Braunwald Nutrition

29
Nutrition and Cardiovascular and

Metabolic Diseases
DARIUSH MOZAFFARIAN
ENERGY BALANCE, 531 BEVERAGES, 535 Sodium, Potassium, 539

Sugar-Sweetened Beverages, 535
FOODS, 532 DIETARY PATTERNS, 539
Milk, 535
Fruits and Vegetables, 532
Coffee, Tea, 535 EMERGING AREAS, 540
Nuts and Beans, 532
Alcohol, 535 Food Processing, 540
Whole Grains, Refined Grains, Starches,
Microbiome, 543
Sweets, 532 MACRONUTRIENTS, 535
Personalized Nutrition, 543
Fish, 534 Carbohydrates, 535
Red Meats, 534 Fats, 536 CHANGING BEHAVIOR, 543
Poultry, Eggs, 535 Protein, 538
REFERENCES, 543
Dairy, 535
MICRONUTRIENTS, 539
Plant Oils, 535
Together with physical activity, smoking cessation, sleep, and stress protective foods—e.g., minimally processed, phytonutrient-rich foods
reduction, a healthy diet forms the foundation for prevention and like fruits, seeds, nuts, beans, vegetables, and whole grains—produce
treatment of cardiometabolic diseases, including coronary heart dis- similar or greater disease burdens than excess intakes of unhealthy
ease (CHD), stroke, type 2 diabetes mellitus (DM), obesity, and related factors.
conditions. Dietary factors represent 8 of the top 25 causes of global This chapter reviews the evidence for effects of diet on cardiometa-
deaths, largely owing to effects on cardiometabolic diseases (see also bolic diseases, and highlights key knowledge gaps. Because translation
Chapter 1). Insufficient intakes of healthy foods, such as fruits, nuts, of knowledge into action is essential, this chapter also briefly reviews
whole grains, beans, vegetables, seafood, and yogurt, cause substantial effective behavior change strategies.
burdens; as do excess intakes of salt, sugary beverages, and processed
meats.1 In the United States, suboptimal diet is the leading cause of
poor health, estimated to cause approximately 1 in 4 overall deaths.2 ENERGY BALANCE (SEE ALSO CHAPTER 30)
Obesity, DM, and related conditions have increased in recent
decades, owing to rapid social, cultural, and environmental transitions The global obesity epidemic is strikingly recent, commencing in the
transmitted primarily through changes in diet and other lifestyle hab- 1980s in the United States and many nations after decades of rela-
its. Familiarity with the evidence for effects of different dietary factors, tive stability.5 Abdominal adiposity, which produces largest metabolic
including controversies and uncertainties, is essential to prioritize harms, has also increased more than overall weight in many nations.6
interventions to improve eating habits and reduce diet-related diseases. The breadth, depth, and pace of this epidemic, including in young chil-
For much of the 20th century, research and policy focused on nutri- dren,7 suggest strong environmental drivers, rather than purely behav-
ent deficiency diseases (e.g., scurvy, pellagra) and increased agricul- ioral or genetic explanations.
tural production of inexpensive, shelf stable, starchy crops (e.g., rice, For years, the main scientific and policy responses to obesity have
wheat, corn) to feed a rapidly growing world population.3 These emphasized energy balance and calorie counting. Beyond the empiric
efforts were successful at achieving their goals, leading to a modern failure of this approach to stem the obesity epidemic worldwide, new
global food system that emphasizes commodity crops and shelf-stable, evidence indicates that the quality of food is the major driver of energy
inexpensive packaged and processed foods rich in starch and sugar, imbalance and weight gain.8 Foods represent complex matrices of nutri-
preserved by salt, and fortified with vitamins. This legacy food system ents, ingredients, and processing characteristics, each with pleotropic
was built to address caloric hunger and vitamin deficiencies, not diet- effects on a range of pathways and tissues. More highly processed foods
related chronic diseases. drive greater ad libitum energy intake (+508 kcal/day) and weight gain,9
It was not until the 1980s that modern nutrition science turned to while carbohydrate quality and quantity also influence energy expendi-
focus more on chronic conditions like cardiovascular disease (CVD), ture.10 Diet quality is thus a major determinant of long-term energy imbal-
DM, and obesity. Over the last 40 years, the emerging science has rapidly ance, which can be considered a downstream mediator, not an upstream
advanced from less reliable ecologic (cross-national) comparisons, determinant, of the obesity epidemic.While nearly any popular diet can
short-term experiments, and animal studies to more robust evidence work for short-term weight loss, healthful food-based patterns appear
from prospective cohort studies of disease endpoints, well-conducted most important for long-term weight maintenance.11 Consequently, long-
metabolic trials of diverse risk markers and pathways, and random- term obesogenic effects of foods should not be judged on the basis of
ized clinical trials of disease endpoints. Several new conclusions have calorie content alone, but also the molecular and physiologic effects
emerged.4 First, dietary habits influence not only blood cholesterol (a that drive subsequent long-term energy intake and expenditure.
major focus of the 1980s) and obesity (a major current focus), but also The evidence for effects of foods and diet patterns on obesity and
multiple other established and emerging risk factors (Fig. 29.1). Con- weight control are described further in sections below. Mechanisms
sequently, health effects of any dietary factor cannot be inferred from are being elucidated and involve, beyond conscious cues like hun-
effects on any single intermediate endpoint. Second, specific foods and ger and satiety, unconscious drivers like brain craving and reward,
overall dietary patterns, rather than isolated single nutrients, are most glucose-insulin responses, hepatic fat synthesis, adipocyte function,
important for cardiometabolic health. Third, insufficient intakes of visceral adiposity, metabolic expenditure, and the gut microbiome.8,12,13

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532
IV
PREVENTIVE CARDIOLOGY
Refined grains, starches, sugars Blood pressure

Fruits, vegetables, nuts Glucose-insulin homeostasis
Whole grains, legumes Liver fat synthesis
Yogurt, cheese, milk Blood lipids, apolipoproteins
Fish, shellfish Endothelial function
Processed meats, red meats Systemic inflammation
Plant oils, specific fatty acids Brain reward, craving
Coffee, tea, alcohol Gut microbiome
Sugary beverages, juice Satiety, hunger, obesity
Minerals, antioxidants, phytochemicals Metabolic expenditure
Food-based dietary patterns Adipocyte function
Food processing, preparation methods Cardiac function
Thrombosis, coagulation
Vascular adhesion
FIGURE 29.1 Diet and cardiovascular and metabolic risk—pathways and mechanisms. Most foods, nutrients, and other factors (e.g., additives, processing methods) have
pleotropic effects on diverse pathways of risk. Thus, health effects can rarely be inferred from a single pathway (e.g., changes in blood cholesterol alone). Selected major effects
are detailed in the text sections on each dietary factor. (From Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive
review. Circulation. 2016;133:187–225.)
Other interacting factors include physical activity, industry marketing, or vegetable intake does not associate with DM, perhaps due to greater
TV watching, sleep duration, circadian alignment, and maternal-fetal importance of certain subtypes.25 100% fruit juice similarly appears
(e.g., trans-generational) influences. For example, lower sleep duration fairly neutral for glycemia and DM,26,27 and associates with modestly
and altered circadian rhythms alter hunger, food preferences toward lower risk of CVD.28 In controlled trials lasting up to two years, diets
“comfort foods” and leptin, ghrelin, insulin, and gut-peptide concentra- including an emphasis on fruits and vegetables improve BP, lipid levels,
tions.14 TV watching increases obesity and weight gain, but mediated insulin resistance, inflammation, adiposity, and endothelial function.4
by changes in diet (e.g., eating in front of the TV, less healthy choices Such benefits likely derive from the combinations of micronutrients,
due to TV marketing) rather than physical inactivity.15–18 Liquid calories phytonutrients, and fiber in fruits and vegetables, as well as their
from sugary drinks and alcohol, larger portion sizes, and more meals replacing less healthful foods. Together these studies provide con-
away from home also associate with adiposity. Changes in social norms sistent evidence that fruits and vegetables improve cardiometabolic
and networks, industry marketing, and local food availability also health. Phytonutrient-rich fruits, such as berries, may have particular
appear important.19,20 Because habitual excess energy intakes as small benefit.22,29,30
as approximately 50 to 100 kcal/d may explain much of the obesity epi-
demic, subtle effects on these pathways are sufficient, when sustained,
to account for population shifts in weight (see Fig. 25.4). Nuts and Beans
Notably, while global obesity has appropriately highlighted the cen- Nuts are rich in unsaturated fats, vegetable protein, fiber, folate, min-
tral role of nutrition in health, a focus on obesity alone misses the many erals, tocopherols, and phenolic compounds. Consumption of nuts
other health consequences of dietary habits (see Fig. 29.1). Changes in lowers total cholesterol, LDL-cholesterol, ApoB, triglycerides, and insu-
diet quality substantially improve cardiometabolic risk factors within lin resistance in trials;31,32 associates with lower incidence of CHD in
6 to 8 weeks, even without weight loss.4 Thus, obesity should be con- prospective studies (see Fig. 29.2);25,33 and was a key component of a
sidered only one mediating pathway for health effects of diet, and the large Mediterranean diet trial that reduced abdominal obesity34 and
main nutritional targets and metrics of success for individuals and risk of hard CVD endpoints by 30%.35 While their energy density has
populations should be for overall health, not weight. raised theoretical concerns for weight gain, nuts are rich in healthy
fats, fiber, and phenolics, and both long-term observational studies and
controlled trials demonstrate that nuts and seeds do not promote, and
FOODS actually may reduce, weight gain and visceral adiposity.15,36
Cardiovascular effects of beans (used herein to include pulses
The successes of nutritional science and dietary guidelines in the 20th [edible seeds] and legumes) are less well established. Like nuts, beans
century to address vitamin deficiency diseases ensconced a reduc- contain bioactive compounds including phenolics, minerals, and fiber;
tionist approach to food that emphasized isolated single nutrients.3 although also more starch, compared with unsaturated fat-rich nuts. In
As chronic diseases emerged as a major public health problem in observational cohorts, bean intake inversely associates with total CVD,
the 1980s, this scientific emphasis on single nutrients lingered. Thus, CHD, and incident hypertension, but not significantly with stroke or
dietary fat was considered the major cause of obesity; and saturated fat DM (see Fig. 29.2).25,37 Meta-analyses of small trials of soy foods suggest
and cholesterol, the major causes of heart disease. Advances in nutri- modest improvements in blood cholesterol levels and arterial stiffness;
tion science demonstrate that, except for certain major additives like and small to no effects on other risk factors such as glycemic control,
sodium, sugar, or trans fat, single nutrients in isolation are less relevant blood pressure, inflammation, and body weight.38–40 Based on available
than food types and overall diet patterns—which comprise complex evidence, eating nuts is a priority for cardiometabolic health; legumes
matrices of processing, carbohydrate types, fatty acids, proteins, micro- may also be beneficial.
nutrients, and phytonutrients.11,21
Whole Grains, Refined Grains, Starches, Sweets

Fruits and Vegetables Carbohydrate-rich foods dominate most diets: bread, rice, white pota-
Higher fruit and vegetable intake associates with less long-term weight toes, breakfast cereals, crackers, pastas, chips and fries, salty snacks,
gain22 and lower incidence of CHD and stroke (Fig. 29.2).23,24 Total fruit muffins, sweet bakery products, sugar- sweetened beverages (SSBs),
533
No. of No. of No. of
Endpoint studies subjects events Unit RR Reference
29
CHD 24 1,555,553 43,336 Each 1 serving/d (100 g/d) 0.95 (0.93–0.97) Aune 2017
Nutrition and Cardiovascular and Metabolic Diseases

Fruits Stroke 17* 987,983* 43,702* Each 1 serving/d (100 g/d) 0.90 (0.85–0.95) Zurbau 2020
Diabetes 13 853,985 53,317 Each 1 serving/d (100 g/d) 0.98 (0.97–1.00) Schwingshackl 2017
CHD 20 1,047,071 20,853 Each 1 serving/d (100 g/d) 0.92 (0.89–0.95) Aune 2017
Vegetables Stroke 13 441,670 14,973 Each 1 serving/d (100 g/d) 0.93 (0.89–0.98) Aune 2017
CHD 7 301,257 10,663 Each 1 serving/d (150 g/d) 1.03 (0.96–1.09) Schwingshackl 2019
Potatoes Stroke 6 1259,537 7,825 Each 1 serving/d (150 g/d) 0.98 (0.93–1.03) Schwingshackl 2019
Diabetes 8 359,680 22,352 Each 1 serving/d (150 g/d) 1.08 (1.03–1.12) Quan 2020
CHD 10 306,814 7,786 High vs. low 50 g/d 0.90 (0.83-0.99) Viguiliouk 2019
Beans/legumes Stroke 8 342,079 8,570 High vs. low 50 g/d 0.98 (0.86-1.11) Viguiliouk 2019
Diabetes 12 595,641 31,297 Each 50 g/d 1.00 (0.92–1.09) Schwingshackl 2017
CHD 6 NR 7,697 High vs. low 0.80 (0.70–0.91) Reynolds 2019

Whole
Stroke 3 NR 1,247 High vs. low 0.86 (0.61–1.21) Reynolds 2019
grains
Diabetes 10 385,868 19,829 Each 1 serving/d (50 g/d) 0.81 (0.74–0.89) Aune 2013
CHD 4 243,438 1,942 Each 1 serving/d (30 g/d) 1.01 (0.99–1.04) Bechthold 2019
Refined grains
CHD 7 275,812 12,654 Each 1 serving/d (28 g/d) 0.75 (0.64–0.88) Becerra-Tomas 2019
Nuts Stroke 7 302,888 12,646 Each 1 serving/d (28 g/d) 1.06 (0.97–1.15) Becerra-Tomas 2019
CHD 15 479,657 14,056 Each 1 serving/d (100 g/d) 0.88 (0.79–0.99) Bechthold 2019
Fish Stroke 15 370,844 11,326 Each 1 serving/d (100 g/d) 0.86 (0.75–0.99) Bechthold 2019
Diabetes 15 567,771 42,005 Each 1/2 serving/d (50 g/d) 1.03 (0.98–1.09) Yang 2020
CVD mortality 8 389,528 NR Each 3 servings/wk (360 g/wk) 1.11 (1.10–1.14) Zeraatkar 2019
Unprocessed
Stroke 6 102,024 NR Each 3 servings/wk (360 g/wk) 1.06 (1.02–1.11) Zeraatkar 2019
red meat
Diabetes 11 531,843 NR Each 3 servings/wk (360 g/wk) 1.10 (0.97–1.25) Zeraatkar 2019
CVD mortality 7 1,240,634 NR Each 3 servings/wk (150 g/wk) 1.11 (1.03–1.19) Zeraatkar 2019
Processed meat Stroke 6 254,742 NR Each 3 servings/wk (150 g/wk) 1.06 (1.02–1.09) Zeraatkar 2019
Diabetes 14 669,530 NR Each 3 servings/wk (150 g/wk) 1.18 (1.09–1.27) Zeraatkar 2019
CVD mortality 5 1,197,805 31,535 Each 1/2 serving/d (50 g/d) 1.00 (0.93–1.07) Abete 2014
Poultry
Diabetes 8 219,926 13,865 Each 1/2 serving/d (50 g/d) 1.02 (0.98–1.07) Fan 2019
CHD mortality 7 NR NR Each 1 egg/d (50g/d) 0.95 (0.76–1.18) Godos 2020

Eggs Stroke mortality 7 NR NR Each 1 egg/d (50g/d) 0.86 (0.69–1.06) Godos 2020
Diabetes 22 589,559 41,248 Each 1 egg/d (50g/d) 1.07 (0.99–1.15) Drouin-Chartier 2020
CHD 13 2,231,651 9,176 Each 1 serving/d (200 g/d) 1.01 (0.97–1.04) Soedamah-Muthu 2018
Milk
Stroke 18 4,381,604 25,377 Each 1 serving/d (200 g/d) 0.92 (0.88–0.97) Soedamah-Muthu 2018
CVD 11 234,447 15,519 Each 1 serving/d (30 g/d) 0.94 (0.86–1.00) Guo 2017
Cheese
CHD 7 (6 in dose) 554,323* 14,698* Each 1 serving/d (30 g/d) 0.94 (0.90–0.97) Jakobsen 2021
CVD mortality 4 214,725 NR Each 100 g/d 0.96 (0.93–0.99) Gao 2020
Yogurt CHD 6 (5 in dose) 552,342* 14,226* Each 100 g/d 0.98 (0.93–1.03) Jakobsen 2021
Diabetes 14 5,184,590 37,223 Each 80 g/d 0.86 (0.83–0.90) Soedamah-Muthu 2018
CHD 8 416,185 19,812 Each 10 g/d 0.96 (0.93–0.99) Morze 2020

Chocolate Stroke 7 275,070 9,087 Each 10 g/d 0.90 (0.82–0.98) Morze 2020
Diabetes 6 276,893 21,583 Each 10 g/d 0.94 (0.88–1.01) Morze 2020
0.67 1 1.5
Relative risk (95% Cl)
FIGURE 29.2 Meta-analyses of foods and associations with cardiometabolic outcomes. CHD, Coronary heart disease; CVD, cardiovascular disease; NR, not reported.
and candy. Health effects of such foods appear determined by several providing fatty acids, antioxidants, and phytonutrients). Refined carbo-
characteristics that only partly overlap: whole grain versus refined car- hydrates include refined grains (e.g., white flour, white rice), stripped of
bohydrate (starch+sugar) content, dietary fiber content, glycemic load, their bran and germ to leave only starchy endosperm, and added sug-
and food processing (Fig. 29.3). ars. All refined carbohydrates (sugars or starch) produce rapid, dose-
A whole grain is a seed including its bran (exterior skin; provid- dependent glycemic responses, with similar overall health harms.4,15,41
ing fiber, B-
vitamins, minerals, flavonoids, and tocopherols), endo- Thus, refined carbohydrate (i.e., starch) in foods should be considered
sperm (starchy interior; nearly all glucose), and germ (plant embryo; a “hidden sugar.”
534
IV Endpoint studies subjects events Unit RR Reference
CVD 2 65,018 4,087 2.3 servings/wk (18.7 oz/d) vs. none 0.90 (0.83–0.97) D’Elia 2020
100% fruit juice (non-linear)

Diabetes 11 407,288 34,549 Each 1 serving/d (8 oz/d) 1.06 (0.98–1.14) Imamura 2015
CVD 10 198,388 16,999 Each 1 serving/day (8.5 oz/d) 1.08 (1.02–1.14) Yin 2020
SSB Diabetes 7 464,937 38,253 Each 1 serving/day (8 oz/d) 1.27 (1.10–1.46) Imamura 2015
CVD mortality 29* 2,631,398 * 81,188 * Each 1 cup/d 0.96 (0.95-0.97) Kim 2019
Coffee
Diabetes 38 1,185,210 53,018 Each 1 cup/d 0.94 (0.93–0.95) Carlstrom 2018
CHD 7 235,368 8,328 Each 1 cup/d 0.90 (0.81–0.996) Zhang C 2015

Tea Stroke 13 407,068 NR Each 1 cup/d 0.96 (0.93–0.99) Chung 2020
Diabetes 8 307,968 11,329 Each 1 cup/d 0.94 (0.90–0.97) Zhang C 2015
0.67 1 1.5
FIGURE 29.3 Meta-analyses of beverages and associations with cardiometabolic outcomes. BMI, Body mass index; CHD, coronary heart disease; CVD, cardiovascular disease;
NR, not reported; SSB, sugar-sweetened beverage.
Foods rich in refined grains, starches, and added sugars associate grains, starches, and added sugars should be a top priority for most
with risk of long-term weight gain.15 While the quantity of intake of individuals.
refined grains does not significantly associate with CHD or DM (see
Fig. 29.2), more discriminatory measures such as glycemic index and
especially glycemic load, that account for both quantity and rapidity of Fish
digestion, strongly associate with CHD, stroke, and DM (see Fig. 29.3).42– Regular fish consumption (1 to 2 servings/week) associates with mod-
45
Metabolic feeding studies confirm harms of refined carbohydrates,46 estly lower risk of CHD and stroke (see Fig. 29.2).61 Mechanistic, obser-
while clinical trials demonstrate substantial weight loss and improved vational, and trial data suggest that fish may have stronger benefits for
glycemia on diets that reduce refined carbohydrates and glycemic fatal CHD rather than nonfatal myocardial infarction (MI) or stroke, sug-
load.47–49 Added sugars in beverages appear most deleterious, perhaps gesting potential specificity for pathways of acute ischemia-induced
owing to a combination of large portion sizes, rapid intake patterns, ventricular arrhythmia.62 Because fish are a rich source of omega-3 fats,
and limited effects on satiety.4 fish oil supplements have also been evaluated in trials (see n-3 PUFA,
In contrast, foods containing whole grains or dietary fiber asso- below). In observational studies, fish consumption associates with less
ciate with lower risk of CVD, DM, and long-term weight gain (see ischemic stroke, but fish oil supplements have not influenced stroke in
Figs. 29.2 and 29.3).8,50,51 In trials, replacing refined grains with whole post-hoc analyses of CHD trials.63 Observational studies of atrial fibril-
grains improves blood cholesterol levels, glycemia, and possibly sys- lation and heart failure have produced mixed findings.64 Meta-analyses
temic inflammation.52 Similarly, fruits, bean, legumes, whole grains, suggest no significant associations with incident DM.65
and yogurt also contain some sugar or starch, yet are linked to Types of fish consumed and preparation methods may influence
metabolic and cardiovascular benefits as well as long-term weight CVD effects. Greatest benefits may accrue from nonfried oily (dark
maintenance.4 Such benefits appear related to a combination of meat) fish, that contain up to 10-fold more omega-3 fats than other
factors, rather than any one characteristic.4,53 Glycemic responses types.64 Fish also contain other unsaturated fats, selenium, and vita-
of carbohydrate-rich foods can be further mitigated by food order min D, which could provide benefit. Methylmercury in fish has no
or mixed meals, such as by adding fats or proteins preceding or detectable influence on CVD events or incident hypertension.66,67
accompanying the meal, or even by a healthier long-term back- Presence of persistent organic pollutants (e.g., dioxins, polychlori-
ground diet.54,55 nated biphenyls) may partly reduce but does not appear to fully off-
Several uncertainties exist. First, it remains unclear whether bene- set cardiometabolic benefits of fish intake.68,69 In sum, the evidence
fits of whole grains relate to displacing refined carbohydrates in the supports recommendations to consume 1 to 2 servings of fish, espe-
diet; or to additional health benefits of the germ (providing minerals, cially oily fish, per week.
fatty acids, phytonutrients) and bran (providing fiber, minerals, phyto-
nutrients). Dietary fiber, for instance, appears essential for gut microbial
health and their bioactive metabolites (e.g., short-chain fatty acids).56 Red Meats
Second, the independent relevance of food processing is unclear. Most Prevalent guidelines recommend lean meats to lower dietary choles-
commercial “whole grain” breads, cereals, and crackers are made by terol and saturated fat. However, effects on cardiometabolic risk may be
finely milling, separating, and reconstituting the endosperm, germ, and more complex, with other factors such as preservatives, heme iron, and
bran. Fiber and nutrient contents are retained, but loss of intact food cooking methods being more relevant.Available evidence suggests that
structure exposes the endosperm to rapid digestion by salivary and processed meats (i.e., preserved with sodium or other additives, such as
pancreatic enzymes, increasing its glycemic index compared with less deli meats, sausage, hot dogs, bacon, etc.) increase risk of CVD, stroke,
finely milled whole grains (e.g., steel-cut oats, stone-ground bread). and DM; with unprocessed red meats having generally smaller associa-
Third, the best simple metric for selecting healthier grain products is tions, gram for gram, with these endpoints (see Fig. 29.2).65,70,71 Because
uncertain (see Fig. 29.3). One pragmatic rule-of-thumb is to choose unprocessed versus processed meats contain similar average amounts
foods containing at least 1 g of fiber for every 10 g of carbohydrate of total fat, saturated fat, and cholesterol,72 the stronger associations
per serving (carbohydrate:fiber ratio <10:1), which implicitly balances for processed meats suggest that sodium c ontent—about 400% higher
the relative proportions of starch, sugar, whole grain, bran, and added in processed meats—or other preservatives such as nitrites (hidden
fiber.57–60 as “celery juice” in “nitrate-free” processed meats) may contribute.73
The relevance of personalization in carbohydrate responses is also Heme iron, a risk factor for DM in animal experiments, gestational DM,
of growing interest. Health effects of carbohydrate-rich foods can vary and inborn errors of iron metabolism such as hemochromatosis, may
depending on insulin sensitivity, background diet, physical activity, explain the higher risk of DM seen with both processed and unpro-
or microbiome composition (see Microbiome and Personalization, cessed red meats.74–76 Based on available evidence, processed meats
below). Given the high rates of adiposity, prediabetes and DM, poor should be avoided, and unprocessed meats eaten up to 1 to 2 servings/
diet, and physical inactivity in most populations, reducing refined wk or less.
535
Poultry, Eggs 29.3,26,105 likely related to weight gain and other additional harms of
In prospective observational studies, poultry intake appears generally the high sugar and glycemic load. Given clear evidence for harms, and 29
neutral for CVD and DM risk (see Fig. 29.2).77,78 When combined with multiple alternatives (e.g., water, seltzer, unsweetened tea, diet soda,

its relatively low content of bioactive nutrients, these findings suggest milk), SSBs should be largely eliminated from the diet.
that poultry consumption has minimal cardiometabolic effects. Eggs Alternative sweeteners can be artificial (e.g., saccharin, aspartame)
appear similarly neutral for CVD risk in general populations (see Fig. or naturally low-calorie (e.g., stevia). Based on observational studies
29.2).79–81 Overall evidence suggests minimal cardiometabolic effects and clinical trials, alternative sweeteners are better for cardiometabolic
of poultry intake or occasional egg intake (e.g., up to 2 to 3 per week); health than added sugars.15,106 Yet, alternative sweeteners may not be
consistent with recent similar conclusions on dietary cholesterol11 completely benign: animal experiments and limited human data sug-
(see Dietary Cholesterol, below). gest influences on brain reward, taste perception, oral-gastrointestinal
taste receptors, glucose-insulin and energy homeostasis, metabolic hor-
mones, and the gut microbiome.107–111 For instance, if a child becomes
Dairy accustomed to intense sweet tastes, will that reduce attractiveness of
Cardiometabolic effects of dairy foods have generally been considered naturally sweet foods such as apples or carrots? In sum, alternative
in relation to a limited set of nutrients: saturated fat, calcium, vitamin sweeteners can be a useful bridge to eliminate SSBs, but should not be
D. Yet, more diverse dairy nutrients and processing methods appear considered innocuous; and subsequent shifts to non-sweetened drinks
relevant. These include fermentation of yogurt and cheese (creating (e.g., seltzer, tea) should be encouraged.
menaquinones), branch- chain, odd-chain, and medium- chain fatty
acid contents, probiotics in yogurt, milk fat globule membrane content,
and more.82,83 In long-term cohorts, milk intake associates with lower Milk
risk of stroke, cheese with lower risk of CHD, and yogurt, cheese, and See Dairy.
possibly butter with lower risk of DM (see Fig. 29.2).84–86 In randomized
trials, milk or total dairy consumption increases lean mass and reduces
body fat and waist circumference.87 In long-term observational stud- Coffee, Tea
ies, yogurt associates with relative weight loss,15 potentially related to While coffee and tea provide caffeine, these plant extracts—derived
probiotic-microbiome interactions.88–91 from beans and leaves—contain other bioactive compounds. Unre-
In contrast, lower dairy fat content (reduced-fat or non-fat) does not lated to caffeine content, frequent coffee intake (e.g., 3 to 4 cups/day)
consistently relate to lower cardiometabolic risk. Indeed, in a pooled associates with less insulin resistance, DM, CVD, and in a few studies,
analysis of 16 global cohorts, individuals with higher blood biomarkers heart failure (see Fig. 29.3).112,113 Yet, clear physiologic benefits have not
of dairy fat consumption had significantly lower incidence of DM.92 been established to support these observations. Acutely, caffeinated
Recent experimental evidence suggests that odd- chain saturated coffee worsens BP, insulin resistance, and glucose intolerance;114,115
fats such as 15:0, fairly unique to dairy fat, reduce inflammation and longer-term, habitual coffee intake does not affect BP, endothelial func-
dyslipidemia by binding to key metabolic regulators and repairing tion, nor glucose metabolism, suggesting tachyphylaxis and/or other
mitochondrial function.93 In sum, current evidence supports recom- partly offsetting factors.116,117 In mendelian randomization analyses,
mendations for modest dairy intake (2 to 3 servings/day), especially of genetic variants linked to coffee intake do not associate with CHD,
yogurt and cheese, with more research needed to define the relevant stroke, or DM.118–120 Based on lack of physiologic benefits in trials or
active ingredients and health effects of dairy fat. lower risk in mendelian randomization studies, the cardiometabolic
benefits of coffee intake should still be considered questionable.
Like coffee, frequent tea drinking (e.g., 3+ cups/day) associates with
Plant Oils lower CVD and DM, with borderline statistical significance (see Fig.
While “industrial” or “refined” plant oils, especially those rich in n-6 29.3).121,122 In randomized trials, certain types of tea modestly lower
PUFA, have been theorized to be harmful to health, little evidence BP (green, black, sour), LDL-cholesterol (green), and fasting glucose
supports this concern. The great majority of interventional and obser- (green, sour).116,123–126 In contrast to coffee, these physiologic effects
vational studies of total PUFA, n-6 PUFA, and MUFA have assessed support potential causal cardiometabolic benefits of tea, but larger
industrialized plant oils like soybean, canola, and safflower oil. The and more rigorous studies are still needed.
cumulative evidence supports clear benefits of such plant oils (see
Macronutrients, below). Whether virgin versions of these oils would
have even greater benefits, for example due to greater concentrations Alcohol
of phenolics and phytosterols,94,95 is possible and requires investigation. See Chapter 84.
Few studies have evaluated tropical oils (e.g., palm, coconut), beyond
their known effects on blood lipids (raising both LDL-cholesterol and
HDL-cholesterol).96–98 MACRONUTRIENTS
Carbohydrates
BEVERAGES For decades, carbohydrates were recommended as the foundation of
a healthful diet, e.g., grain products at the base of the 1992 Food Guide
Sugar-Sweetened Beverages Pyramid. Current science makes clear that the quality and food source,
Ecologic data, prospective cohorts, and trials provide convincing evi- rather than total amount, of carbohydrate is most relevant for car-
dence that SSB intake increases adiposity. In the United States, calories diometabolic health (Fig. 29.4)4 (also see Whole Grains, Refined Grains,
consumed from beverages rapidly increased after the 1960s, doubling Starches, Sweets). Because most carbohydrate in modern diets derives
to 21.0% of all calories consumed by 2002—an increase of 222 daily from refined starches and sugars, a “low-carb” diet will often produce
kcal per person.99 This was largely due to increased SSBs (sodas, metabolic benefit. Yet, healthful carbohydrate-containing foods like
energy drinks, sweetened ice teas, fruit drinks), although that peak has fruits, legumes, and minimally processed whole grains should not be
been followed by gradual declines in SSB consumption thereafter.100,101 avoided. For most patients with metabolic risk factors, a focus on reduc-
Per serving, SSBs more strongly associate with long-term weight gain ing refined grains, starches, and added sugars should be a priority.4,8,11
than nearly any other dietary factor.15 Randomized trials confirm that While marketing claims are often made about different forms of sug-
reducing SSBs decreases weight gain and fat accumulation.102,103 Calo- ars (disaccharides), major types (cane sugar, beet sugar, high-fructose
ries in liquid form, compared with solid foods, appear to be less satiat- corn syrup) are molecularly similar: about half glucose and half fruc-
ing and increase total calories consumed.104 SSB intake also associates tose.Thus, health differences between total free sugars, added sugars, or
with significantly higher incidence of CVD and especially DM (see Fig. different subtypes of sugars have not been clearly demonstrated.127–129
536
Type Processing and Structure Examples

IV
Intact whole grains Whole grain with the bran, germ, and Barley, sorghum, millet,
endosperm from the natural cereal intact brown rice, bulgur wheat,
amaranth, wheat berries
Minimally processed whole Some processing is performed to improve Stone-ground whole wheat
grains palatability or digestibility, yet the bran bread, cracked wheat, steel-
and germ remain partially intact cut oats
Milled whole grains The whole grain, including bran, germ, Most commercially available
and endosperm, is milled to fine flour whole grain breads, whole
grain breakfast cereals, whole
grain pasta
Starchy vegetables* Plants that have been bred or engineered to Potatoes, corn, green peas†
contain high levels of starch with relatively
low dietary fiber and micronutrients
Refined grains* The bran and germ are removed during White bread, white rice, most
processing, leaving the endosperm ready-to-eat breakfast cereals,
comprised largely of refined starch instant oatmeal, regular pasta
Refined sugars* Natural and industrially produced Candies, other sugars added
monosaccharides, disaccharides, and to foods
oligosaccharides, including sucrose,
glucose, fructose, high-fructose corn syrup,
maltose, dextrose, and maltodextrin
Sweetened refined grains* Refined grains with added refined sugars Sweetened breakfast cereals,
grain-based desserts (cakes,
cookies, pies, doughnuts,
sweet rolls, muffins)
Refined sugars in liquid Natural and industrially produced Sugar-sweetened beverages,

form monosaccharides and disaccharides in including sodas, iced teas,
liquid form sports drinks, and fruit drinks
FIGURE 29.4 A hierarchy of carbohydrate quality. Dietary fiber content, whole versus refined grain content, glycemic response to ingestion, and extent of processing of grains,
cereals, and sugars can be separately altered, creating a complex hierarchy of effects from healthiest (dark green) to most harmful (dark red). *Simple and complex refined carbo-
hydrates induce similarly high glycemic responses following ingestion and, in amounts typically consumed in Western diets, induce hepatic de novo lipogenesis, that is, synthesis
of fat from carbohydrate. †Corn, peas, and certain potatoes provide reasonable fiber and modestly lower glycemic responses than white potatoes. Yams and sweet potatoes are
not included here due to higher nutrient contents and lower glycemic responses.
The monosaccharides glucose and fructose—together forming trials have established that the percent of total fat in foods or diets has
sugar—have differing physiologic effects. When consumed at high, negligible effects on CVD, DM (Fig. 29.5), or weight loss, weight gain,
rapidly digested doses, both appear to cause metabolic harm. Glucose or overweight/obesity (see Energy Balance).4,8,11,135,136 In contrast, differ-
induces postprandial hyperglycemia, hyperinsulinemia, and related ent types of fats and fatty acids have important health effects. Conven-
disturbances, as well as hepatic de novo lipogenesis at high levels; tionally, dietary fats are categorized based on chemistry—the number
while fructose has little influence on blood glucose or insulin, but and position of double bonds—rather than physiologic effects. This
more directly stimulates hepatic de novo lipogenesis, hepatic and vis- classification obscures differences in dietary sources and biologic
ceral adiposity, and uric acid production.130,131 Such harms are avoided effects of individual fatty acids, which influence gene transcription,
by modest, slowly digested doses of either glucose or fructose (e.g., as cell membrane fluidity, receptor function, and lipid metabolites and
found in fruit or beans). Thus, the dose, rapidity of digestion, accom- more importantly, their diverse food sources. This chapter follows the
panying nutrients, and food structure (liquid, solid) may each modify conventional categories but discusses effects of individual fatty acids
health effects of sugars. where sufficient data exist.
Resistant starches are of growing interest but understudied. Starches
can be resistant to digestion due to physical inaccessibility (e.g., intact Saturated Fats
whole grains), crystalline form (e.g., raw potatoes, green bananas, high Major sources include meats, dairy products, and tropical oils (e.g.,
amylose maize), retrogradation (realignment of cooked, gelatinized palm, coconut). Based on ecologic comparisons, effects on LDL-
starches during cooling, e.g. stale bread, cold rice), or chemical mod- cholesterol, and animal experiments, SFA intake would be expected
ification (e.g., many emulsifiers, stabilizers, thickening agents).132 Like to increase CHD risk.Yet, actual health effects are more complex. First,
dietary fiber, resistant starches feed the microbiota in the large intestine, when replacing total carbohydrate, SFA increases LDL-cholesterol but
producing short-chain fatty acids and other microbial metabolites.Two at least partly due to increasing LDL-cholesterol particle size, rather
recent meta-analyses identified only small, short-term trials of resistant than increasing ApoB; and SFA also reduces triglyceride-rich particles
starch, conducted in mixed patient populations.133,134 Evaluating body and lipoprotein(a) and raises HDL-cholesterol and Apo-A1.137 In com-
weight, satiety, and glucose-insulin homeostasis, some benefits were parison to total carbohydrate, SFA has no significant effects on fast-
identified, but these are of uncertain relevance given the small number ing glucose, HbA1c, or insulin resistance.135,138 These summed effects
of studies, heterogeneity, and uncertain risk of bias. would predict relatively neutral effects of SFA on CVD events or DM,
compared with carbohydrate or the average background diet. Pro-
spective cohort studies confirm null associations with CHD and DM
Fats and possible inverse associations with stroke (see Fig. 29.5).135,136,139 In
Total Fat a large randomized trial targeting total fat reduction, SFA intake was
Whereas early ecologic (cross-national) studies suggested that fat intake reduced by approximately 27%, largely replaced with carbohydrates,
increased cardiometabolic risk, prospective cohorts and randomized without effects on incident CHD (RR=0.98), stroke (RR=1.02), or DM
537
Endpoint Unit RR Reference
studies subjects events
29
CHD 10 319,288 NR Each 10 unit increase 1.24 (1.12–1.38) Livesey 2019

Glycemic index Stroke 10 225,205 3,046 High vs. low 1.10 (0.99–1.21) Cai 2015
Diabetes 17 NR NR Each 10 unit increase 1.16 (1.06–1.26) Livesey 2019
CHD 11 302,089 NR Each 65 unit/d increase 1.44 (1.25–1.65) Livesey 2019

Glycemic load Stroke 9 222,308 2,951 High vs. low 1.19 (1.05–1.36) Cai 2015
Diabetes 22 669,229 28,832 Each 80 unit/d increase 1.33 (1.21–1.45) Livesey 2019
CVD 3 167,430 8,174 High vs. low 1.01 (0.90–1.13) Khan 2019
Total sugars CVD mortality 3 362,607 11,393 High vs. low 1.09 (1.02–1.17) Khan 2019
Diabetes 12 105,846 13,727 High vs. low 0.91 (0.76–1.09) Tsilas 2017
CHD 9 NR NR Each 8 g/d 0.81 (0.73–0.90) Reynolds 2019

Fiber Stroke 11 NR NR Each 8 g/d 0.90 (0.85–0.95) Reynolds 2019
Diabetes 11 NR NR Each 8 g/d 0.85 (0.82–0.89) Reynolds 2019
CHD mortality 5 NR NR Each 5 g/d 0.97 (0.92–1.02) Reynolds 2019

Cereal fiber

Fruit fiber

Vegetable fiber
CVD mortality 7 NR NR Each 3% energy 0.98 (0.97–1.00) Naghshi 2020

Total protein
Diabetes 12 344,573 20,211 Each 5% energy 1.08 (1.05–1.11) Fan 2019

Animal protein

Plant protein
CVD 45 NR NR Each 5% energy 0.99 (0.97–1.01) Zhu 2019

Total fat
Diabetes 15 102,305 20,015 Each 5% energy vs. 0.98 (0.94–1.02) Merino 2019
carbohydrate

Saturated fat
carbohydrate

Monounsaturated fat
carbohydrate
Polyunsaturated fat CVD 28 NR NR Each 5% energy 0.92 (0.84–1.01) Zhu 2019

carbohydrate
CVD 16 NR NR 2% energy 1.16 (1.07–1.25) Zhu 2019

Trans fat
carbohydrate
CVD 20 NR NR Each 1 g/d 1.06 (1.01–1.11) Wang 2020

Sodium
Stroke 14 253,449 9,877 Each 1 g/d 1.06 (1.02–1.10) Jayedi 2019
Potassium Stroke 13 NR NR Each 1 g/d 0.91 (0.88–0.94) Adebamowo 2015
0.67 1 1.5
FIGURE 29.5 Meta-analyses of nutrients and associations with cardiometabolic outcomes. CHD, coronary heart disease; CVD, cardiovascular disease; NR, not reported.
(RR=0.96).140,141 In the international PURE study,142 very low SFA con- effects remain unclear.137 Finally, health effects of SFA vary depending
sumption was linked to higher risk of stroke, consistent with other on the food source, with very different relationships for processed
reports.139 Replacement of total SFA with polyunsaturated fats (PUFA) meats, unprocessed red meats, different types of dairy, plant oils, etc.
reduces CHD risk (see PUFA, below), but this appears largely attribut- (see Foods, above).
able to benefits of PUFA, rather than harms of SFA. While major dietary guidelines continue to recommend a limit on
Second, there are several different SFA: lauric (12:0), myristic (14:0), SFA, guidance has shifted over time to specify replacement with PUFA,
palmitic (16:0), and stearic (18:0) acid; odd-chain SFA in dairy (15:0, rather than carbohydrates or monounsaturated fats (MUFA).11 Yet, the
17:0); and very long-chain SFA (20:0, 22:0, 24:0). Each of these has recommendation to limit total SFA is increasingly controversial, with
different effects on blood lipids; potential differing long-term health many scientists stating that heterogeneity in health effects of different
538
SFA and their food sources indicates a need to move away from limits other CVD risk factors (REDUCE-IT), supplementation with high-dose
IV on total SFA and toward guidance on individual foods.143,144 purified EPA (4 g/day) reduced combined CVD by 25% (HR 0.75;
95% CI 0.68 to 0.83).166 A large primary prevention trial of low-dose
Monounsaturated Fats fish oil (1 g/day) did not significantly reduce the primary endpoint
While MUFA favorably affect BP, cholesterol levels, and glycemic con- of combined CVD (HR 0.92; 0.80 to 1.06), but did reduce secondary
trol in trials,137,138,145 MUFA intake does not consistently associate with endpoints of total MI (0.72; 0.59 to 0.90) and total CHD (HR 0.83; 0.71
lower risk of CVD in cohort studies, and associates with higher risk to 0.97).167 Reasons for the discrepant results of different fish oil trials
of DM (see Fig. 29.5).135,136 Because both animal fats and plant oils remain unclear and may relate to differences in dose, population risk,
(e.g., olive, canola) provide MUFA, the food source may modify overall background diet, and endpoints.
health effects, as seen with SFA. For instance, olive oil, but not mixed
animal and plant sources of MUFA, associates with lower CHD;146 while Trans Fats
plant oil sources of MUFA reduce LDL proteoglycan binding, suggest- Trans fats (TFA) are unsaturated fats with one or more double bonds
ing anti-atherogenic effects.147 Thus, focusing on specific foods and oils, in the trans, rather than cis, position. TFA cannot be synthesized by
rather than MUFA content per se, may be most prudent. Extra-virgin mammals. Natural sources include small amounts in ruminant meats
olive oil, mixed nuts, avocados, and canola oil are sources of MUFA and milk (formed by gut microorganisms in cows, sheep, and goats),
with reasonable evidence for cardiometabolic benefits. which contribute minimally to diet (<0.5%E) and do not associate with
CVD risk.168 Indeed, higher blood levels of trans-16:1n-7, a natural TFA in
Polyunsaturated Fats dairy fat, associate with lower risk of DM.92
PUFA are classified as n-6 or n-3, based on the carbon location of the Much higher levels of industrial TFA, coming from partially hydro-
first double bond. The predominant PUFA is n-6 linoleic acid (LA, genated vegetable oils, consistently associate with higher CVD (see
18:2n-6), derived principally from plant oils. Flaxseed, canola, walnuts, Fig. 29.5).136 Unique among dietary fats, TFA consumption raises LDL-
and soybeans provide alpha-linoleic acid (ALA, 18:3n-3); and seafood, cholesterol, ApoB, triglycerides, and lipoprotein(a), and lowers HDL-
eicosapentaenoic acid (EPA, 20:5n- 3) and docosahexaenoic acid cholesterol and ApoA1.169 TFA also exhibit non-lipid effects, promoting
(DHA, 22:6n-3). Both LA and ALA are essential fatty acids—i.e., they inflammation, endothelial dysfunction, insulin resistance, visceral adi-
cannot be synthesized by humans and must be derived from the diet. posity, and arrhythmia, although strength of evidence for these non-
lipid effects varies.170 In sum, the implicated pathways suggest effects
n-6 PUFA of TFA on adipocyte dysfunction and insulin resistance. Emerging evi-
While harms of n-6 PUFA have been speculated upon, metabolic inter- dence suggests that 18:2 TFA isomers may be most adverse, formed not
ventions, cohort studies, and clinical trials demonstrate health bene- only by partial hydrogenation but also other industrial processes such
fits. LA lowers LDL-cholesterol and triglyceride-rich lipoproteins, raises as oil deodorization and high-temperature cooking.171,172 Because par-
HDL-cholesterol, lowers HbA1c and fasting insulin, and improves insu- tially hydrogenated oils are food additives with clear adverse effects,
lin secretion capacity.137,138 While pro-inflammatory effects have been their elimination is a public health priority. The Food and Drug Admin-
theorized, such effects are not seen in humans.148,149 LA may actually istration recently ruled that partially hydrogenated oils are no longer
reduce hepatic steatosis and systemic inflammation.150,151 Arachidonic “generally regarded as safe,” greatly reducing industrial TFA in the U.S.
acid, the prototypical metabolite of LA, is commonly considered pro- food supply.
inflammatory, but also gives rise to specialized proresolving mediators
(SPMs) of inflammation,152 and in prospective studies associates with Dietary Cholesterol
lower CHD.153 LA also associates with lower CHD and DM (see Fig. Dietary cholesterol raises both LDL-cholesterol and HDL-cholesterol,
29.5), whether replacing carbohydrate or saturated fat.135,136,154 Objec- resulting in small net change in the total HDL-cholesterol ratio. In cer-
tive blood biomarker levels of LA associate with lower incidence of tain animals, dietary cholesterol is pro-atherogenic. Yet, in long-term
CVD events and DM in pooled cohort studies, while AA levels do not prospective studies, dietary cholesterol and its major sources (e.g.,
associate with higher risk.155,156 In meta-analysis of clinical trials, intake eggs, shellfish) have inconsistent associations with incident CHD and
of n-6 rich plant oils like soybean oil, in place of animal fats, reduces stroke.173–175 Among patients with prevalent DM, dietary cholesterol
CHD events.157 associates with higher CHD risk;176 associations with incident DM
appear mixed.177,178 In sum, dietary cholesterol appears to have minor
n-3 PUFA (see Chapters 25 and 27) CVD effects in the general population, but may increase CVD among
CVD effects of ALA, the plant- derived n-3 PUFA, remain inconclu- diabetic patients. Elucidation of reasons for this potential difference
sive.63,158,159 In a Dutch trial, an ALA-rich margarine did not significantly requires further investigation.
reduce total CVD events (RR=0.91; 95% CI: 0.78 to 1.05).160 However, in
a pooling project of 19 cohorts across 16 countries, blood biomarker
levels of ALA associated with lower risk of fatal CHD, but not total CHD Protein
or nonfatal MI.161 This is consistent with a reduction in cardiac arrhyth- Increased dietary protein in combination with strength- training
mia in a meta-analysis of two trials of ALA supplementation.63 More increases muscle mass more than strength-training alone in gener-
research is needed. ally healthy middle-aged and older adults.179,180 Given relevance of
The long- chain n-
3 PUFA EPA and DHA, derived from fish and lean muscle mass for insulin sensitivity, this suggests protein con-
shellfish, produce multiple physiologic benefits in human trials, sumption plus strength training could improve metabolic health.
improving heart rate, blood pressure, triglyceride- rich lipoproteins, Yet, studies of dietary protein and satiety, weight control, or meta-
endothelial function, adiponectin, cardiac function, and inflammatory bolic health show mixed findings. In meta-analysis of randomized
responses.64,162 In observational studies, dietary EPA+DHA most consis- trials, increased protein consumption had little effect on metabolic
tently associate with fatal CHD,153,158,163 consistent with dog and primate risk factors including adiposity, lipids, blood pressure, inflammation,
experiments showing benefits for ischemia-induced ventricular fibril- or glucose.181 In prospective cohorts, total protein intake has bor-
lation.64 Similarly, in pooling projects of international cohorts, blood derline associations with CVD and is associated with higher risk
biomarker levels of long-chain n-3 PUFA associated with lower risk of of diabetes (see Fig. 29.5).78,182 When food sources were separately
fatal CHD, not total CHD or nonfatal MI; and lower risk of DM.161,164 evaluated, animal protein sources were associated with higher DM
Multiple clinical trials have evaluated CVD effects of n-3 PUFA sup- risk; and plant protein sources, with lower risk. In interventional
plements, most often in the form of fish oil.63,64,165 Meta-analyses are studies, high protein diets induce variable effects on the gut micro-
most consistent with reduced risk of CHD mortality, similar to find- biome, again with differences for animal versus plant sources.183
ings for dietary fish and EPA+DHA intake, but individual trial results Given the broadly similar amino acid profiles of animal and plant
have been conflicting.63,165 In a recent trial of patients with elevated proteins (indeed, the former are often more complete and bio-
triglycerides, on statins, with either established CVD or diabetes plus available), these variable findings suggest that, like health effects of
539
carbohydrates and fats, cardiometabolic effects of dietary protein randomized trials, flavonoid-rich cocoa or dark chocolate has small but
depend on the food source and not the protein content per se. measurable benefits on BP, endothelial function, insulin resistance, and
blood lipids,201,202without increases in body weight or adiposity.200 BP-
29
lowering has been shown with as little as 6.3 g/day of dark chocolate

MICRONUTRIENTS and correlates with increased endothelial nitric oxide production.203
Observational studies and trials of dietary flavan- 3-
ols also suggest
cardiometabolic benefits.204 In extra virgin olive oil, oleocanthal is an
Sodium, Potassium (see Chapter 26) anti-inflammatory flavonoid that inhibits cyclooxygenase 1 and 2 isoen-
In Western countries, most sodium (approximately 75%) comes from zymes and may partly explain health benefits.205 Supplementation with
packaged foods and restaurant meals (rather than home cooking or flavonoids prevents diet-induced weight gain in several animal models,
table salt); while in Asian countries, most comes from soy sauce or salt even on calorie-matched diets.82 Some observational studies evaluating
added during cooking or at the table.184 Nearly every country in the total or selected dietary flavonoids observe lower risk of cardiometa-
world exceeds the recommended mean intake of 2000 mg/d.185 Sodium bolic events;82,204 one large clinical trial is ongoing. The heterogeneity of
raises BP in a dose-dependent fashion, with stronger effects among different flavonoids and their dietary sources limits inference for class
effects, and clinical benefits and dose-responses remain unclear. Yet,
older individuals, hypertensives, and Blacks.186 In meta-analyses, high
many foods with evidence for cardiometabolic benefits—e.g., berries,
sodium intakes associate most strongly with incident stroke (see Fig. nuts, extra-virgin olive oil—are rich in phenolics, and their physiologic
29.5).187,188 Animal studies further suggest that habitually high dietary and molecular effects are highly promising for further study.
sodium induces long-term renal, myocardial, and vascular fibrosis.189
While some observational studies suggest a potential J-shaped relation,
with higher CVD risk at low intakes (e.g., <3000 g/day), specific biases
related to sodium assessment in observational studies could produce a DIETARY PATTERNS
spurious J-shape.190 The National Academies of Sciences, Engineering,
and Medicine reviewed all the evidence and set the recommended Evidence- based healthful diet patterns, which represent overall
intake at below 2300 mg/day.191 combinations of foods consumed, share several key characteristics
In trials, potassium lowers BP, with stronger effects among hyper- (Table 29.1): more minimally processed, bioactive-rich foods such as
tensive individuals and when dietary sodium intake is high;192 and fruits, nuts or seeds, nonstarchy vegetables, beans, whole grains, sea-
potassium- rich diets associate with lower risk of stroke (see Fig. food, yogurt, and plant oils; and fewer red meats, processed (sodium-
29.5).187,193,194 Potassium also attenuates, while insufficient dietary preserved) meats, and processed and packaged foods rich in refined
potassium exacerbates, the BP-raising effects of sodium. Overall, the grains, starches, added sugars, salt, and trans fat. Two of the most stud-
evidence supports the importance of potassium-rich foods for reduc- ied, each with clear cardiometabolic benefits, are the traditional Medi-
ing BP and CVD. terranean and DASH dietary patterns.11
Randomized trials in both primary and secondary prevention
CALCIUM, MAGNESIUM populations confirm significant cardiometabolic benefits of such
In short-term trials, calcium and magnesium supplements also modestly healthful, food-based diet patterns.35,206–208 This contrasts with small
lower BP, although with substantial heterogeneity between studies. effects of nutrient-based approaches to dietary guidance, such as
However, calcium supplements with or without vitamin D may increase low-fat, low- saturated fat diets, in observational cohorts and ran-
risk of MI in controlled trials.195 In observational analyses, dietary and domized trials.137,140,141,153 The main exceptions are additives, such as
blood Mg inversely associate with CVD and DM;196,197 long-term trials sodium, added sugar, and trans fats: because these can be added to
have not been performed. Calcium and magnesium supplements can- or removed from otherwise similar foods and diet patterns, a specific
not yet be recommended for general CVD prevention.
nutrient focus on these additives is warranted. Focusing on overall
ANTIOXIDANT VITAMINS diet patterns can lead to health benefits from modest changes across
Certain dietary vitamins and nutrients associate with lower CVD in multiple foods, rather than large changes in a few factors, potentially
observational studies, but fail to lower risk when given as supplements increasing effectiveness and compliance. This flexibility can also
in trials, including folate, B-vitamins, beta-carotene, vitamin C, vitamin facilitate behavioral counseling, permitting more room for more per-
E, and selenium.198 Most of these trials, for reasons of power, evalu- sonalized focus (Table 29.2).11
ated up to a few years of treatment in high-risk individuals or patients People who follow vegetarian or vegan diets are often health-
with established CVD. In contrast, most observational studies evaluated conscious and select healthier, minimally processed foods. Yet such
long-term or habitual intake among generally healthy people. Thus, diets can vary dramatically in their healthfulness, as much of what
discrepancies in findings could partly relate to different time periods
of biologic sensitivity; for example, some vitamins and nutrients could
is harmful in modern foods—refined grains, starches, sugars, salt—is
be important only early in the disease course. Discrepancies may also plant-based. A cardioprotective diet pattern is best characterized by
relate to residual bias in observational studies from other behaviors (i.e., being rich in specific healthful foods (see Table 29.1).
observed benefits are not due to diet) or due to other nutritional factors Newer popular dietary patterns include low-carbohydrate, keto-
in vitamin-rich foods (i.e., observed benefits are due to diet but not to genic, and paleo diets. In a network meta-analysis of 56 randomized
the specific isolated vitamin or mineral). Diets higher in antioxidant vita- trials in patients with diabetes, Mediterranean, paleo, and vegetar-
mins tend to be rich in fruits, vegetables, nuts, and whole grains, foods ian diets appeared most effective at reducing fasting glucose, while
that contain multiple other beneficial factors including other vitamins, low-carb, Mediterranean, and paleo diets appeared most effective to
minerals, phytonutrients, and fiber, as well as replacing unhealthful reduce HbA1c.209 In exploratory subgroup analyses, low-carb diets
foods. Thus, isolating limited nutrients in these foods as supplements
may not produce similar effects as consuming the whole food.
appeared more effective in shorter- term studies, smaller studies,
and older individuals (age 60+ years), while Mediterranean diets
VITAMIN D appeared more effective in longer-term studies, larger studies, and
Higher plasma vitamin D levels associate with lower CVD, but are largely younger adults (age <60 years). For weight loss in diabetic patients, a
driven by sun exposure, not diet. Meta-analysis of 21 large supplement meta-analysis of 20 randomized trials of various popular diets found
trials shows no significant benefits,199 nor do vitamin D supplements significant weight loss only with a Mediterranean diet.210 Nearly all of
improve blood pressure or glycemic control.200 Vitamin D supplementa- these trials did not exceed 1 year, raising questions about long-term
tion is not indicated to improve cardiometabolic health. effects.
Low-carbohydrate diets generally produce similar or greater weight
POLYPHENOLS
Bioactive polyphenols include more than 5000 different flavanols (in
loss than low-fat diets, with corresponding improvements in CVD risk
onions, broccoli, tea, various fruits), flavones (parsley, celery, chamomile factors,47,211 and are superior to low-fat diets for glycemic control in dia-
tea), flavanones (citrus fruits), flavanols (flavan-3-ols) such as catechins betic patients.49,212,213 A “low-carbohydrate” focus appears to be a simple
and procyanidins (cocoa, apples, grapes, red wine, tea), anthocyani- rule to reduce selection of ultraprocessed foods rich in refined carbo-
dins (colored berries), and isoflavones (soy). In laboratory studies and hydrates.209 However, when minimally processed, phytonutrient- rich
540
TABLE 29.1 Food-Based Components of Dietary Patterns that Improve Cardiometabolic Health*
IV GOAL† SERVING SIZES
Consume More
Fruits 3 servings per day About 100 g, e.g., 1 medium-sized fruit; ½ cup
of fresh, frozen, or canned fruit; ¼ cup of dried
fruit; ½ cup of 100% juice. Goals should not be
met with juice alone
Vegetables and beans 3–4 servings per day About 100 g, e.g., 1 cup of raw leafy vegetable;
½ cup of cut-up raw vegetables, cooked
vegetables, or 100% juice. Limit potatoes to ½
cup or less per day
Whole grains‡ 3 servings per day, in place of refined grains About 50 g, e.g., 1 slice of whole-grain bread;
1 cup of high-fiber whole-grain cereal; ½ cup
cooked whole-grain rice, pasta, or cereal
Nuts 4–5 servings per week About 28 g (1 oz)
Fish and shellfish 2+ servings per week, preferably oily About 100 g (3.5 oz). Goals should not be met
with commercially prepared deep-fried or
breaded fish
Dairy products§ 2–3 servings per day 1 cup of milk or yogurt; 1.5 oz of cheese
Plant oils 2–6 servings per day About 1 teaspoon of oil, e.g., in cooking or salad
dressing; or 1 tablespoon of vegetable spread
Consume Less
Refined grains and starches Minimize intake 1-oz equivalents, e.g., slice of bread, bowl of cereal
Processed meats (e.g., bacon, sausage, hot dogs, Avoid intake or at most modest intake, e.g., up to About 100 g (3.5 oz)
processed deli meats) 1 serving per week
Foods containing partially hydrogenated plant oils Avoid intake
(industrial trans fat)
Sugar-sweetened beverages, sweets, and bakery Avoid intake or at most modest intake, e.g. up to 5 8 oz of soda; 1 small cookie, doughnut, or muffin;
foods servings per week 1 slice of cake or pie
Alcohol Up to 2 daily drinks for men, 1 daily drink for 5 oz wine; 12 oz beer; 1.5 oz spirits
women
Energy Balance Eat healthy foods as above, reduce portion sizes of unhealthy foods, eat fewer fast-food and prepared
meals, increase physical activity, limit TV watching, and ensure adequate (7–8 hr) sleep
*Adapted from the evidence described in this chapter.

†
Based on a 2000 kcal/day diet. Servings should be adjusted accordingly for higher or lower energy consumption.
‡
A practical rule-of-thumb for selecting healthier grain or carbohydrate-rich products is to choose foods containing at least 1 g of dietary fiber for every 10 g of total carbohydrate
per serving (a carb:fiber ratio<10:1), based on the Nutrition Facts Panel.
§
Based on available evidence, the types of dairy (yogurt, cheese, milk, butter) appears more relevant than fat content (whole or reduced fat); yogurt and cheese seem most
beneficial (see text for details).
foods are emphasized, low-carbohydrate and low-fat diets lead to sim- EMERGING AREAS
ilar weight loss, without caloric restriction.9,214 Overall, a diet rich in
minimally processed foods and healthy fats and low in ultraprocessed Food Processing
foods and refined grains, starches, and sugars appears optimal. Over the past 70 years, changes in plant and livestock breeding, agricul-
Extreme low-carbohydrate (i.e., ketogenic) diets can lead to mean- tural practices, and food processing methods have transformed global
ingful weight loss and metabolic benefits.215 However, such diets may food systems. The health implications of these changes are receiving
be challenging to sustain and do not leverage health benefits of fruits, increasing attention, with new food classification systems and even
nonstarchy vegetables, beans/legumes, and minimally processed Brazil’s national guidelines focusing on processing of foods.8,9,217–220
whole grains. Also, the biologic need for ketosis per se (vs. simply Processing can increase palatability, nutrient bioavailability, shelf life,
reducing refined starches and sugars) remains unclear. Extreme low- and convenience; and reduce food-borne pathogens. Processing can
carb diets may be most useful for initial weight loss (e.g., over 6 to also reduce fiber, phenolics, minerals, fatty acids, vitamins, and other
12 months), followed by transitions toward slowly incorporating carbs bioactives; increase the doses and flux of starch and sugar; and intro-
from minimally processed, bioactive-rich foods as tolerated. Potential duce compounds such as sodium, other preservatives and additives,
long-term health effects require further investigation. trans fats, heterocyclic amines, and advanced glycation endproducts
Paleo diets aim to conform to foods consumed during human evo- (AGEs). Food processing can also impact the microbiome (see below).
lution over millennia. Benefits include avoidance of poor quality car- Processed meats and refined grains, starches, and added sugars
bohydrates (refined starches, sugars) and other ultra-processed foods; are convincingly linked to cardiometabolic harms.21 Yet, more “nat-
and positive emphasis on nonstarchy vegetables, nuts, and fish; which ural” foods such as eggs, butter, and unprocessed red meats do not
together can produce weight loss and corresponding metabolic ben- improve metabolic health, while some processed products (e.g., yogurt,
efits.216 Yet some interpretations of paleo diets include liberal intakes cheese, plant oils, margarines, canned fish, fruit-or nut-rich snacks) are
of red meats (including non-paleo processed meats), lard, and salt; beneficial. Because most foods must undergo some processing prior
plus avoidance of protective plant oils, legumes, and dairy; which may to consumption—for example, milling, refining, cooking, ferment-
reduce net benefits. ing, etc.—more research is essential to understand which aspects of
TABLE 29.2 Effects of Food and Nutrients on Specific Cardiometabolic Risk Factors and Disease Endpoints
STRENGTH OF EVIDENCE FOR BENEFITS*
CONVINCING PROBABLE POSSIBLE INSUFFICIENT EVIDENCE FOR EFFECTS
Hypertension Higher intakes of: Higher intakes of: Higher intakes of: Isoflavones
Mediterranean-or DASH-type dietary pattern Tea Whole grains
Coffee or tea
Dietary fiber Magnesium
Lower intakes of:
Fruits and vegetables Calcium PUFA or carbohydrate in place of SFA
Caffeine
Fish or fish oil Vitamin D
Cocoa or dark chocolate Soy foods
Potassium MUFA in place of SFA
Lower intakes of:
Sodium
Alcohol
High LDL-cholesterol Higher intakes of: Higher intakes of: Higher intakes of:
MUFA or PUFA Butter Cheese
Dietary fiber Whole grains Yogurt
Fruits and vegetables Soy foods Cream
Green tea Tea
Soy protein
Lower intakes of:
Lower intakes of: Unfiltered coffee
Trans fat
SFA (12:0-16:0)
Dietary cholesterol
Atherogenic Dyslipidemia Higher intakes of: Lower intakes of: Higher intakes of:
(low HDL-cholesterol, Mediterranean-or DASH-type dietary pattern Sugar-sweetened beverages Fruits and vegetables
high triglycerides) MUFA or PUFA Dairy
Fish or fish oil
Lower intakes of:
Simple or complex refined carbs (high GI or GL)
Trans fat
Insulin Resistance, Type 2 Higher intakes of: Higher intakes of: Higher intakes of: Carbohydrate in place of SFA
Diabetes Whole grains MUFA Fruits
Vegetables
Dietary fiber Yogurt Beans
PUFA or plant oils Lower intakes of: Coffee Beans
Unprocessed meats Cheese Poultry
Lower intakes of:
Dairy fat
Processed meats Fish or fish oil
Sugar-sweetened beverages Lower intake of:
Simple or complex refined carbs (high GL) Eggs Milk
Dietary cholesterol Butter
Trans fat
Tea
Obesity Higher intakes of: Higher intakes of: Higher intakes of: Total fat (% E)
Whole unprocessed foods (e.g., whole grains, nuts, Dietary fiber Green tea
SFA, MUFA, or PUFA
fruits, vegetables, beans) Yogurt Protein
Lower intakes of: Lower intakes of: Lower intakes of:
Sugar-sweetened beverages Ultra-processed foods Deep-fried foods
Simple or complex refined carbs (high GL) Large portion sizes of unhealthy foods Meals from quick service restaurants
Red meats Trans fat
Processed meats
Less television watching
Greater sleep duration
541
Continued
29
IV
TABLE 29.2 Effects of Food and Nutrients on Specific Cardiometabolic Risk Factors and Disease Endpoints—cont’d
542
STRENGTH OF EVIDENCE FOR BENEFITS*

CONVINCING PROBABLE POSSIBLE INSUFFICIENT EVIDENCE FOR EFFECTS
Systemic Inflammation Higher intakes of: Higher intakes of: Higher intakes of: SFA or MUFA
Fruits and vegetables Mediterranean-or DASH-type diet Fish, fish oil (diet), ALA
pattern PUFA
Whole grains Nuts
Fish oil (supplements). Lower intakes of:
Simple or complex refined carbs (high
Lower intakes of:
GI/GL)
TFA
Coronary Heart Disease Higher intakes of: Higher intakes of: Higher intakes of: Total fat (% E)
Mediterranean-or DASH-type dietary pattern Beans Fish or fish oil (nonfatal CHD)
Carbohydrate in place of SFA
Fruits and vegetables Cheese
Lower intakes of:
Whole grains Antioxidant or vitamin supplements
Simple or complex refined carbs (high ALA
Nuts Poultry
GI or GL) MUFA in place of SFA
Dietary fiber
Sodium Vitamin D Eggs
PUFA in place of SFA
Fish (CHD mortality) Moderate alcohol use Lower intakes of: Yogurt
Unprocessed meats
Lower intakes of: Milk
Dietary cholesterol in patients with
Trans fat
DM Coffee or tea
Processed meats
Dietary cholesterol in patients without
DM
Ischemic Stroke Higher intakes of: Higher intakes of: Poultry
Mediterranean-or DASH-type dietary pattern Whole grains
Eggs
Fruits Vegetables
SFA Milk
Lower intakes of:
Fish or fish oil ALA
Sodium
Tea
Cheese Antioxidant or vitamin supplements
Lower intakes of:

Processed meats
Red meats
Hemorrhagic Stroke Higher intakes of: Higher intakes of: Fish or fish oil
Whole grains Total fat
Mediterranean-or DASH-type dietary SFA
pattern Animal protein
Tea
Lower intakes of:
Sodium
Heart Failure† Lower intakes of: Higher intakes of:
Heavy alcohol use Mediterranean-or DASH-type dietary
pattern
Whole grains
Fish
Moderate alcohol use
Atrial Fibrillation Lower intakes of: Higher intakes of:
Heavy alcohol use Fish or fish oil
*Strength of evidence based on Bradford-Hill and World Health Organization criteria. For most dietary factors, evidence is derived from controlled trials of risk factors plus long-term prospective cohorts of disease endpoints. For fish/
EPA+DHA, n-6 PUFA, total fat, and Mediterranean-type dietary patterns, evidence is also derived from randomized clinical trials of clinical endpoints.
†
Incidence. Limited data on dietary treatment for secondary prevention, except for one large, randomized trial of EPA+DHA supplementation that reduced total mortality, and clinical experience with sodium restriction to prevent fluid
overload.
543
modern processing are detrimental and to define optimal processing to improve nutrition, such as within schools, worksites, federal feed-
of different foods for health. ing programs, the retail food environment, government structure and 29
coordination, and business innovation and entrepreneurship.245 Major

scientific questions around food, nutrition, and health also remain
Microbiome uncertain and unanswered, requiring a new federal prioritization of
Eating habits exert large, rapid effects on gut microbial composition coordination and investment in federal nutrition research.246 For all
and function, influencing host health.221–224 Prebiotics like dietary of these strategies, a focus on foods, rather than single nutrients, facil-
fibers, fructans (e.g., inulin in chicory root), other oligosaccharides, itates dietary guidance and behavior change.
resistant starch, and certain phenolics (e.g., cocoa-derived flavanols) Such broader approaches are also essential to help reduce pro-
feed the microbiome.53,225,226 Probiotics—live bacteria or yeasts in fer- found diet-related health disparities in the United States and globally.
mented foods like yogurt, cheese, kefir, kimchi, kombucha, miso, natto, Ever-widening disparities in diet quality and diet-related chronic dis-
sauerkraut, and tempeh—can also alter gut microbial composition.226 eases are occurring by race/ethnicity, income, and education, further
Trials of probiotic-containing foods and supplements demonstrate exacerbated by the COVID-19 pandemic.246 Poor diets lead to a vicious
benefits on weight control, glycemia, and possibly nonalcoholic fatty cycle of lower academic achievement in school, lost productivity at
liver disease.88–91 work, increased chronic disease risk, increased out-of-pocket health
Food processing can adversely impact the microbiome.8,219,227 costs, and poverty for the most vulnerable Americans.
Many processing methods (e.g., milling, refining) strip away key prebi- The economic consequences of diet-related CVD, DM, obesity, and
otics. Even when reconstituted (e.g., added bran, fiber), loss of intact related conditions are a clarion call for action. Since 1970, US health
food structure (termed “acellular nutrition”) may alter digestion and care expenditures have risen from 6.9% to 17.9% of gross domestic
absorption in the proximal gut219 and deprive the (dominant) distal product (GDP), largely owing to costs of chronic diseases. In constant
gut microbiome of prebiotics.227 In some animal models and limited 2017 dollars, health care spending per capita has skyrocketed from
human experiments, artificial sweeteners alter host microbial com- $1797 to $10,739 per year.247 Much of this relates to management of
position and adversely influence satiety, glucose-insulin homeostasis, diet-related chronic diseases,248 with total economic costs of CVDs esti-
caloric intake, and weight gain.228,229 In some experiments, emulsifi- mated at $316 billion/year; of diabetes, at $327 billion/year;249 and of
ers and thickeners influence the gut microbiome, gut mucosa, and all obesity-related conditions, at $1.72 trillion/year.250 These costs are
related inflammatory pathways.230,231 Further investigation of effects straining budgets of governments, businesses, and families. The large
of different food processing applications on the microbiome is impacts of the food and agricultural system on sustainability and
urgently needed. climate change also have major implications for human health.251,252
Given the core role of nutrition in cardiometabolic health, disparities,
and health care costs, multi-sectoral approaches and policies for better
Personalized Nutrition nutrition should be a top priority for patients, clinicians, health systems,
While genetics as a predictor for personalized nutrition have shown payers, businesses, and governments.
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29

Nutrition and Cardiovascular and

ENERGY BALANCE, 531 BEVERAGES, 535 Sodium, Potassium, 539

Refined grains, starches, sugars Blood pressure

Whole Grains, Refined Grains, Starches, Sweets

Nutrition and Cardiovascular and Metabolic Diseases

CHD 6 NR 7,697 High vs. low 0.80 (0.70–0.91) Reynolds 2019

CHD mortality 7 NR NR Each 1 egg/d (50g/d) 0.95 (0.76–1.18) Godos 2020

CHD 8 416,185 19,812 Each 10 g/d 0.96 (0.93–0.99) Morze 2020

100% fruit juice (non-linear)

CHD 7 235,368 8,328 Each 1 cup/d 0.90 (0.81–0.996) Zhang C 2015

Nutrition and Cardiovascular and Metabolic Diseases

Type Processing and Structure Examples

Refined sugars in liquid Natural and industrially produced Sugar-sweetened beverages,

Nutrition and Cardiovascular and Metabolic Diseases

CHD 11 302,089 NR Each 65 unit/d increase 1.44 (1.25–1.65) Livesey 2019

CHD 9 NR NR Each 8 g/d 0.81 (0.73–0.90) Reynolds 2019

CHD mortality 5 NR NR Each 5 g/d 0.97 (0.92–1.02) Reynolds 2019

CHD mortality 5 NR NR Each 2 g/d 0.90 (0.82–0.98) Reynolds 2019

CHD mortality 5 NR NR Each 2 g/d 0.94 (0.90–0.98) Reynolds 2019

CVD mortality 7 NR NR Each 3% energy 0.98 (0.97–1.00) Naghshi 2020

CVD mortality 5 NR NR Each 3% energy 0.98 (0.94–1.02) Naghshi 2020

CVD mortality 6 NR NR Each 3% energy 0.96 (0.89–1.04) Naghshi 2020

CVD 45 NR NR Each 5% energy 0.99 (0.97–1.01) Zhu 2019

CVD 33 NR NR Each 5% energy 0.99 (0.95–1.04) Zhu 2019

CVD 29 NR NR Each 5% energy 0.96 (0.91–1.02) Zhu 2019

Polyunsaturated fat CVD 28 NR NR Each 5% energy 0.92 (0.84–1.01) Zhu 2019

CVD 16 NR NR 2% energy 1.16 (1.07–1.25) Zhu 2019

CVD 20 NR NR Each 1 g/d 1.06 (1.01–1.11) Wang 2020

Potassium Stroke 13 NR NR Each 1 g/d 0.91 (0.88–0.94) Adebamowo 2015

Nutrition and Cardiovascular and Metabolic Diseases

*Adapted from the evidence described in this chapter.

STRENGTH OF EVIDENCE FOR BENEFITS*

Lower intakes of:

Nutrition and Cardiovascular and Metabolic Diseases

Nutrition and Cardiovascular and Metabolic Diseases

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