The Role of Food Patterns, Nutrition, and (Phyto)Nutrients in Cardiovascular Disease: The Clinical Trials, Their Implications, and Clinical Application for the Prevention and Treatment of Cardiovascular Disease, Coronary Heart Disease, Stroke, Hypertension, Dyslipidemia, and Diabetes Mellitus



The Role of Food Patterns, Nutrition, and (Phyto)Nutrients in Cardiovascular Disease: The Clinical Trials, Their Implications, and Clinical Application for the Prevention and Treatment of Cardiovascular Disease, Coronary Heart Disease, Stroke, Hypertension, Dyslipidemia, and Diabetes Mellitus


Deanna M. Minich, MS, PhD, FACN, CNS, IFMCP



Introduction

Currently, there is a global health crisis and accompanying financial burden related to lifestyle-induced chronic disease, which largely encompasses cardiovascular disease (CVD) and type 2 diabetes. Fortunately, the cause of these related conditions is also part of the solution. Regardless of population stratifications like gender or ethnicity, it is generally accepted that about 80% of CVD can be prevented with a combination of nutrition and lifestyle therapies.1 Owing to their shared etiologies, cardiovascular and diabetic conditions are often approached with similar nutritional interventions.2 Epidemiological studies have consistently shown that there is an association between whole food-based, plant-rich dietary patterns, such as the Mediterranean diet, and lowered risk of cardiometabolic concerns, including total mortality, CVD mortality,3 hemoglobin A1C,4 inflammatory markers,4 endothelial function,4systolic blood pressure, and arterial stiffness.5


Purpose

In this chapter, a concise overview of the recent science on dietary patterns, specific classifications of components such as macronutrients and micronutrients, and select whole foods will be discussed as they relate to cardiovascular and metabolic conditions. In addition to the detailed summary the reader will be provided, it is imperative to acknowledge the application of these findings within a personalized therapeutic plan that considers genotype, phenotype, toxin exposure and overall toxin load, age, gender, ancestry, environment, and pregnancy.6 These will not be extensively addressed within this short chapter. It is becoming increasingly recognized and appreciated that an individual’s responses to foods must be evaluated within the context of one’s entire exposome,7 suggesting that the way a meal is received physiologically is not independent but dependent on several variables, including, but not limited to, socioeconomic status.


There is heightened clinical focus on the translation of nutrigenomics to dietary recommendations. As part of developing a therapeutic plan for the patient, the clinician needs to consider gene polymorphisms, such as those involved with one-carbon metabolism (often referred to as methylation), familial hypercholesterolemia, salt sensitivity, hypertension (angiotensinogen, ß2-adrenergic receptor, and kallikrein),6,8 and Apolipoprotein E (APOE). These will not be discussed in this chapter, but it is worthwhile to mention these as features to incorporate in designing a therapeutic plan that is truly individualized.

Further to nutrition, lifestyle behaviors such as sleep, relationships, stress level, and physical activity can all alter how one responds to nutrients. Nine modifiable risk factors (both food and lifestyle) were reported in the INTERHEART study9 to account for over 90% of the risk of an initial acute myocardial infarction, which suggests that the clinician would serve the patient best by developing a comprehensive food and lifestyle plan consistent with the 21st century concepts of personalized medicine. This chapter will be specific to providing an overview of the recent science on whole foods, whole food patterns, and food constituents as they relate to CVD and metabolic dysfunction.


Dietary Patterns: Looking at the Whole of Food

Even though specific food components such as meat, dairy, and vegetables have long been the cornerstone of nutrition science recommendations for cardiometabolic disorders, the trend for research has been to examine the entire food pattern one eats.10,11 After all, people do not specifically eat certain types of fats or carbohydrates but a matrix of foods that may combine in synergistic or antagonistic ways.12 Further to this point, it is clinically practical as well as relevant to discuss foods rather than specific nutrients with patients.13

There are a host of established and emerging dietary patterns for cardiometabolic dysfunction that have been researched and/or reviewed for their efficacy. Perhaps the two classic food patterns, at least for CVD risk reduction, have been the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet. There have also been hybridized dietary patterns discussed that incorporate cultural context and tradition such as the “MediterrAsian” diet14 and, most recently, the “MedÉire” diet.15

Aside from the trending dietary patterns and their evolving nomenclature, it is essential to investigate the nutritional framework of what makes these and other diets helpful in the prevention and treatment of cardiovascular and diabetic conditions. This framework can be viewed in two ways: one as what is important to include in the diet and the other as what needs to be excluded. For the former, “prudent,” healthy dietary patterns have been generally described as primarily plant-based foods such as fruits, herbs, legumes, nuts, olive oil, seeds, spices, vegetables, and whole grains. On the contrary, foods that seem to warrant caution include high amounts of red and processed meats, solid fats, and foods with little to no nutrient reserves, such the category of processed carbohydrates, which includes refined sugars, sugar-sweetened beverages, desserts, and refined (ready-to-eat) cereals.16

Relevant to the discussion in this chapter, healthful dietary patterns may help favorably modulate the profile of cardiometabolic parameters such as body weight, fat mass, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma insulin and glucose, homocysteine, cholesterol (total, high-density lipoprotein [HDL], and low-density lipoprotein [LDL]), and inflammatory markers such as high-sensitivity C-reactive protein (hsCRP),17,18,19,20 together with lowering the risk of morbidity and mortality from CVD and the incidence of myocardial infarction (MI),21 stroke,22 atherosclerosis,23 and diabetes.24


A Cultural Eating Pattern: The Mediterranean Diet

A recent literature search on the “Mediterranean diet” at the time of writing this chapter reveals over 4000 published articles in PubMed.25 This diet has been purported to have benefit for several chronic lifestyle-induced conditions, including CVD, metabolic syndrome and type 2 diabetes, cancer, liver disease, depression, and anxiety.3 Based on the quantity of articles published, the Mediterranean diet could be considered the most “well-studied” diet, even though its scientific recognition roughly began only 2 decades ago when it was observed that people living on the Greek island of Crete had reduced risk of CVD.26 In addition to being one of the most researched dietary patterns, it is shared by multiple countries in the Mediterranean basin within the context of varying populations of people living within different degrees of industrialization of food production. As a result of the intercountry differences, it has become necessary to more specifically define the contents of this dietary pattern for research purposes.

Although it varies to some degree, the broad definition of the traditional Mediterranean diet has been deemed to have these characteristics27:



  • Plant-based (cereals, fruits, vegetables, legumes, spices, tree nuts, seeds, and olives)


  • Olive oil as the main dietary fat


  • High to moderate intakes of fish and seafood


  • Moderate consumption of eggs, poultry, and dairy products (cheese and yogurt)


  • Low consumption of red meat


  • Moderate intake of alcohol (primarily red wine during meals)

For maintaining consistency and for research study purposes, a quantitative and qualitative research tool has been developed to assess a percentage compliance to the Mediterranean diet.28 Such a questionnaire may be valuable for patients who are following this way of eating so that the clinician can better assess their adherence to the dietary program. Several studies29 indicate that various levels of adherence (from first quartile to fourth) are associated with
differing health benefits (eg, reduced risk for metabolic syndrome) with the highest compliance being associated with greatest benefit.30 Factors that may determine compliance include the following: dietitian involvement, education, goal setting, mindfulness, recipe books and other materials such as meal plans, consistent contact with staff, clinic visits, and recipes.3

Numerous studies tout the efficacy of the Mediterranean diet for cardiovascular and metabolic benefit, specifically being protective against ischemic stroke, MI, and vascular death.31 A 10% lower incidence of nonfatal and fatal CVD was documented for each two-unit increment in the Mediterranean diet score in a meta-analysis and review of prospective cohort studies.32 With greater adherence to this dietary pattern, there was a 56% lower incidence of fatal CVD in a Dutch cohort compared with the group who had lower adherence over an almost 12-year period.33

Furthermore, the Mediterranean diet has been shown to be superior in its ability to produce clinically relevant shifts in body weight, BMI, blood pressure, fasting glucose, total cholesterol, and hsCRP compared with the long-standing, widely recognized and advocated low-fat diet.34 The well-known PREDIMED trial indicated that a Mediterranean diet in conjunction with nuts or olive oil led to a 30% reduction in major cardiovascular events compared with a low-fat diet.35

An overall summary of the cardiovascular and metabolic benefits of the Mediterranean diet include the following as based on the review article by Houston et al.1:



  • Lowers blood pressure


  • Improves serum lipids: lowers total cholesterol, LDL, triglycerides; increases HDL; lowers oxidized low-density lipoprotein (oxLDL) and Lp(a) lipoprotein. Shifts LDL size and decreases LDL-P to a less atherogenic profile


  • Improves type 2 diabetes and dysglycemia


  • Improves oxidative defense and reduces oxidative stress: F-2 isoprostanes and 8-Oxo-2′-deoxyguanosine


  • Reduces inflammation: lowers hsCRP, interleukin 6 (IL-6), soluble vascular cell adhesion molecule, and soluble cell adhesion molecule


  • Reduces thrombosis and factor VII after meals


  • Decreases brain natriuretic peptide


  • Increases nitrates/nitrites


  • Improves membrane fluidity


  • Reduces MI, coronary heart disease (CHD), and cerebrovascular accident (CVA)


  • Reduces homocysteine


The Dietary Approaches to Stop Hypertension Dietary Pattern

The DASH diet was unlike the Mediterranean diet in that it had no cultural underpinning, but it was unique for its time because it emphasized a pattern of eating instead of simply avoiding certain foods, which was the nutritional trend at that time.36 The DASH diet was conceived in the 1990s to create an evidence-based dietary prescription to reduce the incidence of hypertension.37

The DASH diet is similar to the Mediterranean diet. It touts high intake of fruits, vegetables, whole grains, low-fat dairy foods, legumes, and nuts; moderate intake of poultry and fish; and low intake of sodium, sweetened beverages, and red and processed meat.38 In general, it was designed to reduce cholesterol, saturated fat, trans fat, salt, and added sugars, and, at the same time, increase minerals such as potassium, magnesium, and calcium, along with protein and fiber.39 There were two versions of the DASH diet: DASH 1 had a sodium content of about 3100 mg per day,40 whereas DASH 2 had about half as much sodium at 1500 mg daily.41 As one might anticipate, the second version was more effective in reducing blood pressure.41

Although the DASH diet was designed for hypertension specifically, its implementation has led to significant improvements in cardiovascular risk factors, such as vascular and autonomic function (pulse wave velocity, baroreflex sensitivity), reduced left ventricular mass, and a lowering of total cholesterol and LDL-cholesterol.42 A meta-analysis43 of 12 prospective cohort studies (n = 548,632) with 5.7 to 24 years of follow-up found that greater adherence to the DASH diet was related to a reduced risk of stroke (relative risk, 0.88), with a greater benefit in Asian compared with Western populations. For each four points in the DASH diet score, there was a 4% risk reduction in total stroke events. Additionally, a meta-analysis of prospective studies found that the DASH diet, along with the Mediterranean diet and Alternative Healthy Eating Index, reduced the risk of type 2 diabetes.44

In contrast, the DASH diet has led to no effect on triglycerides and a reduction in HDL-cholesterol.42 Additional effects include reductions in homocysteine, C-reactive protein (CRP), and IL-645,46 and an even better blood pressure lowering response in those who are carriers of the A allele of the β2-adrenergic receptor.8,47

Proposed mechanisms for reduction in cardiovascular risk include1:



  • Increased nitric oxide and plasma nitrate


  • Natriuresis


  • Decreased oxidative stress and increased oxidative defense


  • Reduced urinary F2-isoprostanes


  • Improved endothelial function


  • Decreased pulse wave velocity and augmentation index


  • Reduced arterial stiffness


Vegetarian/Vegan Dietary Patterns

The sum of current evidence would suggest that vegetarian diets are beneficial for cardiometabolic health. Plant-based diets have been touted for both the prevention and treatment of heart failure, cerebrovascular disease, and CHD.48 For decades, Dean Ornish has studied their efficacy, together with lifestyle strategies, for the reversal of CHD.49,50 Vegetarian dietary patterns can reduce the risk of metabolic syndrome, type 2 diabetes, and CHD (by 40%),48 in addition to being able to lower blood pressure, blood lipids, and reduce platelet aggregation
over nonvegetarian diets. In a prospective investigation51 of 131,342 participants from both the Nurses’ Health Study and Health Professionals Follow-up Study, it was found that high plant protein intake was negatively associated with all-cause and cardiovascular mortality (hazard ratio [HR], 0.90 per 3% energy increment; 95% confidence interval [CI], 0.86-0.95; P for trend < .001, and HR, 0.88 per 3% energy increment; 95% CI, 0.80-0.97; P for trend = .007, respectively), whereas animal protein intake was positively correlated with cardiovascular mortality. Substituting plant protein for animal protein (processed or unprocessed red meat, and eggs) led to lower mortality.

Depending on the type of vegetarian diet, there may be certain nutrients that require additional supplementation52 such as vitamins B12 and D, omega-3 fatty acids, the minerals iron and zinc, L-carnitine, and possibly some high-quality amino acids, especially sulfur-containing amino acids, and protein.


Gluten-Free Diets

Avoiding gluten-containing foods, including select whole grains and even processed foods and beverages, has been on the rise for a variety of reasons. Traditionally, it is held that following a gluten-free diet is a necessity for individuals with celiac disease, an autoimmune condition that leads to gastrointestinal and systemic dysfunction in response to the intake of the gluten protein commonly found in wheat, barley, and rye. However, there is awareness of the potential health effects of dietary gluten in nonceliac populations. Laboratory testing is available to detect nonceliac gluten sensitivity (NCGS), which is associated with the dysfunctional effects on gastrointestinal tight junctions through the protein zonulin.53

With respect to cardiometabolic health, there is some emerging research in the literature. In a review of published studies on celiac disease and cardiovascular conditions,54 the authors noted that there were studies on the relationship between celiac disease and cardiomyopathy (33 studies), thrombosis (27 studies), cardiovascular risk (17 studies), atherosclerosis (13 studies), stroke (12 studies), arterial function (11 studies), and ischemic heart disease (11 studies). They concluded that there can be cardiovascular issues in those with celiac disease, particularly if they are untreated.

Some concern has been raised about the quality of a gluten-free diet and whether it may result in decreased intake of vitamins and minerals and increased exposure to environmental toxins such as arsenic (which is high in rice, an alternate grain in the gluten-free diet).55 In a systematic review55 of the literature of the gluten-free diet and cardiometabolic parameters (blood pressure, glycemia, BMI, waist circumference, and serum lipids), it was noted that most studies were done in those with celiac disease and there were consistent increases in total cholesterol, HDL, fasting blood glucose, and BMI.

Moreover, one study56 in 185 patients with celiac disease found an increased risk of developing both metabolic syndrome (3.24% before gluten-free diet and 14.59% after the gluten-free diet) and hepatic steatosis after following a gluten-free diet (1.7% at the time of diagnosis and 11.1% after the gluten-free diet). The authors report that several criteria of metabolic syndrome were increased after the gluten-free diet compared with baseline at celiac disease diagnosis, including elevated waist circumference and BMI >25, hypertension, hyperglycemia, hypercholesterolemia, and lowered HDL-cholesterol.

However, more studies are required to look more specifically at NCGS and the exact dietary composition, as there can be a wide spectrum of unhealthy and healthy gluten-free diets.57


Calorie and Food Restriction Patterns

Presently, the timing of eating and the amount of food eaten, along with patterns of caloric cycling, have been gaining traction in the cardiovascular and diabetic arenas. Indeed, there are a plethora of animal studies to suggest that fasting to the point of maintaining normal body weight in the absence of malnutrition may be highly beneficial for extending lifespan and enhancing cardiovascular and metabolic health58,59 by reducing oxidative stress, inflammation, and atherosclerosis.60 Although limited, some clinical studies suggest that these benefits may translate to humans as well.61 In general, preliminary and observational clinical studies indicate that several cardiovascular and diabetic risk factors may improve with some degree of caloric restriction, from body composition to inflammation, blood pressure, and insulin sensitivity.62

Similar effects, such as weight loss and reductions in cardiometabolic parameters such as CRP, cholesterol fractions, triglycerides, and blood pressure,63,64,65 are being reported with alternate-day (fasting 1 day and eating ad libitum the next) or intermittent fasting (typically described as a 12- to 16-hour nightly fast), which has become popular within certain nutrition-focused groups.

Whether it is caloric restriction, food restriction, or some pattern of food withdrawal and fasting, it is best to advise patients to plan for engaging in such a protocol to the extent that when they are eating, they are eating nutrient-dense foods such as fruits, vegetables, nuts, seeds, and other high-quality protein- and fat-containing foods so as to ensure they are not becoming nutritionally depleted, hungry, or not feeling satiated, all of which can affect compliance to the regimen.66


Cooked Food Patterns: Avoiding Advanced Glycation End Products

Eating cooked food has advantages of improving digestibility and, at the same time, the downside of creating glycosylated protein compounds known as advanced glycation end products (AGEs). This acronym provides an effective way for patients to remember the effect of these deleterious compounds that cause premature aging,67 like what is seen in cardiometabolic conditions, especially type 2 diabetes.68

AGEs are formed endogenously, such as the case with hemoglobin A1C (a glycosylated protein), or taken in
exogenously through the diet, primarily though cooked foods as heat facilitates this inflammatory complex of carbohydrate and protein (known as the Maillard reaction). Often, patients will be able to recognize the presence of AGEs in food as it can appear as the “browning” of food through broiling, frying, grilling, roasting, and searing.69 A list of AGE content in a wide array of foods can be found in the practical guide by Uribarri et al.69 It is of note that animal-based foods high in fat and protein (eg, bacon, fried chicken) tend to be high in AGE content, whereas vegetables, fruits, whole grains, and even milk (with some cheeses as exceptions) contain relatively less AGEs, even with heat methods applied. Although cooking is one of the primary drivers of AGE formation, some foods are naturally high in AGEs and should be reduced in the diet. High-fat and aged cheeses are among the highest in AGE levels, so choosing a lower-fat cheese or one that has not been cured as long would be preferred.69

Eating less AGEs in the diet directly translates to lower circulating AGE levels in serum, along with lower inflammatory cytokines.70 A single meal consisting of a chicken breast, potatoes, carrots, tomatoes, and vegetable oil caused significant postprandial endothelial function and oxidative stress in type 2 diabetic patients when the meal underwent frying or broiling rather than when it was steamed or boiled.71 In a crossover design with healthy subjects fed for 1 month a meal containing either high AGEs formed by cooking with high temperatures or low AGEs through mild steaming, it was reported that the high-AGE meals caused lower insulin sensitivity, omega-3 fatty acids, and vitamins C and E and increased cholesterol and triglycerides.72 In contrast, diabetic patients following a low-AGE diet had lower inflammation and oxidative stress compared with those eating a standard diet.73

Clinically, in some cases, it may be easier to effect change in a patient’s eating by first starting with altering cooking methods rather than asking them to shift the foods in their dietary pattern. From a therapeutic perspective, there is great benefit in doing so, and it can be easily done. One way to reduce AGEs in foods is by foregoing the high-heat methods of cooking such as frying and grilling and substituting with slow, moist, lower-heat methods including boiling, poaching, steaming, and stewing.74 Or, if cooking with heat, preferentially use water to steam, and as a second tier to use an oil with a higher smoke point such as olive oil or avocado oil. Oil use over butter led to 50% to 75% less AGE formation.69 The second way is to reduce or avoid foods high in AGEs, such as full-fat cheeses, whole milk, meats, and highly processed foods (eg, crackers, French fries, potato chips).


An Alkaline Dietary Pattern

A cornerstone concept recognized in naturopathic medicine and discussion on Paleolithic dietary principles is that of an alkaline versus an acidic diet.75 More specifically, diet-induced “low-grade” metabolic acidosis translates to the imbalance between foods in the diet due to their differing electrolyte content. Potassium alkali salts found primarily in vegetables and fruits would be desirable and essentially reduce the dietary net acid load, whereas eating foods that are low in essential minerals and rich in either amino “acids” and/or fatty “acids” such as animal products would lead to increased acid (low alkaline) load.76,77 The general basis for this concept in nutritional medicine seems to have come, in part, from exploration into the Paleolithic diet by Loren Cordain78 and others,76 as it would have featured high-fiber, wild-cultivated, highly alkalizing plant foods and less of the more “acidic” foods that came into being with the agricultural revolution such as cereal grains, dairy products, and meats.

Although it may be difficult to discern if the therapeutic benefit of eating more “alkaline” is simply because of eating more fruits and vegetables, a large, prospective, population study with 22,034 men and women aged 39 to 78 years did find that urinary pH shifted to more alkaline with a diet higher in fruits and vegetables.79 With respect to cardiovascular markers, Murkami et al.80 demonstrated that higher dietary acid load was associated with CVD risk factors such as blood pressure, total and LDL-cholesterol, and body composition metrics, including BMI and waist circumference. Furthermore, lowering risk of hypertension has been noted in some studies utilizing dietary acid load, although results are not consistent.81,82 There is also an indication that diet-induced acidosis may perturb insulin sensitivity and, ultimately, CVD risk.83

Quite simply, although the science for such positioning is not as compelling, the outcome or therapeutic approach is in line with what has been discussed previously. It entails an approach that is like that of both the Mediterranean and DASH diets, both of which are high in plant-based, “alkalizing” foods and lower in animal-based, “acidifying” foods.


Macronutrients

As each section for the individual macronutrients (carbohydrate, fats and oils, protein) is discussed, please note that it is often difficult to isolate and attribute a result to a particular macronutrient because of the complex variety of compounds that foods contain.84 As is well recognized, food components may interact in unacknowledged ways or means that cannot be accounted for; therefore, please keep this point in mind as each category is detailed as they each relate to the trending studies on cardiometabolic parameters. Furthermore, unlike it is portrayed in nutrition media at large, there does not seem to be a single culprit or offender in the development of chronic disease. Much depends on the larger context of food, including quantity, quality, and variety.


Dietary Carbohydrates

Because of its implication in blood glucose balance, dietary carbohydrate is often seen as a significant macronutrient for type 2 diabetes, whereas dietary fat is typically associated with
CVD. However, dietary carbohydrate quality and quantity are essential for both type 2 diabetes and CVD. In some nutrition-oriented protocols, there is discussion that a patient should have no carbohydrate whatsoever. Yet, there are many forms of carbohydrate that need to be acknowledged and assessed as there is sufficient evidence that whole-food sources of plant-based carbohydrates, including fruits, legumes, vegetables, and whole grains, may not only be suitable for those with type 2 diabetes and/or CVD but also actually be therapeutic and serve as part of a treatment protocol. Hence, there is no need to vilify the entire class of carbohydrates when instructing a patient.

The role of carbohydrate quantity has been evaluated in several studies, one of which was a meta-analysis by Hu et al.85 who surveyed the impact of either a low-carbohydrate or low-fat diet on cardiometabolic parameters in 2788 participants from 23 trials. Low-carbohydrate diets were better at lowering total cholesterol, LDL-cholesterol, and triglycerides, and, at the same time, improving HDL-cholesterol, compared with the low-fat diets. These findings are not always consistent, however, as Nordmann et al.86 did a meta-analysis with five trials consisting of 447 overweight individuals and found that the low-fat diet led to better reductions in total cholesterol and LDL-cholesterol (but not triglycerides or HDL-cholesterol). Another meta-analysis published by Santos et al.87 found similar mixed results with the low-carbohydrate diet lowering systolic and diastolic blood pressure, plasma triglycerides, and raising HDL-cholesterol, but there was no significant change in the primary CVD marker of LDL-cholesterol. In a review by Jung and Choi,88 high-carbohydrate diets were found to be comparable with low-carbohydrate diets on metabolic parameters in patients with type 2 diabetes. Indeed, as explained previously, the discrepancies within these studies may be due to the quality of carbohydrate that was consumed, the glycemic index, glycemic load, and even the phytochemicals the food contains.


GLYCEMIC INDEX AND GLYCEMIC LOAD

One of the most popularized concepts within carbohydrates is that of the glycemic index. Glycemic index (GI) refers to the ability of a standardized amount of carbohydrate to alter blood glucose levels, whereas glycemic load (GL) takes the GI into account with the total amount of food consumed. Foods that are high in GI/GL are thought to lead to greater glucose levels in the blood and, consequently, a greater need for insulin, which is undesirable over decades of chronic consumption. A review of 73 scientific articles published between 2006 and 2018 on glycemic index, glycemic load, diabetes, CVD, body weight, satiety, and obesity resulted in the finding that there is an equivocal relationship between GI/GL and disease outcome.89 Although this is an important concept to consider, it may be that there are several variables that can determine an individual’s glycemic response at each feeding.90 GI/GL may not be as predetermined as originally thought, based on newer research involving the microbiome.

Although there may be other factors to consider, there are, however, studies that would suggest increased risk of CVD with higher GI/GL. One of the more significant and recent studies was a meta-analysis by Ma et al.,91 in which 14 studies with a total of 229,213 participants were analyzed. They reported that women were more at risk than men. Similar to what was identified by Ma et al.,91 Dong et al.92 assessed eight prospective studies with the sum of 220,050 subjects and found not only that dietary GI and GL were responsible for an increased risk for CHD but that women had a greater risk of 69%.

Although there could be several mechanisms as to why GI and GL could potentially be associated with cardiometabolic indications, one of the proposed routes is through inflammation. A low-GI diet has been shown to favorably reduce CRP.93,94 The FUNGENUT study reported that two types of carbohydrate-containing meals both equal in caloric load had varying effects in individuals with metabolic syndrome. The rye pasta (low GI) group had lesser upregulation of genes related to inflammation, stress, and immunity after 12 weeks compared with the group eating the high-GI oat-wheat-potato meal.95 This breakthrough study indicates the impact of glycemic index and specific carbohydrate types on gene expression within 12 weeks of consumption.


FIBER

Fiber is one of the constituents of carbohydrate-containing foods that can help in reducing the release of dietary glucose into the systemic circulation, thereby beneficially altering the GI of a food or meal. It may explain, to some extent, why high-carbohydrate diets may be beneficial in some studies investigating cardiometabolic health as discussed earlier. High-fiber foods tend to be plant based and include fruits, legumes, vegetables, and whole grains, all of which, as discussed, have favorable effects on cardiometabolic health, such as reducing body weight, blood lipids, blood glucose, blood pressure, and inflammatory cytokines.96,97,98

There have been studies that have attempted to distinguish the effects of different fiber types on cardiometabolic risk. In general, there is a preponderance of studies that suggest that there is an inverse association between dietary fiber intake and CVD risk, especially for cereal fiber, which outperforms fruit or vegetable fiber.96 Soluble fiber, from sources such as fruits, vegetables, whole grains, guar gum, konjac, pectin, and psyllium, most likely owing to its adsorbent characteristics, is therapeutic for cardiometabolic outcomes, such as lowering systolic and diastolic blood pressure.99 Yet, there are some indications that high-fiber foods may be beneficial not just for their fiber content but also for some of the other constituents, such as the phytochemicals, caffeic acid, p-coumaric acid and ferulic acid, and secoisolariciresinol diglucoside.100,101,102

Recommendations for fiber intake are 14 g per 1000 kcal consumed as per the Dietary Guidelines for Americans 2015-2020, equating to roughly 28 and 35 g for women and men, respectively.103



SWEETENERS

There is consistent alignment among the breadth of nutrition research findings that daily high intake of added sugars, such as sucrose, fructose, high-fructose corn syrup, and the overwhelming intake of high-calorie, nonnutritious sugar-sweetened beverages are detrimental to cardiometabolic health.104 Added sugar intake displaces nutrient-dense foods and increases the risk chronic diseases such as diabetes and CVD through multiple mechanisms, including metabolic dysfunction, obesity, immune dysregulation, dyslipidemia, inflammation, and oxidative stress.105,106 As a result, opinion-leading organizations6 such as the American Heart Association have suggested reductions in added sugar intake.107

Dietary fructose is controversial. When it is included in fruit sources, it does not seem to have the same consequences as when it is part of high-fructose corn syrup (HFCS), most likely because of the beneficial additional components in fruit and the absence of healthy compounds in processed foods containing HFCS.108 The amount ingested may also need to be considered, as there appears to be a threshold at which fructose (according to the meta-analysis by Livesey and Taylor,109 ≤90 g daily for acceptable levels of hemoglobin A1C; <50 g daily for fasting triglycerides; ≤100 g daily for body weight) may lose its effectiveness and, instead, be implicated in metabolic derangement.109,110 Mechanistically, excessive dietary fructose can be concerning for cardiometabolic risk because of its ability to increase triglycerides and uric acid.105 This is a case where investigating a patient’s single nucleotide polymorphisms to determine their propensity to metabolize fructose might be warranted (eg, as in cases of hereditary fructose intolerance).111

When it comes to HFCS, sugar-sweetened beverages (SSBs) are thought to be implicated in metabolic health. Indeed, there are studies that indicate a relationship between SSBs and hypertension.112,113,114 Participants in the Framingham Heart Study cohort114 who drank one or more SSBs daily had a higher incidence of hypertension, hypertriglyceridemia, and low HDL-cholesterol. Specific patient populations might be more at risk as high intakes of sugars (fructose, glucose, sucrose) are associated with more pronounced effects in men than in women, those who eat a low-fiber diet, and those who are sedentary, are overweight, or already have metabolic syndrome.115,116,117,118

Regarding artificial or nonnutritive sweeteners, there are limited data to suggest that they may cause metabolic dysfunction, possibly through nutrient signaling119 and/or via changes they may create in the gastrointestinal tract, particularly through the gut microbiome.120 Overall, it would seem prudent to avoid artificial sweeteners entirely because of their negative effects on the microbiome, decreased satiety signals, alterations in glucose homeostasis, and overall increase in calorie intake and weight gain.121


Dietary Fats and Oils

Among the three classes of macronutrients, dietary fats and oils have been most scrutinized for their implication in CVD risk and, to some degree, cardiometabolic dysfunction. The same principle mentioned in the section on carbohydrates would apply here: that the universal guideline of quality and quantity needs to be considered. As Harvard epidemiologist Walter Willett122 suggested, the amount of total fat in the diet is likely not as important as the diet itself. Along similar lines, there is complexity within the different fatty acids, including a variety of carbon chain lengths, single or double bonds, and configuration (cis- and trans-).

For the most part, dietary fat provides a substantial source of energy (9 kcal/g), and fatty acids comprise the bilayer membrane of the cell, which implies that they can be responsible for the activity of receptor sites and cell signaling cascades that could ultimately lead to inflammation, insulin resistance, and stress response intracellularly.123


POLYUNSATURATED FATS: THE ESSENTIAL OMEGA-3 AND OMEGA-6 FATTY ACIDS

Polyunsaturated fatty acids (PUFAs) have two or more carbon-carbon double bonds and are often found in liquid fats and oils. Overall, diets containing PUFAs translate to CVD risk reduction124: a 5% increase in caloric energy has resulted in a 10% CVD risk reduction.125 Substituting saturated fat with PUFAs has been shown to lead to favorable effects compared with monounsaturated fats and carbohydrate.122 Specifically, when replacing dietary saturated fat with PUFAs, compensatory decreases in total, LDL-, and HDL-cholesterol have been documented.126,127

Within this category of PUFAs, there are two main fatty acid families to consider as it relates to inflammatory-induced chronic diseases such as diabetes and CVD: omega-6 and omega-3 fatty acids. Omega-6 fats tend to be found in nuts, seeds, whole grains, and vegetable oils, whereas fish, seafood, nuts, seeds, and leafy vegetables are good sources of omega-3 fatty acids.

Essential fatty acids are specific fatty acids that are not made endogenously and, therefore, must be taken in the diet for system-wide regulation of cell membrane fluidity, cell receptors, and processes such as inflammation via prostaglandin synthesis. An imbalance in the ratio of the essential omega-6 to the omega-3 fatty acids is one of the underlying mechanisms associated with dysregulation of inflammation, the foundation of both CVD and diabetes.128 A patient’s essential fatty acid status can readily be determined from a simple dried blood spot test or from a blood sample. Established percentages are defined for each fatty acid measured, often 64 total; however, only a select few of them are in the essential fatty acid category. Research by William Harris129 has demonstrated that levels of omega-3 fatty acids (specifically the sum of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) at 8% of the total amount are consistent with lower rates of CVD. Levels below 4% are associated with increased CVD.

Larsson et al.130 studied 34,670 Swedish women over a mean of 10.4 years in a prospective study and reported an inverse relationship between dietary omega-3 PUFA intake and risk of stroke. Furthermore, a more recent and larger analysis131 of omega-3 intake (18 randomized controlled
trials [RCTs] with a cumulative 93,000 subjects in addition to 16 prospective cohort studies comprising 732,000 participants) from foods or supplements revealed a nonstatistically significant 6% reduction in CHD risk with EPA and DHA. However, subgroup analyses of high-risk populations such as in those with elevated triglycerides and LDL-cholesterol had a statistically significant CHD risk reduction (14%-16%).

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Feb 27, 2020 | Posted by in CARDIOLOGY | Comments Off on The Role of Food Patterns, Nutrition, and (Phyto)Nutrients in Cardiovascular Disease: The Clinical Trials, Their Implications, and Clinical Application for the Prevention and Treatment of Cardiovascular Disease, Coronary Heart Disease, Stroke, Hypertension, Dyslipidemia, and Diabetes Mellitus

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