am J Pathol 34: 209-235, 1958 24. Fredrickson DS, Levy RI: Familial hyperlipoproteinemia, In Stanbury JB, Wyngaarden JB, Fredrickson DS (Eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1972, pp 546-614 25. James FW, Glueck CJ, Fallat RW, et al: Maximal exercise stress testing in normal and hyperlipidemic children. Atherosclerosis 25:85-94, 1976 26. Stone NJ, Levy RI, Fredrickson DS, et al: Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 49:476-488, 1974 27. Frerichs RR, Srinivasan SR, Webber LS, et al: Serum cholesterol and triglyceride levels in 3446 children from a biracial community-The Bogalusa Heart Study. Circulation 54:302-309, 1976 28. deGroot I, Morrison JA, Kelly KA, et al: Lipids in school children ages 6-17: Upper normal limits. Pediatrics 60:437-443, 1977 29. Glueck CJ, Stein EA: Pediatric considerations in the treatment and management of hyperlipoproteinemia, In Rifkind BM, Dennis BH, Ernst ND (Eds): Nutrition and Coronary Heart Disease. New York, Raven Press, 1978, Vol I, pp 285-309 30. Lauer RM, Connor WE, Leaverton PE, et al: Coronary heart disease risk factors in school children: The Muscatine Study. Pediatrics 36:697-706, 1975 31. Glueck CH, Kwiterovich PO: The lipid hypothesis, genetic basis, In Buchwald H (Ed): The hyperlipidemias and their management. Arch Surg 113:35-41, 1978
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C~~~dM~~~don.032. Connor WE, Cerqueira MT, Connor RW, et al: The plasma lipids, lipoproteins, and diet of the Tarahumara Indians of Mexico. Am J Clin Nutr 31:1131-1143, 1978 33. Motulsky AG, Boman H: Screening for the hyperlipidemias, In Milunsky A (Ed): The Prevention of Genetic Disease and Mental Retardation. Philadelphia, WB Saunders Co, 1975, pp 306-316 34. McGandy RB: Adolescence and the onset of atherosclerosis. Bull NY Acad Med 47:590-600, 1971 35. Witchi JC, Singer M, Wu-Lee M, et al: Family cooperation and effectiveness in a cholesterol-lowering diet. J Am Diet Assoc 72:384-388, 1978 36. Friedman G, Goldberg SJ: An evaluation of the safety of a low saturated diet, low cholesterol diet, beginning in infancy. Pediatrics 58:655-657, 1976 37. Stein EA, Mendelsohn D, Bersohn I, et al: Lowering of plasma cholesterol levels in free-living adolescent males: Use of natural and synthetic polyunsaturated foods to provide balanced fat diets. Am J Clin Nutr 28:1204-1216, 1975 38. Keys A (Ed): Coronary heart disease in seven countries. (American Heart Association Monograph No. 29). Circulation 41(Suppl 1) :1-1-1-211, 1970 39. Stamler J, Berkson DM, Lindberg HA: Risk factors: Their role in the etiology and pathogenesis of the atherosclerotic diseases, In Wissler RW, Geer JC (Eds): The Pathogenesis of Atherosclerosis. Baltimore, Williams & Wilkins, 1972, pp 41-119 40. Kannel WR, McGee D, Gadon T: A general cardiovascular risk profile: The Framingham Study. Am J Cardiology 38:4651, 1976 41. Castelli WP, Doyle JT, Gordon T, et al: HDL cholesterol and other lipids in coronary heart disease-Cooperative lipoprotein phenotyping study. Circulation 55:767-772, 1977 42. Glueck CJ, Gartside P, Fallat lW, et al: Longevity syndromes: Familial hypobeta and familial hyperalphalipoproteinemia. J Lab Clin Med 88:941-957, 1976 43. Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habits, relative weight, and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project. J Chron Dis (In press, 1979) 44. Dayton S, Pearce ML, Hashimoto S, et al: A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 40(Suppl II) :I-1-II-63, 1969 45. Miettinen. M, Turpeinen 0, Karvonen MJ, et al: Effect of cholesterol lowering diet in mortality from coronary heart disease and other causes. Lancet 2:835-838, 1972 46. Leren P: Effect of plasma cholesterol lowering diet in male survivors of myocardial infarction. Acta Med Scand, Suppl 466, 1966, pp 1-92
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47. Blankenhorn DH, Brooks SH, Selzer RH, et al: Rate of atherosclerosis change during treatment of hyperlipoproteinemia. Circulation 57:355-361, 1978 48. Connor WE, Hodges RE, Bleiler RE: The serum lipids in men receiving high cholesterol and cholesterol-free diets. J Clin Invest 40:894-901, 1961 49. Mattson FH, Erickson FA, Kligman AM: Effect of dietary cholesterol in man. Am J Clin Nutr 25:589-594, 1972 50. Keys A, Grande F, Anderson JT: Bias and misrepresentation revisited: Perspective on saturated fat. Am J Clin Nutr 27:188212, 1974 51. Keys A, Anderson JT, Grande F: Prediction of serum cholesterol responses of man to change of fat in the diet. Lancet 2:959, 1957 52. Mattson FH, Hollenbach EJ, Kligman AM: Effect of hydrogenated fat on the plasma cholesterol and triglyceride levels of man. Am J Clin Nutr 28:726-731, 1975 53. West RO, Hayes OB: Diet and serum cholesterol levels: A comparison between vegetarians and non-vegetarians in a SeventhDay Adventist group. Am J Clin Nutr 21:853-862, 1968 54. Sacks FM, Castelli WP, Donner A, et al: Plasma lipids and lipoproteins in vegetarians and controls. N Engl J Med 292: 1148-1151, 1975 55. Sinnett PF, Whyte HM: Epidemiological studies in a total highland population, Tukisenta, New Guinea.-Cardiovascular disease and relevant clinical, electrocardiographic, radiological, and biochemical findings. J Chron Dis 26:265-290, 1973 56. Keys A, Kimura N, Kusukawa A, et al: Lessons from serum cholesterol studies in Japan, Hawaii and Los Angeles. Ann Intern Med 48:83-94, 1958 57. Rifkind BM, Levy RI (Eds): Hyperlipidemia: Diagnosis and Therapy. New York, Grune & Stratton, 1977 58. Ashley FW, Kannel WB: Relation of weight change to changes in atherogenic traits: The Framingham Study. J Chron Dis 27:103-114, 1974 59. Nichols AB, Ravenscroft C, Lamphier DE, et al: Independence of serum lipid levels and dietary habits. JAMA 236: 1948-1953, 1976 60. Diamond EL, Lilienfeld AM: Effects of errors in classification and diagnosis in various types of epidemiologic studies. Am J Public Health 52:1137-1144, 1962 61. Frantz ID, Dawson EA, Kuba K, et al: The Minnesota Coronary Survey: Effect of diet on cardiovascular events and deaths. Circulation 51(Suppl II):11-4, 1975 62. Clofibrate and niacin in coronary heart disease-Coronary Drug Project Research Group. JAMA 231:360-381, 1975 63. Paffenbarger RS, Hale WE, Grand RJ, et al: Work energy level: Personal characteristics and fatal heart attack: A birth cohort effect. Am J Epidemiol 105:200-213, 1977
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Diet and Atherosclerosis: :Past, Present and .Future CHARLES J. GLUECK, MD Cincinnati WILLIAM E. CONNOR, MD Portland, Oregon
IGNATOWSKI in 1901 and Anitschkow in 1913 induced atherosclerosis in experimental animals by feeding cholesterol ennched diets, thereby initiating more than six decades of work focused on the relationship of diet to atherosclerosis and diet to plasma lipids and lipoproteins." 2 As indicated by several recent reviews of the relationship of diet to atherosclerosis and serum lipids, many investigators3-6 believe that appreciable reduction in the levels of plasma cholesterol and low density lipoprotein cholesterol would ameliorate atherosclerosis or prevent its inception. However, the degrees of certitude relative to these conclusions may differ widely.3-6 Irrespective of the controversy about the limitations of the diet-coronary heart disease (cHD) relationship,3-6 there have been appreciable secular changes in nutritional intake patterns, plasma cholesterol levels and cHD mortality in the last decade. Since 1970 overall dietary intake of cholesterol has' fallen and the polyunsaturate/ saturate (P/s) ratio of dietary fat has increased.7-9 Referto: Glueck CJ, Connor WE: Diet and atherosclerosis: Past, present and future (Clinical Nutrition Symposium). West J Med 130:117-122, Feb 1979 From the Lipid Research and General Research Center, University of Cincinnati Medical Center, College of Medicine, Cincinnati, Ohio (Dr. Glueck) and from the General Clinical Research Center and the Department of Medicine, University of Oregon Health Sciences Center, Portland, Oregon (Dr. Connor). Supported by U.S. Public Health Service Research Grants HL14230; HL-19130, and HL-06336 from the National Heart and Lung Institute; and by the General Clinical Research Centers Program (RR-334, RR-68, and RR-59) of the Divisiozf of Research Resources of the National Institutes of Health. Partially supported by the Lipid Research Clinic Contract NIH NHLBI N01-HV 2-2914 L. Reprint requests to: Charles J. Glueck, MD, Lipid Research and General Research Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
Dietary cholesterol intake in children, as well as in adults, appears to be lower than had previously been estimated.10 Also, within the last decade there has been a downward trend in plasma cholesterol levels.1' Finally, and perhaps most important, there has been an equitemporal downward trend in cHD mortality.'2"3 In 1975 the reduction in CHD mortality was more than 20 percent overall for persons in the age groups 36 to 74.12,13 A causal relationship among these aggregate changes' in nutritional intake, plasma cholesterol and coronary heart disease has not been unequivocally proven in man. Nevertheless, their equitemporal occurrence leads to speculation'2 that community changes in nutrition might lead to lower plasma cholesterol levels (as shown in the National Diet-Heart Study and- in the California three-community studies)14"5 and, consequently, over time might lead to a reduction in coronary heart disease event rate. This review will examine data for pediatric and adult populations relevant to the relationship of diet to plasma lipids or atherosclerosis, or both, with the emphasis that a reasoned, data-based, unequivocal resolution of the current controversy "can nutritional diet modification prevent or ameliorate atherosclerosis" is not possible at present.3-6 Nevertheless, physicians and scientists often must make working decisions in the absence of absolutely conclusive scientific proof.4 Moreover, after careful assessment of currently available data, three scientific national and representative nutrition councils in the United States have THE WESTERN JOURNAL OF MEDICINE
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ABBREVIATIONS USED IN TEXT CHD=coronary heart disease C-HDL=-cholesterol carried by high density
lipoproteins C-LDL=cholesterol carried by low density lipoproteins
HDL=high density lipoprotein LDL=low density lipoprotein P/S ratio=polyunsaturate/saturate ratio
stressed that reasonable means should be followed to modify the nutritional conditions which contribute to elevated plasma cholesterol and triglyceride levels.'6-'8
In addition, nutritional advisory groups from five other nations have advised that their citizens modify their dietary habits in the direction of lessened intakes of animal and saturated fats.'9 These recommendations have not been made quickly but rather cautiously and over a considerable period (since the early 1960's). Some of the expert committees have been reformed from time to time and yet, after further review of the coptinually developing evidence, they have reached similar or even firmer conclusions. Where legitimate differences of opinion still yet remain is in the realm of how universally prudent dietary practices should be applied. Should the entire population be advised about dietary change, or only those deemed at risk for the development of coronary heart disease? In the judgments of the American Heart Association and the Intersociety Commission for Heart Disease, dietary prudence is recommended for all.'6"18 However, the Food and Nutrition Board of the National Research Council suggests that only those persons with hyperlipidemia (that is, with plasma cholesterol levels above 220 mg per dl) should change their dietary practices.'7 The surprising degree of agreement is that those with mild to severe hyperlipidemia should restrict saturated fat and cholesterol intakes and observe caloric restriction if overweight. No responsible group of physicians anywhere in this country or elsewhere has advocated no dietary treatment for hyperlipidemia in an attempt to prevent atherosclerosis. Because hyperlipidemia is such a common condition in this country (a third of adults), it is clear that dietary change at minimum would involve a very large segment of the population and
probably millions of families. A nutritional principle which has been applied to the mass fortifi118
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cation of foods with vitamins and minerals is that if the nutritional problem is widely distributed (or could be if not prevented), then it is quite appropriate to recommend that the fortified food be given to all. We suggest that our current epidemic of atherosclerotic coronary heart disease warrants similar consideration. This view receives further emphasis from the next section which deals with atherosclerosis in children.
Diet, Plasma Lipids and Atherosclerosis in Childhood It is now generally accepted that the genesis of atherosclerosis is in childhood.20 Coronary and aortic atherosclerosis was reported in a third of soldiers autopsied by Enos and co-workers2' and McNamara and co-workers22 and in the youthful years. There is considerable pathologic evidence that the mature fibrocalcific plaque found in middle adult life evolves during the first 20 years.20-23 There is suggestive, but not unequivocal, evidence that the fatty streak of childhood is a precursor of the mature atherosclerotic lesions.20-23 Symptomatic CHD iS usually present by the age of 10 and is always manifested in the second decade in children homozygous for familial hypercholesterolemia.24 In approximately 30 percent of adolescent boys (average age 13), heterozygous for familial hypercholesterolemia, there are abnormal maximum exercise electrocardiographic findings, compared to 7 percent of agematched normal boys, suggesting the potential of physiologic myocardial ischemia.25 Also, in young adult men heterozygous for familial hypercholesterolemia, morbidity and mortality from coronary artery disease appears between ages 20 and 30, suggesting that development and progression of the mature atherosclerotic lesions are well accelerated by the end of the second decade.26 The aggregate data from pathologic anatomical studies,20-23 and from the most severe manifestations of hypercholesterolemia in children and young adults,24-26 provide the background that persuades many physicians and scientists that to be effective, prevention of CHD must begin in the teenage years and possibly earlier.5'20 Children in the United States have higher plasma cholesterol levels than do children of other populations in which adult atherosclerotic disease is much less frequent.27-30 Approximately 5 percent of United States children, ages 5 to 18, have plasma cholesterol levels greater than 200 to 220
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C mg per dl.27-29 Those children with elevated plasma cholesterol levels in childhood are likely to maintain a similar elevated rank order throughout childhood, into adulthood.529 In addition, children with genetic hyperlipidemia, particularly familial hypercholesterolemia, can be identified in childhood.29'31
Childhood Diet and Hyperlipoproteinemia As summarized by Glueck and Stein,29 "it is estimated that approximately 1 percent of unselected children have monogenic familial hypercholesterolemia, familial hypertriglyceridemia, or familial combined hyperlipidemia." However, studies in population groups show that most hypercholesterolemia is not due to the "monogenic" familial hyperlipoproteinemias,31 but is likely related to the intake of dietary cholesterol, saturated fat and total calories.3-5 31-33 Plasma cholesterol levels in children having low total cholesterol and low saturated fat intake and in vegetarian children are 30 to 40 mg per dl below those of children receiving conventional Western diets.2932 Moreover, nutrition modification in small cohorts of children has been shown to produce significant reduction in plasma cholesterol levels. McGandy and associates34 studied a boarding school population. The calories provided from fat were reduced from 39 to 34 percent. Cholesterol consumption was decreased from 720 to 380 mg per day, and the dietary P/s ratio was increased from 0.2 to approximately 1.2. In 200 schoolchildren, ages 13 to 18, the mean plasma cholesterol level fell approximately 10 percent on this dietary regimen.34 Using a shortterm outpatient protocol in families with adolescent children, Witchi and associates35 reduced dietary cholesterol and saturated fat, and increased polyunsaturated fat. An average reduction in serum cholesterol approximating 10 percent was produced in adolescents over three weeks.35 There was a high degree of dietary cooperation among the free living families in this study. In a longer-term study in younger children, Friedman and co-workers36 provided low cholesterol, low saturated fat diets to normal infants from birth. At age 3, their mean cholesterol levels were 145±4 mg per dl, significantly lower than in 422 controls whose mean values were 154 + 1, having had no dietary intervention. Stein and associates37 evaluated 229 adolescent males in a South African boarding school. The
If
type of dietary fatty acids was altered, but not the amount of total fat or cholesterol. Using polyunsaturate-rich, saturate-poor diets, a 14 percent reduction in total and low density lipoprotein plasma cholesterol was achieved. The final ratio of polyunsaturate to monounsaturates to saturated fats was approximately 1:1:1. The above findings34-37 suggest that prudent, and rdlatively easy-to-achieve dietary changes, similar to those suggested by various nutritional councils,'6"17 would be successful in lowering plasma cholesterol levels in American children. Such diets would be particularly effective in that majority of children whose hypercholesterolemia was secondary to excessive ingestion of cholesterol and saturated fat.29'37 Dietary modification also has considerable utility in children who have familial hypercholesterolemia or hypertriglyceridemia, or both. Approximately a third of children with familial hypercholesterolemia will attain normal total plasma cholesterol and low density lipoprotein (LDL) cholesterol levels with dietary modification which reduces fat to 25 percent to 30 percent of total calories, substitutes polyunsaturates for saturates to reach a P/s ratio of 1:1 and limits dietary cholesterol to less than 200 mg per day, adjusted downward for younger children.5'29 Above age 10 in children heterozygous for familial hypercholesterolemia5'29 such a diet may reduce total and LDL cholesterol by 10 percent to 20 percent, but will not usually bring plasma cholesterol to normal levels. Therapy with bile acid binding resins is often necessary in such children to attain -adequate control.5 Elevated triglycerides in most children with familial hypertriglyceridemia can be brought to normal levels by weight reI
duction.5'29 Epidemiological3-5"6'32 and pathological20-23 evidence in humans and evidence from experimental animals suggests that maintenance of low plasma cholesterol levels beginning in childhood might be much more effective in retarding the progression of atherosclerosis than reducing levels beginning in the fourth or fifth decades.5 A controlled and blinded test to this hypothesis has not and probably never will be done due to overwhelmingly expensive logistics and the necessity for a four to' five decade follow-up if the study begins in the first decade of life.5 Although opinion is widely divided about the advisability of recommending a modified diet for all children,29 there is near unanimity that children falling in the THE WESTERN JOURNAL OF MEDICINE
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top decile of their age and sex distribution for plasma cholesterol and triglyceride levels should be treated.5'29,35
Diet-Atherosclerosis Relationships in Adults Three decades of detailed epidemiological studies have identified major risk factors for CHD including age, sex, hypercholesterolemia (elevations of LDL cholesterol), hypertension, cigarette smoking and diabetes.3-6'38-40 Obesity, personality type and lack of physicial activity are additional, but less well-established risk factors.3-6'38-40 These established risk factors "may be causal agents, intervening variables, or secondary indicators of a more fundamental disturbance."5 The amounts of cholesterol carried by the low density lipoproteins and by the high density lipoprotein (HDL) are more specific and have opposing risk factors for CHD (positive for C-LDL, inverse for C-HDL).41'42 Recommendations for dietary modification in population groups'6 blanket a heterogeneous group of subjects whose CHD risk status could be better gauged individually by measurement of fasting plasma cholesterol, C-HDL and triglyceride, allowing estimation of C-LDL.4'5 Specific lipoprotein sampling would facilitate identification of the approximately one out of 250 unselected Americans29 with familial hypercholesterolemia, who usually require individually determined diet and drug treatment.24-26 29 The approximate 30 percent of Americans having total plasma cholesterol levels of 250 mg per dl or greater would also be identified,43 a group of subjects shown to be at sharply increased CHD risk.43 Since CHD risk increases along with total plasma cholesterol throughout its entire distribution,39'40 (one basis for populationwide dietary modification recommendations),16 specific lipoprotein measurement would locate persons within the distribution. As is the case for children, hypercholesterolemia in adults is probably for the most part not due to the familial hyperlipoproteinemias,293'33 or to polygenic traits, but is most likely related to the intake of dietary cholesterol, saturated and polyunsaturated fat, and total calories. Moreover, in adults the development, progression and potential regression of the atherosclerotic lesion appears to be closely related to the plasma cholesterol level.6'43-47 Connor and associates and Mattson and associates have shown48'49 that dietary cholesterol has a close correlation with plasma cholesterol levels over a dietary range of 0 to 600 mg per day, but 120
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a further increase above 600 mg per day does not further substantially increase plasma cholesterol levels.48'49 Over a 20-year period of study, Keys and coworkers50'51 have shown that increments in dietary saturated fatty acids elevate serum cholesterol levels, whereas polyunsaturated fatty acids tend to diminish them. Mattson and associates52 found that sharp increments in trans fatty acids in the diet (present in partially hydrogenated vegetable oils) had no specific effect on plasma cholesterol and triglyceride. Studies in vegetarians and primitive people whose dietary cholesterol, saturated fat and total calorie intake is sharply lower than that in Westernized societies, have suggested overall a significant relationship among diet, plasma lipid levels and coronary heart disease.53-55 Keys and associates56 have shown, in Japanese migrants to Hawaii and California, a close and consistent relationship between dietary saturated fats, blood lipids and CHD event rates. Dietary modification in specific small cohorts can significantly lower serum cholesterol levels particularly when accompanied by a reduction of cholesterol and total saturated fat intake, and a relative increase in polyunsaturated fats.57 Weight reduction and modification of dietary lipids may well have a synergistic effect.58 Despite the incremental evidence relating dietary cholesterol and saturated fat to CHD there are clearly areas of discordance.6 Within culturally homogeneous groups, epidemiologic studies in children and adults may at times (as in the Tarahumara Indians) but not always show significant associations between nutrient intakes and serum lipids'0'32'59 or CHD risk.59 There are certain limitations to the interpretations of such studies.60 Random errors in the collection of dietary data would lead to the underestimation of any relationships between nutrients and CHD.60 Moreaver, recent diet habits do not represent lifetime patterns, and development of atherosclerosis over decades makes it misleading to relate recent dietary practices to the risk of CHD.3-5 A more serious challenge to believability of the diet-heart relationship has been the lack of unequivocal, uniform reduction in "hard" or "soft" end points in populations where diets have been modified44-46'6' or where lipid-lowering drugs have been given.62 In four dietary modification trials completed, there was significant lowering of plasma cholesterol, and suggestive but not un-
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equivocal reduction in "hard" and "soft" end points for CHD.44-46'61 The drug-heart study did not systematically utilize dietary modification.62 Using nicotinic acid and clofibrate (Atromid), there was no conclusive reduction in cHD morbidity and mortality after five years of followup.62 These small clinical trials may (speculatively) have failed to detect a substantial effect on CHD because they were carried out in adults whose atherosclerosis was advanced and potentially' irreversible.44-46 61'62 A controlled trial on the effect of dietary modification on CHD in young adults is probably not feasible,14 due to the requirement for an unmanageably large number of subjects in order to obtain statistically convincing results. There are, however, two very large intervention trials currently underway. It is hoped that the MRFIT trial (modification of diet, smoking and hypertension) and the Lipid Research Clinic (LRC) study (modified diet and cholestyramine resin) will provide incremental evidence relevant to amelioration and prevention of cH in adults. Results from the MRFIT and LRC studies probably will not become available until 1983 or later, and will necessarily be primarily applied generally to a truncated segment of the population distribution selected by virtue of high initial risk. Studies in the future might profitably focus on the essentially unexplored relationships of C-HDL to diet, and to other environmental factors. Since studies designed to lower total plasma cholesterol and C-LDL have provided only reduction in CHD in selected groups of the population44-46'61'62 or cases of total vascular disease,44-46'6162 safe and effective methods to elevate C-HDL might open up alternative avenues to amelioration of atherosclerosis. Careful epidemiological studies of the secular trends towards reduction in dietary cholesterol and saturated fats, plasma cholesterol and cHD event rates should be continued and expanded, perhaps to include prospective cohort follow-up, to identify, if possible, any etiological relationships between these variables. Further assessment and documentation of the possible CHD-sparing effects of balanced exercise programs,63 and their long-term relationship to plasma lipids and lipoproteins may be an exciting and -underevaluated area for future work. REFERENCES 1. Ignatowski A: Ueber die Wirkung des tierischen Eiweisses auf die Aorta und die Parenchymatosen Organe der Kaninchen. Virchow's Arch Pathol Anat Physiol 198:248-270, 1909 2. Anitschkow N, Chalatow S: Ueber experimentelle Cholesterinsteatase und ihre Bedeutung fur die Enstehung einiger patholigischer Prozesse. Centralbl Aug Pathol Anat 24:1-9, 1913
3. Glueck CJ, Connor WE: Diet-coronary heart disease relationships reconnoitered. Am J Clin Nutr 31:727-737, 1978 4. Glueck CJ, Mattson F, Bierman EL: Diet and coronary heart disease: Certitude, effectiveness, feasibility, safety. N Engl J Med 298:1471-1474, 1978 5. Glueck CJ, McGill HS, Shank R, et al: The value and safety of diet modification to control hyperlipidemia in childhood and adolescence. Circulation 58:A381-A385, 1978, 6. Connor WE, Connor SL: The key role of nutritional factors in the prevention of coronary heart disease. Prey Med 1:49-83, 1972 7. Agricultural Statistics. US Dept. of Agriculture, US Govt Print Off, 1975 8. Kromer GW: Fats and oils: Natural and processed foods, In White PL, Fletcher DC (Eds): Nutrients in Processed Foods, Fats, and Carbohydrates. Acton, MA, Publishing Sciences Group, Inc, 1975 9. Chandler CA, Marston RM: Fat in the U.S. diet. Nutrition Program News, US Dept of Agriculture, 1976, pp 1-8 10. Frank GC, Berenson GS, Webber LS: Dietary studies and the relationship of diet to cardiovascular disease risk factor variables in 10-year-old children: The Bogalusa Heart Study. Am J Clin Nutr 31:328-340, 1978 11. A comparison of levels of serum cholesterol of adults 18-74 years of age in the United States in 1960-1962 and 1971-1974Advance data. Vital and Health Statistics of the National Center for Health Statistics, US Dept. of Health, Education, and Welfare, Feb 5, 1977 12. Walker W: Changing United States life-style and declining vascular mortality: Cause or coincidence? (Editorial). N Engl J Med 297:163-165, 1977 13. National Heart, Blood Vessel, Lung and Blood ProgramFourth Report of the Direction of the National Heart, Lung, and Blood Institute, DHEW publication No. (NIH)77-1170, US Dept of Health, Education and Welfare, Public Health Service, Natl Institutes of Health, 1977 14. National Diet-Heart Study Research Group: National dietheart study final report. Circulation 37(Suppl I) :1-1-1-428, 1968 15. Meyer AJ, McAlister A, Nash J, et al: Maintenance of cardiovascular risk reduction: Results in high risk subjects. Circulation (Suppl II):11-226, 1976 16. Primary prevention of the atherosclerotic diseases-Report of the Inter-society Commission for Heart Disease Resources. Circulation 42:A55-A95, 1970 17. Diet and coronary heart disease: A joint policy statement of the AMA Council on Foods and Nutrition and the Food and Nutrition Board of the National Academy of Sciences-National Research Council. JAMA 22:1647, 1972 18. American Heart Association Committee on Nutrition: Diet and Heart Disease. Dailas, American Heart Association, 1978 19. Manning GW, Haust MD (Eds): Atherosclerosis: Metabolic, Morphologic, and Clinical Aspects. New York, Plenum Press, 1977 20. McGill NC, Jr: Atherosclerosis: Problems in pathogenesis, In Gotto AM, Paoletti R (Eds): Atherosclerosis Reviews. New York, Raven Press, 1977, pp 27-65 21. Enos WF, Beyer JC, Holmes RH: Pathogenesis of coronary disease in American soldiers killed in Korea. JAMA 158:912-914, 1955 22. McNamara JJ, Molot MA, Stremple JF, et al: Coronary artery disease in combat casualties in Vietnam. JAMA 216:11851187, 1971 23. Holman RL, McGill HS Jr, Strong JP, et al: The natural history of atherosclerosis-The early aortic lesions as seen in New Orleans in the middle of the 20th century. Am J Pathol 34: 209-235, 1958 24. Fredrickson DS, Levy RI: Familial hyperlipoproteinemia, In Stanbury JB, Wyngaarden JB, Fredrickson DS (Eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1972, pp 546-614 25. James FW, Glueck CJ, Fallat RW, et al: Maximal exercise stress testing in normal and hyperlipidemic children. Atherosclerosis 25:85-94, 1976 26. Stone NJ, Levy RI, Fredrickson DS, et al: Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 49:476-488, 1974 27. Frerichs RR, Srinivasan SR, Webber LS, et al: Serum cholesterol and triglyceride levels in 3446 children from a biracial community-The Bogalusa Heart Study. Circulation 54:302-309, 1976 28. deGroot I, Morrison JA, Kelly KA, et al: Lipids in school children ages 6-17: Upper normal limits. Pediatrics 60:437-443, 1977 29. Glueck CJ, Stein EA: Pediatric considerations in the treatment and management of hyperlipoproteinemia, In Rifkind BM, Dennis BH, Ernst ND (Eds): Nutrition and Coronary Heart Disease. New York, Raven Press, 1978, Vol I, pp 285-309 30. Lauer RM, Connor WE, Leaverton PE, et al: Coronary heart disease risk factors in school children: The Muscatine Study. Pediatrics 36:697-706, 1975 31. Glueck CH, Kwiterovich PO: The lipid hypothesis, genetic basis, In Buchwald H (Ed): The hyperlipidemias and their management. Arch Surg 113:35-41, 1978
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C~~~dM~~~don.032. Connor WE, Cerqueira MT, Connor RW, et al: The plasma lipids, lipoproteins, and diet of the Tarahumara Indians of Mexico. Am J Clin Nutr 31:1131-1143, 1978 33. Motulsky AG, Boman H: Screening for the hyperlipidemias, In Milunsky A (Ed): The Prevention of Genetic Disease and Mental Retardation. Philadelphia, WB Saunders Co, 1975, pp 306-316 34. McGandy RB: Adolescence and the onset of atherosclerosis. Bull NY Acad Med 47:590-600, 1971 35. Witchi JC, Singer M, Wu-Lee M, et al: Family cooperation and effectiveness in a cholesterol-lowering diet. J Am Diet Assoc 72:384-388, 1978 36. Friedman G, Goldberg SJ: An evaluation of the safety of a low saturated diet, low cholesterol diet, beginning in infancy. Pediatrics 58:655-657, 1976 37. Stein EA, Mendelsohn D, Bersohn I, et al: Lowering of plasma cholesterol levels in free-living adolescent males: Use of natural and synthetic polyunsaturated foods to provide balanced fat diets. Am J Clin Nutr 28:1204-1216, 1975 38. Keys A (Ed): Coronary heart disease in seven countries. (American Heart Association Monograph No. 29). Circulation 41(Suppl 1) :1-1-1-211, 1970 39. Stamler J, Berkson DM, Lindberg HA: Risk factors: Their role in the etiology and pathogenesis of the atherosclerotic diseases, In Wissler RW, Geer JC (Eds): The Pathogenesis of Atherosclerosis. Baltimore, Williams & Wilkins, 1972, pp 41-119 40. Kannel WR, McGee D, Gadon T: A general cardiovascular risk profile: The Framingham Study. Am J Cardiology 38:4651, 1976 41. Castelli WP, Doyle JT, Gordon T, et al: HDL cholesterol and other lipids in coronary heart disease-Cooperative lipoprotein phenotyping study. Circulation 55:767-772, 1977 42. Glueck CJ, Gartside P, Fallat lW, et al: Longevity syndromes: Familial hypobeta and familial hyperalphalipoproteinemia. J Lab Clin Med 88:941-957, 1976 43. Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habits, relative weight, and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project. J Chron Dis (In press, 1979) 44. Dayton S, Pearce ML, Hashimoto S, et al: A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 40(Suppl II) :I-1-II-63, 1969 45. Miettinen. M, Turpeinen 0, Karvonen MJ, et al: Effect of cholesterol lowering diet in mortality from coronary heart disease and other causes. Lancet 2:835-838, 1972 46. Leren P: Effect of plasma cholesterol lowering diet in male survivors of myocardial infarction. Acta Med Scand, Suppl 466, 1966, pp 1-92
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47. Blankenhorn DH, Brooks SH, Selzer RH, et al: Rate of atherosclerosis change during treatment of hyperlipoproteinemia. Circulation 57:355-361, 1978 48. Connor WE, Hodges RE, Bleiler RE: The serum lipids in men receiving high cholesterol and cholesterol-free diets. J Clin Invest 40:894-901, 1961 49. Mattson FH, Erickson FA, Kligman AM: Effect of dietary cholesterol in man. Am J Clin Nutr 25:589-594, 1972 50. Keys A, Grande F, Anderson JT: Bias and misrepresentation revisited: Perspective on saturated fat. Am J Clin Nutr 27:188212, 1974 51. Keys A, Anderson JT, Grande F: Prediction of serum cholesterol responses of man to change of fat in the diet. Lancet 2:959, 1957 52. Mattson FH, Hollenbach EJ, Kligman AM: Effect of hydrogenated fat on the plasma cholesterol and triglyceride levels of man. Am J Clin Nutr 28:726-731, 1975 53. West RO, Hayes OB: Diet and serum cholesterol levels: A comparison between vegetarians and non-vegetarians in a SeventhDay Adventist group. Am J Clin Nutr 21:853-862, 1968 54. Sacks FM, Castelli WP, Donner A, et al: Plasma lipids and lipoproteins in vegetarians and controls. N Engl J Med 292: 1148-1151, 1975 55. Sinnett PF, Whyte HM: Epidemiological studies in a total highland population, Tukisenta, New Guinea.-Cardiovascular disease and relevant clinical, electrocardiographic, radiological, and biochemical findings. J Chron Dis 26:265-290, 1973 56. Keys A, Kimura N, Kusukawa A, et al: Lessons from serum cholesterol studies in Japan, Hawaii and Los Angeles. Ann Intern Med 48:83-94, 1958 57. Rifkind BM, Levy RI (Eds): Hyperlipidemia: Diagnosis and Therapy. New York, Grune & Stratton, 1977 58. Ashley FW, Kannel WB: Relation of weight change to changes in atherogenic traits: The Framingham Study. J Chron Dis 27:103-114, 1974 59. Nichols AB, Ravenscroft C, Lamphier DE, et al: Independence of serum lipid levels and dietary habits. JAMA 236: 1948-1953, 1976 60. Diamond EL, Lilienfeld AM: Effects of errors in classification and diagnosis in various types of epidemiologic studies. Am J Public Health 52:1137-1144, 1962 61. Frantz ID, Dawson EA, Kuba K, et al: The Minnesota Coronary Survey: Effect of diet on cardiovascular events and deaths. Circulation 51(Suppl II):11-4, 1975 62. Clofibrate and niacin in coronary heart disease-Coronary Drug Project Research Group. JAMA 231:360-381, 1975 63. Paffenbarger RS, Hale WE, Grand RJ, et al: Work energy level: Personal characteristics and fatal heart attack: A birth cohort effect. Am J Epidemiol 105:200-213, 1977
