Atherosclerosis 234 (2014) 320e328

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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Dietary fats and cardiovascular disease: Putting together the pieces of a complicated puzzle George Michas a, Renata Micha a, b, Antonis Zampelas a, * a b

Unit of Human Nutrition, Department of Food Science and Human Nutrition, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 December 2013 Received in revised form 11 March 2014 Accepted 16 March 2014 Available online 27 March 2014

Dietary fatty acids play significant roles in the cause and prevention of cardiovascular disease (CVD). Trans fatty acids from partially hydrogenated vegetable oils have well-established adverse effects and should be eliminated from the human diet. CVD risk can be modestly reduced by decreasing saturated fatty acids (SFA) and replacing it by a combination of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). Although the ideal type of unsaturated fat for this replacement is unclear, the benefits of PUFA appear strongest. Both n-6 and n-3 PUFA are essential and reduce CVD risk. However, additional research is needed to better define the optimal amounts of both and to discern the patients and/or general population that would benefit from supplemental n-3 fatty acid intake. Furthermore, consumption of animal products, per se, is not necessarily associated with increased CVD risk, whereas nut and olive oil intake is associated with reduced CVD risk. In conclusion, the total matrix of a food is more important than just its fatty acid content in predicting the effect of a food on CVD risk, and a healthy diet should be the cornerstone of CVD prevention. Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Cardiovascular disease Diet Trans fatty acids Saturated fatty acids Polyunsaturated fatty acids Monounsaturated fatty acids

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 2.1. The traditional diet-heart paradigm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 2.2. Impact of dietary fats on blood lipids and lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 2.3. The impact of dietary fats on cardiovascular morbidity and mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 2.3.1. Saturated FA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 2.3.2. Trans FA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 2.3.3. PUFA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 2.3.4. MUFA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 2.4. The impact of food sources of dietary fats on cardiovascular morbidity and mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 2.4.1. Red and processed meat intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 2.4.2. Milk, other dairy products, and egg intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 2.4.3. Olive oil consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 2.4.4. Nut consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

* Corresponding author. E-mail address: [email protected] (A. Zampelas). http://dx.doi.org/10.1016/j.atherosclerosis.2014.03.013 0021-9150/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

G. Michas et al. / Atherosclerosis 234 (2014) 320e328

1. Introduction The World Health Organization (WHO) defines cardiovascular diseases (CVD) as a group of disorders of the heart and blood vessels that includes: coronary heart disease (CHD), cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, and deep vein thrombosis and pulmonary embolism. The most common acute clinical manifestations of CVD are myocardial infarction and stroke. In the 1960s and early 1970s, CVD mortality had reached record levels in many developed countries [1]. In the USA, in 1963, 805 people per 100,000 died due to CHD, stroke and other diseases of the circulatory system. By 2010, this figure had dropped to less than 236 per 100,000 [2]. Likewise, in the European Union, in 2000, 115 people per 100,000 died due to CHD. By 2010, this figure had dropped to 76 per 100,000 (Fig. 1). However, despite this progress, CVD still represents the major cause of adult morbidity and mortality in most developed and many developing countries [3,4]. Each year CVD causes over 4 million deaths (47% of all deaths) in Europe and over 1.9 million deaths (40% of all deaths) in the European Union (EU). Overall, CVD is estimated to cost the EU economy almost V196 billion a year [5]. In most cases, the underlying cause of CVD is atherosclerosis, a chronic inflammation of the arteries, which develops over decades in response to the biologic effects of underlying risk factors [6,7]. Atherosclerosis is a multi-factorial disease with both genetic and environmental etiology. The primary modifiable risk factors are dyslipidemia (increased low density lipoprotein (LDL) and/or decreased high density lipoprotein (HDL) cholesterol), hypertension and smoking. Nutritional habits, especially dietary fat are implicated in the process of atherosclerosis. Therefore, both the European Society of Cardiology (ESC) and the American Heart Association (AHA) establish clear targets in dietary fat intake in order to prevent CVD [8,9]. The focus of this review is to provide an overview on the complex relationship between dietary fat intake, plasma lipoproteins and cardiovascular morbidity and mortality, especially in light of a significant number of recent meta-analyses, prospective cohort studies, and randomized control trials (RCTs) published in the field over the last few years. 2. Methods We reviewed the literature for English-language articles published through Dec 2013 by performing searches of Medline, handsearching of citation lists, and direct author contact. Inclusion criteria were any systematic review or meta-analysis of RCTs or

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prospective cohort studies in humans evaluating consumption of dietary fats and main food sources with incident CVD risk, as well as individual RCTs or prospective cohorts. Search terms included “trans fatty acid(s)”, “saturated fatty acid(s)”, “polyunsaturated fatty acid(s)”, “monounsaturated fatty acid(s)”, “red meat”, “processed meat”, “milk”, “egg”, “olive oil”, “nut”, “lipoproteins”, “blood pressure”, “cardiovascular disease(s)”, ‘‘coronary heart disease’’ and “stroke”. We focused on identifying systematic reviews and/or meta-analyses of RCTs and prospective cohorts on CVD endpoints, supplemented by review of additional recent RCTs and prospective cohorts. Considering complementary strengths and limitations of these two research paradigms conclusions were considered more robust when findings were concordant [10,11]. Wherever there were not enough data on disease outcomes we focused on intermediate risk factors. We excluded a priori animal experiments, ecological studies, case reports, and commentaries. 2.1. The traditional diet-heart paradigm The diet-heart hypothesis refers to the link between dietary fat intake, blood cholesterol (as the mediating factor) and risk of CVD. Although it stems from animal experimentation undertaken a century ago by Nikolai Anitschkow [12], the Seven Countries Study, led by Ancel Keys, is credited as one of the earliest human epidemiological studies to support this link in humans [13]. The strong correlations between dietary saturated fatty acid (SFA) intake, plasma cholesterol and CVD mortality were sufficient to persuade health professionals that high intakes of SFA, through their effects on plasma cholesterol, were responsible for the high levels of cardiovascular mortality of the 1960s and 1970s across western societies [14,15]. Since then, major advances in clinical and nutritional science have established additional dietary fats (not only saturated fats) and multiple mechanistic pathways (thrombosis, hypertension, insulin resistance, inflammation, endothelial function and arrhythmia) linking diet to CVD [16]. The diet-heart hypothesis has shaped dietary guidelines towards total dietary fat reduction (with an emphasis on saturated fat) without further specifying the replacement nutrient. This historical emphasis has resulted in decreased SFA consumption in the US and many other nations, but with concomitant increases in (mainly refined) carbohydrates; this approach has done little to slow down the increasing rates of obesity and type 2 diabetes [17]. Indeed, a low-(saturated) fat approach, replaced principally by carbohydrates, has not been effective in reducing CHD, stroke, or CVD incidence in a large RCT of women [18]. Nowadays, it is widely recognized that higher-fat diets can be beneficial if healthy fats (polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA)) are consumed, whereas high-carbohydrate diets (particularly those with high glycemic load) might contribute to CHD [19e 21], especially amongst women, overweight, and obese individuals [22e24]. 2.2. Impact of dietary fats on blood lipids and lipoproteins

Fig. 1. Standardized death rate by 100,000 inhabitants due to ischemic heart diseases in the European Union (27 countries). Data are derived from Eurostat (Dec 2013) and are subject to change. (http://epp.eurostat.ec.europa.eu/tgm/table.do? tab¼table&init¼1&language¼en&pcode¼tps00119&plugin¼1).

Keys and Hegsted in the 1950s and 1960s, respectively, were the first to demonstrate the quantitative relationship between plasma cholesterol and the amount and type of fat in the diet [25e28]. Although exhibiting minor quantitative differences, they both arrived at the same basic conclusions: dietary cholesterol has a modest plasma cholesterol-raising effect; dietary SFA have potent plasma cholesterol-raising effects; dietary PUFA have a plasma cholesterol-lowering effect; and the cholesterol raising effect of dietary SFA is more potent than the lowering effect of PUFA. Reducing dietary SFA intake has remained the cornerstone of public health nutrition policy for reducing CVD risk ever since [8,9].

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However, the equations of Keys and Hegsted provide no information about the impact of individual fatty acids on cholesterol associated with specific lipoprotein fractions [15]. With the recognition that high concentrations of LDL cholesterol [29,30] and low concentrations of HDL cholesterol [31] are associated with increased CVD risk, interest shifted to the effects of dietary fatty acids on individual lipoprotein fractions. Predictive equations became available for estimating changes in plasma cholesterol and lipoprotein cholesterol in response to dietary fatty acids [32]. Overall, there is now broad agreement that SFA increase LDL cholesterol, whereas PUFA and MUFA both reduce it, with PUFA being more potent than MUFA. All three fatty acid types have modest HDL cholesterol-raising properties [33]. Dietary trans fatty acids (TFA) have the most deleterious effect on lipoproteins, raising LDL cholesterol to a greater extent than SFA, whereas not increasing HDL cholesterol [33]. 2.3. The impact of dietary fats on cardiovascular morbidity and mortality 2.3.1. Saturated FA Animal fats (meat, milk or other dairy products), certain plant oils (palm oils, coconut oils, and cocoa butter) and commerciallyprepared foods (cookies, cakes, doughnuts, and pies) are a primary source of SFA. Substantial recent evidence from metaanalyses of prospective cohort studies and RCTs indicates that the effects of SFA consumption on CVD risk are not independent, and in fact vary on the replacement nutrient. Skeaff and Miller combined data from 28 individual cohort studies but failed to demonstrate a relationship between either dietary SFA or MUFA intake and CHD mortality [34]. Two recent meta-analyses by Mente et al. of 9 cohorts and Siri-Tarino et al. of 16 cohorts showed that SFA intake is not significantly associated with risk of CHD, stroke, or CVD. However, these studies were unable to separately consider potentially differing effects depending on the replacement nutrient scenario [35,36]. On the other hand, Jakobsen et al. in a pooled analysis of 11 prospective cohorts evaluated the effects of different replacement scenarios [37]. Results from this pooled analysis indicated that SFA consumption was associated with higher CHD events and deaths only compared to PUFA; that is PUFA in place of SFA was associated with reduced CHD risk [37]. In contrast, no significant association was seen for MUFA in place of SFA, whereas carbohydrates as a replacement for SFA was associated with higher CHD risk. Mozaffarian et al. by combining the results of 8 RCTs investigated the effects of consuming PUFA in place of SFA on CHD risk, and found that CHD risk was reduced by 10% for each 5% energy intake from PUFA replacing SFA [38]. Finally, Hooper et al. in their Cochrane Collaboration meta-analysis of 48 RCTs investigated the impact of altering total fat, SFA, MUFA, PUFA and TFA intake on CVD morbidity and mortality [39]. Reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95%CI 0.77e0.96, 24 comparisons). Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction), of long-term (2 yr) duration, in studies of men (not of women), and in those of moderate or high CVD risk at baseline (not in general population). However, there were no clear effects of dietary fat changes on CVD mortality [39]. Lastly, it is worth mentioning that not all SFA behave similarly with regards to their effects on LDL cholesterol [33]. Stearic acid (STA, 18:0) in particular, which is abundant in cocoa and dark chocolate, has a neutral or even cholesterol-lowering effect compared to other SFA [40e42]. Based on the accruing evidence that the effects of SFA consumption on CVD risk vary depending on the replacement nutrient

both the ESC and the AHA advise that one should limit saturated fat intake to whole grains > refined carbohydrates) [43]. 2.3.2. Trans FA All double bonds in natural fatty acids are assumed to be in the cis-configuration except for the naturally occurring TFA in beef, lamb, and dairy products [44]. However, most TFA in the human diet are not of ruminant origin, but industrially produced from the partial hydrogenation of vegetable oils that changes the natural cis configuration of 30e50% of double bonds in MUFA or PUFA to the trans configuration [44]. TFA were shown to increase LDL cholesterol and decrease HDL cholesterol levels, to reduce the particle size of LDL cholesterol, increase blood levels of Lp(a), increase inflammatory factors and adversely affect endothelial function [45]. Skeaff and Miller in their meta-analysis of 28 cohort studies reported a highly significant positive association between TFA intake and CHD morbidity and mortality [34]. This was also observed in the meta-analysis of Mente et al. [35] Mozaffarian and Clarke reached a similar conclusion in their meta-analysis of 4 prospective cohort studies; even replacing partially hydrogenated vegetable oil (PHVO) with SFA-rich fats (e.g. palm oil, butter and lard) reduced predicted CHD risk substantially [46]. Hooper et al. in their meta-analysis of RCTs failed to demonstrate a specific effect of TFA on CVD morbidity or mortality, but cautioned that this may be a result of insufficient data [39]. PHVO consumption has steadily and significantly been reduced over the years due to direct bans and labeling regulations that were implemented in many developed and developing countries around the world [47]. The US FDA recently reached a “preliminary determination” that PHVO “are not recognized as safe” for use in food [48]. With PHVO intake steadily decreasing ruminant TFA have become a more significant dietary source, although still only typically contributing to less than 0.5% of total energy intake [49]. Considerable debate exists as to whether ruminant TFA exert the same impact on CVD risk as industrial TFA. PHVO may contain up to 60% of the fatty acids in the trans configuration compared to the content in ruminant fat which generally does not exceed 6% [49]. Furthermore, PHVO normally contain a wide range of trans isomers of MUFA, which differ in the position of the double bond along the carbon chain. By contrast, vaccenic acid (VA, t11-c18:1) predominates in ruminant products and is a precursor for the production of the c9, t11 conjugated linoleic acid isomer, which has been suggested to have anti-atherosclerotic properties [15]. However, Brouwer et al. in a quantitative review of the effect of TFA on HDL and LDL cholesterol levels, concluded that all fatty acids with a double bond in the trans configuration regardless of their source raise the ratio of plasma LDL to HDL cholesterol [50]. Bendsen et al. in a meta-analysis of 9 prospective cohort studies, compared the impact of industrial (PHVO) and ruminant TFA on risk of CHD [51]. They conclude that industrial-TFA may be positively associated with CHD risk (increase in both events and mortality), whereas ruminant-TFA is not. According to the authors the limited number of available studies prohibits any firm conclusions about whether the source of TFA is important, and the null association of ruminant-TFA with CHD risk may be due to lower intake levels. Considering that industrial TFA represent an additive to food with no intrinsic health value and substantial potential risks, there is no convincing reason to continue their use in food. On the other hand, the public health implications of ruminant TFA intake appear

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to be limited, either due to low levels of consumption, structural differences, or potential health benefits of other nutrients in dairy or meat products that may counterbalance any adverse effects. Therefore, both the ESC and the AHA advise that adults should limit TFA intake to 4 times per week compared to those who never or seldom consume nuts [125]. These findings are further supported by the meta-analysis by Afshin et al. (personal communication) [127]. Consumption of nuts was inversely associated with fatal CHD (6 studies; per 4 weekly 28.4 g servings RR ¼ 0.76, 95% CI ¼ 0.68e0.86), nonfatal CHD (4 studies; RR ¼ 0.78, 0.67e0.92), stroke (4 studies; RR ¼ 0.87, 0.76e0.99) and diabetes (6 studies; RR ¼ 0.87, 0.81e0.94). 3. Conclusion Dietary fatty acids play significant roles in the cause and prevention of CVD (Table 1). TFA from PHVO have well-established adverse effects and should be eliminated from the human diet. On the other hand, the impact of natural TFA, derived from ruminant meat and milk, deserves further investigation. CVD risk can be modestly reduced by decreasing SFA and replacing it by a combination of PUFA and MUFA. Although the ideal type of unsaturated fat for this replacement is unclear, the benefits of PUFA appear strongest. Both n-6 and n-3 PUFA are essential and reduce CVD risk. However, additional research is needed to better define the optimal

amounts of both and to discern the groups of people (patients and/ or general population) that would benefit from supplemental n-3 fatty acid intake. Furthermore, it seems that the consumption of animal products, per se, is not necessarily associated with increased CVD risk, whereas nuts and olive oil intake seems to reduce CVD risk. A few years ago a more global analysis of the impact of dietary factors on CVD risk concluded that overall dietary patterns may be more important [35]. The authors showed that a Mediterranean diet or ‘prudent’ diet were protective from CVD, whereas a Western diet substantially increased risk. These results were recently reinforced by the PREDIMED clinical trial that assessed the effect of the Mediterranean diet on primary prevention of CVD [119]. Evidence continues to accrue to support the notion that the total matrix of a food is more important than just its fatty acid content when predicting the effect of a food on CVD risk [126] and a healthy diet should be recommended as being the cornerstone of CVD prevention [8,43]. Funding sources None. Disclosure The authors have nothing to disclose. References [1] O’Flaherty M, Buchan I, Capewell S. Contributions of treatment and lifestyle to declining CVD mortality: why have CVD mortality rates declined so much since the 1960s? Heart 2013;99:159e62. [2] NHLBI fact book, fiscal year 2012. Bethesda, MD: National Heart, Lung, and Blood Institute; 2013. [3] Wang H, Dwyer-Lindgren L, Lofgren KT, et al. Age-specific and sex-specific mortality in 187 countries, 1970-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2071e94. [4] Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197e223. [5] European Cardiovascular Disease Statistics 2012; 2012. [6] Ross R. Atherosclerosisean inflammatory disease. N Engl J Med 1999;340: 115e26. [7] Nabel EG, Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med 2012;366:54e63. [8] Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33: 1635e701. [9] Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006;114:82e96. [10] Harris WS, Mozaffarian D, Lefevre M, et al. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. J Nutr 2009;139:804Se19S. [11] Micha R, Mozaffarian D. Saturated fat and cardiometabolic risk factors, coronary heart disease, stroke, and diabetes: a fresh look at the evidence. Lipids 2010;45:893e905. [12] Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I. J Lipid Res 2004;45:1583e93. [13] Keys A, Aravanis C, Blackburn HW, et al. Epidemiological studies related to coronary heart disease: characteristics of men aged 40-59 in seven countries. Acta Med Scand Suppl 1966;460:1e392. [14] Gordon T. The diet-heart idea. Outline of a history. Am J Epidemiol 1988;127: 220e5. [15] Salter AM. Dietary fatty acids and cardiovascular disease. Animal 2013;7: 163e71. [16] Willett WC. Dietary fats and coronary heart disease. J Intern Med 2012;272: 13e24. [17] Trends in intake of energy and macronutrientseUnited States, 1971-2000. MMWR Morb Mortal Wkly Rep 2004;53:80e2.

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