The 'diet heart' hypothesis in secondary prevention of coronary heart disease

European Heart Journal (1997) 18, 13-18 Controversy The 'diet heart' hypothesis in secondary prevention of coronary heart disease Introduction For scientists and physicians interested in the relationship between diet, coronary heart disease and the world-wide efforts to counteract the disease, it is important to remember that the 'diet heart' hypothesis was based primarily on the observation of a strong, positive association between saturated fat consumption (essentially animal products) and coronary heart disease mortality and morbidity. Saturated fat and cholesterol intake, known to increase blood cholesterol, also positively correlated with coronary heart disease incidence. It was therefore hypothesized that reduction of blood cholesterol by dietary (or non-dietary, i.e. pharmacological) means might reduce the frequency of cardiac relapses after a first coronary event. The three main secondary prevention dietary trials, designed and conducted during the 1960s and 1970s, investigated whether reduction of blood cholesterol by a diet low in cholesterol and saturated fats and rich in polyunsaturated fats may prevent coronary relapse after a first event' 1 " 3 '. They were intrinsically different from recent trials which tested whether dietary habits known to be cardioprotective in certain populations (Asian vegetarian, Mediterranean or a population regularly eating a certain amount of fish) might reduce coronary heart disease morbidity and mortality in coronary patients, independent of a major effect on blood cholesterol' 4 " 61. In these recent trials, the main question was: could the natural cardioprotection observed in certain groups also be protective when voluntarily transferred to a population at risk of developing acute coronary heart disease complications? No significant alteration of a major recognized risk factor such as blood pressure, weight or blood cholesterol was expected. The simplest of these cardioprotective diets, in the Diet And Reinfarction Trial (DART), consisted in an increased consumption offish (200 to 400 g per week) in combination with a relatively low fat diet (about 35% of total energy)' 41. In the Indian Diet Heart Study, a very low fat diet (less than 25% of Correspondence: M. de Lorgeril, MD, CERMEP CNRS UMR 1216, 59 Boulevard Pinel, 69003 Lyon, France. 0195-668X/97/0100I3+10 S18.00/0 energy) was combined with a very large intake of vegetables, fruit and nuts, and also a moderate increase in the consumption offish' 51.In the Lyon Diet Heart Study, investigators tested a Mediterraneantype of diet (total fat represented 30% of energy) focusing on the quality of the fat (olive and canola oils exclusively), an increased consumption of cereals, bread, vegetables, legumes, fruit and a moderately increased consumption of fish' 61. The three trials had in common an increased intake of omega-3 fatty acids. In dietary trials, it is essential to interpret the results of each trial in the light of the result of other contemporary trials based on similar approaches. Dietary trials cannot be double-blinded because active cooperation of the patients randomized in the experimental groups is indispensable. These studies are, nevertheless, single-blinded since validation and classification of the endpoints are performed blindly by an independent committee, although the sample cannot be of optimum size due to the complexity of the intervention and the need for numerous and prolonged contacts between patients (including ) and investigators (including dieticians). Dietary trials are consequently open to bias, and therefore it is necessary to combine the results of several trials for the best information. Thus, in the present article we will review together the three older trials aimed at reducing blood cholesterol by an experimental diet' 1 " 31 and the three recent trials based either on an augmented intake of fish' 41 or on the concept of cardioprotective ethnic diets' 561. Older dietary trials These were characterized (Table 1) by the relatively small number of patients in each trial, exclusively men (412, 393 and 458 in the Oslo, London and Sydney studies, respectively), the young age of the patients and, apart from the London study, the long delay between the qualifying coronary event and randomization. This was usually several months and never less than 6 to 8 weeks in the London and Sydney studies. The need to recruit only low risk %> 1997 The European Society of Cardiology

14 Controversy Table 1 Main characteristics of the old and recent trials Old studies Recent studies Oslo London Sydney DART Indian Lyon Population Age (years) Post-infarct delay Entry criteria Exclusion criteria Risk-prognosis factors Associated drug treatment Duration of follow-up 412 men 30-64 5^20 month CHD Many?(*) Unknown 5 yearsf 393 men <65 >6 week CHD Many?(*) Unknown 5 years 458 men 30-59 >8 week CHD Many?(*) Unknown 5 years 2033 men <70 mean 41 day AMI Few Well described Reported 2 years 406 (90% men) mean 51 within 24-48 h AMI Few Well described Reported 1 year 605 (90% men) <70 mean 60 day AMI Few Well described Reported 27 months! AMI = acute myocardial infarction; CHD=coronary heart disease, including patients with cardiac pain with or without abnormal Q wave in the electrocardiogram. *for instance, baseline cholesterol was not reported. fa subsequent publication reported an 11-year follow-up (see text). tsimilar results are observed after 45 months of follow-up. patients explains the patients' relative youth and long delay since the qualifying event. Old age is a major risk factor and it was thought, according to the prevalent 'cholesterol theory', that cholesterol lowering could affect prognosis only in the long term. At the time of these trials, recurrence rate was usually higher in the first few months following an acute coronary event, whereas beyond this period, patients were thought to be clinically stable, i.e. less prone to malignant arrhythmias or heart failure, which were considered not to be influenced by a cholesterollowering diet. It should also be noted that the qualifying event was not always clearly defined. The proportion of patients surviving one or several infarcts vs those recruited after a single episode of exercise angina pectoris were not reported. It can only be said that these patients had coronary heart disease as indicated in Table 1. In addition, the associated drug treatments were not reported. For instance, in none of the three trials were we told whether patients were taking anticoagulant, aspirin or beta-blocking agents. It is possible, although unlikely, that most of the patients were taking nothing. In contrast, in the Oslo and London studies (not reported in the Sydney trial), there were many and well specified exclusion criteria. Some of them were inherent to a dietary study: for instance, the inability of patients to follow an experimental diet for any reason, or patients not recruitable in the long-term trial, those who expected to move or those with poor short-term prognosis due to non-cardiac disease, such as cancer or major organ failure. Most of the exclusion criteria tended to eliminate patients with an apparently poor short-term non-cardiac or cardiac prognosis, a prior episode of heart failure, cardiomegaly, malignant arrhythmias etc. Using modern clinical classification, the patients randomized in these trials were clinically stable young men at a low risk of death or infarct recurrence. This is a major point to be considered when comparing older and recent dietary trials, or drug and dietary trials, or before extrapolating the results of a trial conducted in certain groups of patients to other groups, or before making general recommendations. Finally, baseline cholesterol levels were not reported in these trials. This is surprising since the goals of the dietary interventions were precisely to reduce blood cholesterol. It is likely that investigators assumed that reduction of cholesterol was useful whatever the baseline levels. The diets followed by the patients of the three experimental groups are described in Table 2, are comparable to the present recommendations (prudent diet, step 1) of the American Heart Association' 7 ', and are very similar to those of the European Society of Cardiology' 8 '. Dietary habits in the control group were sometimes not specified in the publications. As expected in interventions to lower blood cholesterol, saturated fat and cholesterol intakes were low. However, the main common characteristic of the three trials was the high polyunsaturated to saturated fat ratio (P/S ratio) which indicated an extremely high consumption of polyunsaturated fatty acids, essentially linoleic acid given with soya oil or corn oil. Although not reported in the London study, we can be sure (seeing the total fat and saturate fat intakes and the P/S ratio) that the intake of polyunsaturated fats was between 15% and 20% of total energy. This is considerable and has never been observed in any population around the world. The intake of total lipids around 40% of energy but more than 45% in the London study (Table 2) was also very high in the three trials, compared with the present U.S. and European recommendations' 7 ' 8 '. Despite a Eur Heart J. Vol. 18, January 1997

Controversy 15 significant decrease in blood cholesterol (not a massive reduction), the clinical results of the three trials were disappointing, as shown in Table 3. In the Sydney study, only total mortality was reported and was slightly higher in the experimental than in the control group' 21. There was no difference at all between groups in the London study for both mortality and morbidity' 31. In the Oslo trial, there was a borderline significant difference between groups only when combining cardiac death and non-fatal infarct, showing that were somewhat protected 1 ' 1. Globally, this first generation of dietary trials, with statistically sound sample size and conducted with the minimum of precautions expected for controlled trials, were considered to be failures. The main reasons put forward to explain the failure were that the patients had been recruited too late in the course of the disease and that cholesterol reduction in was not sufficient to slow the progression of atherosclerotic stenosis compared with. Many investigators concluded that primary prevention trials should be organized in younger patients at a time when coronary heart disease is supposed to be commencing (again in accordance with the 'cholesterol theory') and that cholesterol-lowering drugs should be added to the tested lipid-lowering diets. This is, however, another story which is beyond the scope of the present review. Recent dietary trials During the 1980s, new dietary trials were initiated based on the idea, as written above, that dietary habits in certain populations, for instance in Asia' 51 or around the Mediterranean sea' 61, could be protective. Also, the hypothesis was proposed that a moderate consumption of fish may protect against coronary heart disease' 41. In these trials, the number of patients (Table 1) was larger than in previous trials aimed at reducing blood cholesterol. This was especially true for DART (more than 2000 patients) in which the multifactorial design served to test three different diet hypotheses' 41. We will only comment upon the successful one, which concerned a moderate augmentation offish consumption. Other characteristics were that patients were older (up to 70) and were recruited early after the qualifying coronary event, a welldefined acute myocardial infarction in the three trials. In fact, patients were recruited during their stay in the Coronary Care Unit. In DART and in the Lyon study, they were randomized 1 to 2 months after hospital discharge, whereas in the very ambitious Indian trial, patients were randomized within 24 to 48 h after their admission to the Coronary Care Unit. In contrast to the older trials, probably because of major advances in cardiovascular drug treatment, associated drug treatments were clearly reported. In the three trials, randomization was successful to prevent any difference between control and experimental groups in terms of drug treatment. Associated drug treatment is an important point to be considered when evaluating new treatment or new preventive strategy. In the Indian and Lyon trials, the vast majority of the patients were taking antithrombotic drugs, either antiplatelet or anticoagulant drugs, and about half of them were receiving betablockers' 5 ' 61. In DART, patients were apparently under-treated, only 15% were taking antithrombotic drugs, although they were all survivors of a recent infarct' 41. Finally, there were relatively few exclusion criteria and in contrast to a recent lipid-lowering drug trial' 91, patients with altered left ventricular function and/or cardiomegaly were not excluded. The tested diets (Table 2) were more or less complex: monofactorial with a moderate increase in fish consumption, combined with a relatively low fat diet (about 35% energy) in DART, multifactorial in the Indian trial with a very low fat diet (less than 25% energy as lipids) in which patients were encouraged to become vegetarian. About 10% of energy was provided by vegetable proteins, which is certainly a major point, knowing the potential impact of L-arginine and L-glutamine two major amino acids in vegetable proteins in cardiovascular diseases. Also, patients were asked to eat more omega-3 fatty acids both from vegetable sources such as nuts (which are also rich in arginine) and from fish (which are also rich in L-glutamine). The main characteristic of the Mediterranean-type of diet, which was tested in the Lyon study, was moderation (Table 2). Total fat (30% of energy) and saturated fat (8% of energy) intakes were moderately low. Proteins and monosaturated fats (from olive oil and canola oil) were not reduced but taken in moderate amounts, about 17% and 13% of energy, respectively. It was recommended to reduce total polyunsaturated fat intake (less than 5%) but to increase omega-3 fatty acid intake, especially from vegetable source (alpha linolenic acid in canola oil, about 1% of energy) and from fish' 61. With regards to the clinical result (summarized in Table 3), these trials were remarkably successful in reducing coronary heart disease. Patients in the three trials were, at randomization, at high risk of recurrence, especially in the Indian trial. There was, however, an unexpected significant effect on total and cardiac mortality, ranging from 30% to 70% reduction of the risk of death. In fact, the more complex and mulifactorial the experimental diet the higher the protection, as if the degree of protection was Eur Heart J, Vol. 18, January 1997

2 The diets (in % of energy) followed by the and (when data are available) in the old and recent trials and compared with th mendations of the American Heart Association Old studies Recent studies Oslo London Sydney DART Indian Lyon at d s ydrates erol (nig. day ') 39-0 8'5 20-7 101 2-4 150 45-5 264 45-5 2-0 13-4 40-8 258 38-3 9-8 151 111 1-5 210 40-9 248 38 1 13-5 8-9 13-8 0-66 220 40-3 342 <35 (A) 23-8 7-2 8-6 80 1-2 (D) 9-6 (E) 3-8 62-8 147 280 10-8 7-0 10-2 0-65 (D) 6-2 (E) 9-0 56-8 287 305 8-3 (B) 3-6 (C) 0-81 12-9 0-65 17-2 52-3 217 32-7 11-7 5-3 0-27 10-3 0-68 16 5 50-8 318 gmented intake of long-chain fatty acids of the omega-3 family [(20:5(n-3); 22:5(n-3); 22:6(n-3)]; (B): 18:2(n-6); (C): 18:3(n-3). oteins from vegetable and fish. imal proteins. Amcrican Heart Association; PUFA = polyunsaturated fatty acids; MUFA = monounsaturated fatty acids; P/S = polyunsaturated to saturated fat ratio. 3 Recurrence rates (per 100 patients per year of follow-up) in the 6 studies and Risk Ratios (RR) in the recent trials Old studies Recent studies Oslo* London Sydney DART Indian Lyon RR RR contro eaths 40 5-3 deaths 3'7 5-0 3-5 3-2 al infarcts 2-3 30 31 3-2 ed cardiac deaths 6-0 80t 6-6 6-4 on-fatal infarcts 3-3 2-4 4-7{ 3-8 2-4 6-2 6-4 5-7 1-6 73 0 71 0-84 10-3 IO-2 14-7 24-5 18-8 16-8 23-8 40-6 0-55 0-58 0-62 0-59 1-3J 0-5 0-8 l-3 3-4 2-7 2-9 56 5; tp<0-05; P<0'0\. bsequent 11-year report the results were 4-5% (per year) for total deaths in and 4-8 in (not significant) and 3-9% and 4-5% for cardiac deaths (P 0-\0).

Controversy 17 proportional to the number of biological parameters modified. This theoretically included any increase of beneficial factors (oleic acid, omega-3 fatty acids, vegetable proteins and antioxidants) and any decrease of deleterious factors (total, saturated and polyunsaturated fats). It is noteworthy that cardioprotection was observed equally in the high-risk, patients of the Indian trial (the very high recurrence rates indicated in Table 3 comprise in-hospital morbidity and mortality^) and the low-risk patients of the Lyon trial, in which a recurrence rate of 5-6 per hundred patients per year was observed in the control group. This low recurrence rate is likely to indicate that patients took maximum advantage of the modern in-hospital treatments, including thrombolytic treatment in the acute phase of infarction, early exercise testing, coronary angiography and angioplasty before discharge if needed, antithrombotic treatment and beta-blockers at admission unless contraindicated or because of side-effects and angiotensin-converting-enzyme inhibitors when necessary' 61. Further, this low recurrence rate in the control group indicated that the large difference between groups during follow-up was not due to over-mortality and/or over-morbidity in the control group, but to reduced recurrent rates in the experimental group. Finally, apart from major differences in plasma fatty acids, especially in the omega-3 family, in DART [4] and the Lyon study' 61, and in antioxidant vitamins (alpha-tocopherol and ascorbic acid) in the Lyon study 161, classical risk factors including weight, body mass index, blood pressure and plasma lipids were not very different in the two groups of the three studies. Thus, modifications in these factors cannot explain the improved prognosis of. Only in the Indian trial was there a slight reduction of cholesterol level in the experimental group. It should be noted that in the Lyon trial blood cholesterol was similar in the two groups; the control group followed the prudent lipid-lowering AHA diet. This means that the Mediterranean diet tested in the Lyon trial was also lipid-lowering. Summary and conclusions From this detailed analysis of the main dietary trials conducted over the last 30 years in the secondary prevention of coronary heart disease, it can be said that the older trials were conducted on low risk patients and used high fat diets (about 40% of energy as lipids), comprising low saturated fat and cholesterol intake but very high (15 to 20% of energy) polyunsaturated fat intake, particularly from the omega-6 fatty acid family. These experimental diets were designed to reduce blood cholesterol and failed to improve prognosis. By contrast, recent trials were not primarily designed to reduce cholesterol, were conducted in medium- and high-risk patients and used low fat diets supplemented by omega-3 fatty acids from various sources. In two of these trials, the consumption of natural antioxidants, oligoelements and vegetable proteins was increased. Recurrence rate was reduced in the range of 30 to 70%. One conclusion from these well-conducted recent experiments on more than 3000 patients is that new and more specific dietary recommendations are clearly warranted in secondary prevention of coronary heart disease. They should be more specific and more clearly defined and therefore different from those generally provided in the U.S.A. and Europe at present. In a recent Consensus Panel statement, authors wrote less than one line to describe a cardioprotective diet in patients with coronary heart disease, summarized as <30% fat, <7% saturated fat, <200mg.day"' cholesterol' 101. This is both too much (too restrictive to hope that white European and American patients will adhere in the long-term) and insufficient because dietary counselling cannot be restricted to three factors. Ulbricht and Southgate recently emphasized that the relationship between diet and coronary heart disease is more complex than the current cholesterol hypothesis'" 1. They identified at least seven major dietary factors, including fibres, although the evidence of an effect on coronary heart disease is weak. However, they did not mention vegetable and fish proteins which are rich in arginine and L-glutamine, major regulators of cardiovascular function' 12 ' 131. Thus, new dietary advice should include: reduce intake of total (not more than 30% of energy) and saturated (less than 10%) fats maintain intake at least minimally, of the essential omega-6 fatty acids augment consumption of oleic acid and moderately increase consumption of omega-3 fatty acids augment intake of natural antioxidants and oligoelements maintain sufficient intake of vegetable proteins As conceptualized in the 'Mediterranean' and 'Asian-vegetarian' types of diet, it is very important that a healthy diet should be thought of as a whole rather than as a recitation of good and bad components. Although these protective dietary modifications should probably all be used in each patient to obtain maximal efficacy, these scientifically quantitated principles should be adapted to the culture, ethnic origin and 'image of the world' of each patient Eur Heart J, Vol. 18, January 1997

18 Controversy in order to create an environment favourable to the perception of positive associations between various foods and healthy habits'"'. M. DE LORGERIL* P. SALEN* I. MONJAUD* J. DELAYEf *Centre National de la Recherche Scientifique and \H6pital Cardiologique, Lyon, France References [1] Leren P. The Oslo Diet-Heart Study. Eleven-year report. Circulation 1970; 42: 935-42. [2] Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exper Med Biol 1978; 109: 317-31. [3] Report of a Research Committee to the Medical Research Council. Controlled trial of soya-bean oil in myocardial infarction. Lancet 1968; ii: 693-700. [4] Burr ML, Fehily AM, Gilbert JF et al. Effects of changes in fat, fish and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989; ii: 757-61. [5] Singh RB, Rastogi SS, Verma R et ai. Randomised controlled trial of cardioprotective diet in patients with acute myocardial infarction: results of one year follow-up. BMJ 1992; 304' 1015-9. [6] de Lorgeril M, Renaud S, Mamelle N et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343: 1454-9. [7] Chait A, Brunzell JD, Denke MA et al. Rationale of the diet-heart statement of the American Heart Association. Report of the Nutrition Committee. Circulation 1993; 88: 3008-29. [8] Pyorala K, de Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practice. Eur Heart J 1994; 15: 1300-31. [9] Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9. [10] Consensus Panel Statement. Preventing heart attack and death in patients with coronary disease. Circulation 1995; 92: 2-4. [11] Ulbricht TLV, Southgate DAT. Coronary heart disease: seven dietary factors. Lancet 1991; 338: 985-92. [12] Cooke JP, Tsao P, Singer A, Wang BY, Kosek J, Drexler H. Anti-atherogenic effect of nuts: is the answer NO? Arch Intern Med 1993; 153: 896. [13] Hamon M, Vallet B, Bauters C, et al. Long-term oral administration of L-arginine reduces intimal thickening and enhances neoendothehum-dependent acetylcholine-induced relaxation after arterial injury. Circulation 1994; 90. 1357-62. European Heart Journal (1997) 18, 18-22 The low fat/low cholesterol diet is ineffective Ask almost any member of the general public about a diet which would reduce their chance of heart disease and the reply is the same: 'a low fat diet'. On closer questioning, this means a diet with a reduction in cholesterol and saturated 'animal' fats, i.e. less meat, butter, milk and cheese. Most national and international recommendations for the prevention of heart disease, whether for primary prevention or for patients who have developed the clinical manifestations of coronary heart disease, have made dietary restriction of total and saturated fats and of cholesterol the primary advice and often the sine qua non in relation to all other forms of management. To this extent they are to be congratulated that the message appears to be so universally accepted. Unfortunately, the available trials provide little support for such recommendations and it may be that far more valuable messages for the dietary and non- Correspondence: Dr Laura A. Corr, MB. BS, MRCP, PhD, FESC, Consultant Cardiologist. Guys and St. Thomas" Hospitals, St. Thomas Street, London SE1 9RT. dietary prevention of coronary heart disease are getting lost in the immoderate support of the low fat diet. The origin of the 'low fat' diet The international bodies which developed the current recommendations based them on the best available evidence 1 '" 3 '. Numerous epidemiological surveys confirmed beyond doubt the seminal observation of Keys in the Seven Countries Study of a positive correlation between the intake of dietary fat and the prevalence of coronary heart disease' 4 ' although recently a cohort study of more than 43 000 men followed for 6 years has shown that this is not independent of fibre intake' 5 ' or risk factors. The prevalence of coronary heart disease has been shown to be correlated with the level of serum total and low density lipoprotein cholesterol (LDL) as well as inversely with high density lipoprotein. As a consequence of these Eur Heart J. Vol. 18, January 1997