Atherosclerosis and Cardiovascular Disease

Atherosclerosis and Cardiovascular Disease

1 Overview

Summary and Quick Facts

  • Atherosclerosis can occur anywhere in the body, but it is particularly dangerous when it affects the arteries that supply oxygenated blood to the heart muscle. This is called coronary artery disease (CAD), and is the most common type of heart disease, affecting 16.5 million Americans.
  • Scientific studies have revealed that several nutrients effectively protect against endothelial dysfunction caused by atherogenic factors. Unlike mainstream medicine’s approach to treating atherosclerosis, which involves addressing only very few proven cardiac risk factors, a comprehensive nutritional regimen can be designed to target all of the risk factors that contribute to atherosclerosis.
  • Comprehensive blood testing helps aging individuals identify and target their specific risk factors, allowing for the development of a personalized, targeted treatment regimen that can be used to preserve and improve cardiovascular health.

What is Atherosclerosis?

Atherosclerosis is the narrowing and hardening of arteries due to the accumulation of plaque. If left unchecked, atherosclerosis can lead to cardiovascular disease, the deadliest disease in the United States. Unfortunately, many people simply focus on reducing a few of the risk factors, such as cholesterol and high blood pressure, yet ignore a host of other risk factors.

The underlying cause for all cardiovascular disease is endothelial dysfunction. Endothelial cells line the inside of arteries, and over time they are exposed to atherogenic factors and become damaged. When the endothelial cells cannot function properly, plaque builds up and calcifies, narrowing the artery.

Natural interventions such as quercetin and omega-3 fatty acids can help protect endothelial function and fight cardiovascular disease.

What are Risk Factors for Atherosclerosis and Cardiovascular Disease?

  • Elevated LDL cholesterol and low HDL cholesterol
  • Elevated triglycerides
  • Hypertension
  • Elevated glucose and insulin levels
  • Insufficient vitamins D and K
  • Hormonal imbalances
  • Smoking
  • Obesity, and others

What are the Signs and Symptoms of Atherosclerosis?

Atherosclerosis is generally asymptomatic until very late stages. It is therefore critical for all aging individuals to take preventative measures and visit a doctor regularly.

What are the Conventional Medical Treatments for Atherosclerosis?

  • Cholesterol-lowering drugs
  • Blood pressure-lowering drugs
  • Angioplasty and stents
  • Surgery (coronary artery bypass), and others

What Dietary and Lifestyle Changes Can Benefit Atherosclerosis?

  • Consider low-dose aspirin therapy
  • Eating a balanced diet rich in fruits and vegetable (Mediterranean style diets can be beneficial)
  • Exercise regularly
  • Quit smoking
  • Limit alcohol intake

What Natural Interventions Can Benefit Atherosclerosis?

  • Omega-3 fatty acids. Omega-3 fatty acids help to prevent the development and progression of cardiovascular disease through multiple mechanisms including lowering triglycerides, lowering blood pressure, improving endothelial function, and raising HDL levels.
  • L-arginine. This amino acid is a precursor of nitric oxide, a vasodilator. Treatment with L-arginine improved brachial artery dilation, a measure of endothelial function, in patients with coronary artery disease.
  • Coenzyme Q10 (CoQ10). CoQ10 is involved in the production of ATP, the energy currency in the human body. Treatment with CoQ10 improved vascular endothelial function in patients with atherosclerosis or significant risk factors for atherosclerosis.
  • Lipoic acid. Lipoic acid is an antioxidant that serves as a coenzyme in energy metabolism of fats, carbohydrates, and proteins. It improved endothelial function in patients with metabolic syndrome.
  • Quercetin. Quercetin is a polyphenol with antioxidant and anti-inflammatory properties. Quercetin supplementation has been linked to improved measurements of inflammation in patients with high blood pressure.
  • Niacin. Niacin can improve cholesterol profile and endothelial function. Heart attack survivors who took niacin supplements had reduced recurrence of heart attacks and incidence of stroke.
  • Lactobacillus reuteri 30242. This probiotic strain, and other Lactobacillus strains, have been shown to support cardiovascular health.
  • Other natural interventions that can aid in preventing atherosclerosis and cardiovascular disease include propionyl L-carnitine, garlic, ginkgo biloba, resveratrol, vitamins C, K, and E, hesperidin, and others.

2 Introduction

Atherosclerosis is a long-term disease process in which arteries narrow and stiffen due to the accumulation of plaque.1,2 This plaque, made up of cholesterol, cellular waste products, blood clotting materials, and fatty substances, builds up in the lining of the arteries and restricts blood flow.1 As atherosclerosis progresses, these plaques may rupture or break apart, which can cause a blood clot. This can lead to serious complications such as a heart attack or stroke.2

Atherosclerosis can occur anywhere in the body, but it is particularly dangerous when it affects the arteries that supply oxygenated blood to the heart muscle. This is called coronary artery disease (CAD), and is the most common type of heart disease, affecting 16.5 million Americans.3 About 20% of American men and 13% of women aged 60 to 79 years have CAD, and the prevalence increases with age: 31% of men and 25% of women over age 79 have CAD.4,5 However, atherosclerosis is not confined to older people; the atherosclerotic process can begin as early as adolescence.2,6

Many factors contribute to the development of atherosclerosis, some of which are modifiable. Lifestyle factors that can increase the risk of atherosclerosis include being overweight, poor diet and lack of physical activity, smoking, and excessive alcohol consumption. Factors that can damage the delicate lining of the arteries (called the endothelium) and contribute to atherosclerosis include elevated blood pressure, high cholesterol and/or triglycerides, diabetes and insulin resistance, and inflammation.1 Non-traditional risk factors that strongly correlate with atherosclerosis include blood levels of homocysteine and C-reactive protein (hs-CRP).7-10 Tracking both traditional and non-traditional risk factors through periodic blood testing can help you monitor your overall vascular health and plan your diet, lifestyle, and nutrient supplementation regimen accordingly.

In this protocol, you will learn how atherosclerosis develops and contributes to potentially deadly cardiovascular events. You will also learn how you can use blood testing and other strategies to assess your cardiovascular risk. This protocol will also help you understand the different medical options available to treat vascular disease, and how dietary and lifestyle changes, along with targeted nutritional supplementation, can help support overall cardiovascular health.

Because cardiovascular health is influenced by a variety of factors, readers should also review Life Extension’s protocols on Cholesterol Management, High Blood Pressure, Homocysteine Reduction, Stroke , Blood Clot Prevention, Weight Loss, and Diabetes and Glucose Control.

3 How Atherosclerosis Develops

Atherosclerosis develops over many years. During the course of the disease, several changes occur in the arteries, culminating in arterial plaques that may rupture and cause major cardiovascular events such as heart attack or stroke.11

Endothelial cells are critical to the health and function of blood vessels. They line the inside of vessels and help facilitate healthy blood flow. In atherosclerosis, injury causes the endothelial cells to become dysfunctional and produce proteins that attract circulating immune cells called monocytes. The monocytes enter the blood vessel lining and transform into macrophages. Macrophages are specialized cells whose role is to engulf and destroy infectious agents, cancer cells, or other unhealthy substances. The macrophages become so-called “foam cells” by absorbing excess fatty deposits on the blood vessel walls, including low-density lipoproteins (commonly known as LDL). As macrophages become filled with lipids, they develop a foamy appearance.12,13

Foam cells can also derive from vascular smooth muscle cells, which exist in normal blood vessels just below the endothelium (the lining of the blood vessels) and are responsible for contraction and relaxation of blood vessels. They can change their cell type to become more like macrophages and, ultimately, foam cells.14

The accumulation of foam cells, along with the proliferation of smooth muscle cells and excess connective tissue, are key drivers of atherosclerosis. Fortunately, the accumulation of foam cells is a reversible process, and a reduction of foam cells is associated with an improvement in the size of atherosclerotic plaque.15

Phases of Atherosclerotic Plaque Development

The formation of atherosclerotic plaque begins with injury to the blood vessel lining, or endothelium. Many conditions can lead to endothelial injury.16 For example, elevated levels of certain blood lipids, such as oxidized low density lipoproteins (ox-LDL), can damage endothelial cells, as can high blood pressure and pro-inflammatory biochemicals.

Intimal thickening. During intimal thickening, the inner layers of blood vessels (ie, the intima) thicken. Intimal thickening, which is the earliest vascular change in atherosclerosis, can be seen with a microscope. It mainly consists of the accumulation of smooth muscle cells and extracellular matrix (non-cell components of body tissue).17

Fatty streak formation. Fatty streaks are so named because they can be seen by the naked eye at autopsy as irregular, yellowish streaks on the inside of blood vessels. Fatty streaks are considered an early sign of atherosclerosis and may be observed as early as childhood. They have even been detected in human fetal aortas and are increased in number and size if the mother has high cholesterol.18 Fatty streaks can progress to full-developed atherosclerosis or may sometimes regress with healthy dietary and lifestyle changes.19

Fibro-calcific plaque formation. Atherosclerosis that progresses beyond the fatty streak phase is characterized by fibrous plaques, which are growths that can restrict blood flow. They are composed of a thick (fibrous) cap that encapsulates cellular debris.20 The collection of cellular debris within the fibrous plaque is referred to as the necrotic core.

Atherosclerotic plaques can also become depots for abnormal calcium accumulation.20 In advanced atherosclerosis, plaques begin to calcify via both active and passive processes. In fact, some of the processes by which calcium accumulates in arterial plaques resemble those involved in bone formation. Degree of vascular calcification correlates with the risk of major adverse cardiovascular events.21-25

Vulnerable plaque. Atherosclerotic plaques are considered vulnerable when they are prone to rupture. Plaque rupture is the most common cause of heart attacks, near heart attacks (unstable angina), and sudden death. These outcomes occur when a coronary artery is suddenly blocked and therefore cannot supply enough blood to the heart muscle. The underlying mechanism is the formation of a blood clot within the blood vessel, known as thrombosis. Thrombosis mostly occurs in association with plaque rupture; less often, blood clots form around plaque erosions or calcified nodules.17 Plaques that rupture can cause blood clots that block blood flow or break off and travel to another part of the body, known as an embolism. If a blood clot blocks a vessel to the heart, it causes a heart attack. If a blood clot blocks a vessel that goes to the brain, it causes a stroke.26

Certain conditions are associated with softening of the cap’s strength, making it more likely that the cap will burst. These conditions include increased shear stress (due to high blood pressure), calcium and iron deposition, and an increase in macrophage-derived enzymes called matrix metalloproteinases, which lead to the breakdown of the extracellular matrix.17 Hemorrhage (bleeding) within the core may also make a fibrous plaque more vulnerable. Over time, a fibrous plaque’s core may be subject to small hemorrhages. These hemorrhages are more commonly observed at autopsy in ruptured plaques than intact plaques.17

Please see Life Extension’s protocol on Blood Clot Prevention for more information.

4 Atherosclerosis: Signs, Symptoms, and Diagnosis

Atherosclerosis rarely causes signs or symptoms until there is severe artery blockage. Many people are unaware that they have the disease until they suffer from a cardiac event such as stroke or heart attack. When plaque develops in a coronary artery (the arteries that supply oxygenated blood to the heart), angina (chest pain), shortness of breath, and irregular heartbeat may occur. Plaque in smaller coronary arteries may also cause sleep problems and fatigue.27

When plaque develops in the carotid arteries, which are the arteries that supply oxygenated blood to the brain, stroke symptoms may develop, including weakness, confusion, problems breathing or moving, dizziness, and headaches. Atherosclerosis in the peripheral arteries (which supply blood to the legs, arms, and pelvis) may cause numbness and pain, and in the renal (kidney) arteries, it may cause chronic kidney disease and decreased kidney function.27

Diagnosis occurs after a physical exam, where the doctor may check your pulse and listen to your arterial function. Other diagnostic tests include:

  • blood tests for lipids and inflammatory markers;
  • a chest X-ray to visualize heart failure;
  • an electrocardiogram to detect the heart’s electrical activity;
  • an echocardiogram to determine the size and shape of the heart and identify poor blood flow or irregular muscle contractions in the heart;
  • computed topography (CT) scanning to display hardened or narrow arteries in the heart;
  • stress test to show abnormal changes in heart rate or blood pressure during exercise, and provide imaging of blood flow in the heart;
  • angiography, magnetic resonance imaging (MRI), and positron emission tomography (PET) to help visualize arterial plaque.27

5 Atherosclerosis Risk Factors

The development of atherosclerosis is a complex process, and it has many risk factors. This section highlights several of the key risk factors known to contribute to the development of atherosclerosis and increase risk of cardiovascular disease. In addition, this section discusses numerous biomarkers that correlate to varying degrees with atherosclerotic burden and/or risk of cardiovascular events.28 Many of these risk biomarkers can be measured and tracked through periodic blood testing to help monitor disease risk. Some of these biomarkers can be normalized or at least improved in most cases with dietary and lifestyle changes, medications, and/or nutritional supplements.

For a greater understanding of the factors that influence cardiovascular health, refer to Life Extension’s protocols on Cholesterol Management, High Blood Pressure, Homocysteine Reduction, Stroke, Thrombosis Prevention, and Diabetes and Glucose Control. For more information about cardiovascular risk biomarkers, please see the Life Extension Magazine article titled How to Circumvent 17 Independent Heart Attack Risk Factors.

Obesity

Obesity is a chronic disease characterized by the accumulation of visceral and subcutaneous fat. It is associated with an increased risk of several diseases, including cardiovascular and metabolic conditions. Excess body fat (especially abdominal fat ) is linked to atherosclerosis by a number of mechanisms.29 For instance, fat cells produce leptin, high levels of which can contribute to endothelial dysfunction, increased inflammation, high blood pressure, and thrombosis.30 Fat cells also produce reactive oxygen species (ROS) and contribute to oxidative stress, which is in turn linked to obesity and insulin resistance.31

When abdominal obesity is present alongside high blood sugar, low HDL, high triglycerides, and high blood pressure, it creates a condition called metabolic syndrome.32 Whether metabolic syndrome imparts more risk of atherosclerosis than the sum of its parts is unclear, but metabolic syndrome is associated with increased mortality risk, both from cardiovascular disease and all causes.33,34

Poor Diet

Research has long linked diet with the progression of atherosclerosis.35 Excess calories, fat, sugar, and cholesterol all play a role in cardiovascular disease promotion. A diet high in saturated fat and cholesterol may raise cholesterol levels, which may increase the amount of plaque in the arteries. Epidemiological research suggests that consuming fruits and vegetables may reduce the risk of atherosclerosis and coronary artery disease.36

The American Heart Association recommends a diet that includes a variety of fruits and vegetables, whole grains, low-fat dairy, lean poultry and fish, nuts and legumes, and non-tropical vegetable oils, such as canola, olive, and corn oil. In addition, saturated fats, trans fats, sodium, sugar, and red meats should be limited.37

Please see the “Adopt a Healthy Diet” section later in this protocol for more information.

Lack of Physical Activity

The link between physical activity and cardiovascular health was first established in the early 1950s, and research has since consistently found that high levels of physical activity are associated with reduced risk of CHD morbidity and mortality.38 Research suggests that in both men and women, there is an inverse relationship between physical activity and cardiovascular disease, and this relationship persists after control for other risk factors.39 One older study involving nearly 17,000 men found that those who maintained a moderately vigorous exercise habit had a 28% reduction in mortality from all causes over a 16-year follow-up period compared with sedentary men.39 Maintaining or increasing physical activity level in late middle age was associated with a reduction in mortality rates, and light activities appeared to be sufficient to produce this benefit in older men.40 Among people with established cardiovascular disease, mortality is lower among those who participate in an exercise program than among those who do not.41

Regular exercise combats atherosclerosis by reducing the amount of fat circulating in the blood, lowering blood pressure and cholesterol levels, and helping maintain a healthy weight.42 See the “Be Active” section for more information.

Cigarette Smoking

Tobacco use is a major modifiable risk factor for many diseases, including cardiovascular diseases such as coronary artery disease, stroke, vascular disease, and congestive heart failure. Smoking cigarettes is known to damage the heart and blood vessels as well as elevate cholesterol and blood pressure levels. It also prevents oxygen from adequately reaching all of the body’s organs and tissues.27 Smokers have elevated levels of ROS, cell adhesion molecules, and pro-inflammatory biochemicals. Smokers also have excess intimal thickening of the carotid artery, even when the results are statistically controlled to eliminate other atherosclerosis risk factors.43

For more information, see the section titled “Avoid Tobacco Use and Second-hand Exposure.”

Age and Family History

Aging is the dominant risk factor for clinically significant atherosclerotic lesion formation.44 Risk increases after age 45 in men and 55 in women. Plaque buildup that has been occurring for many years as a result of genetic factors, poor diet, and lack of physical activity may begin to cause health problems during middle-age.27

Family history is also an important risk factor for atherosclerosis, as an individual’s risk increases if their father or brother was diagnosed with heart disease before age 55 or if their mother or sister was diagnosed before age 65.27 A prospective trial with over 5,000 subjects found that a family history of premature coronary heart disease is associated with the progression of coronary artery calcification. The greatest risk was with a combined parent and sibling history.45

Elevated Blood Lipids (Cholesterol and Triglycerides)

Cholesterol is a wax-like steroid molecule that plays a critical role in metabolism. It is a major component of cellular membranes and serves as a precursor to a variety of steroid hormones in the body. Cholesterol is also the precursor to vitamin D and provides the framework for the synthesis of bile acids, which emulsify dietary fats for absorption.46

Low-density lipoproteins (LDLs) carry cholesterol from the liver to cells that require it. In aging people, LDL often transports cholesterol to the linings of their arteries, where it may not be needed. Because of the correlation between elevated blood levels of cholesterol carried in LDL and the risk of heart disease, LDL is commonly referred to as “ bad cholesterol.” Ox-LDL is a particularly damaging form of LDL that can infiltrate and damage arterial walls and lead to the development of lesions and arterial plaques.13,47 Another process, called glycation, can also modify LDL particles and make them more atherogenic. LDL glycation occurs when a sugar molecule modifies the LDL structure. LDL glycation can play a direct role in the development of atherosclerosis and may also make the LDL more prone to oxidation.48

High-density lipoproteins (HDLs) transport excess cholesterol back to the liver, where it can be re-processed and/or excreted from the body. HDL can remove excess cholesterol from the arterial wall.46,49

Triglycerides also play a role in atherosclerosis. High triglycerides can decrease HDL levels and increase oxidative stress and the production of pro-inflammatory biochemicals. High triglycerides can also lead to the production of small, dense LDL, a subtype of LDL that is more atherogenic than larger, more buoyant LDL. In addition, high triglycerides can increase blood clot risk by increasing production of certain clotting factors.13 Research indicates that elevated non-fasting triglyceride levels (blood draws completed two to eight hours after a meal), even more so than fasting triglyceride levels (blood draws done 12 hours after eating), may be associated with increased risk of heart attack and stroke.50

Maintaining healthy cholesterol and triglyceride levels is a key factor in cardiovascular risk reduction. Lowering serum cholesterol to a healthful range—total cholesterol about 160–180 mg/dL and LDL cholesterol ideally under 80 mg/dL—is an important strategy for managing heart disease risk.46 For young adults (age 20‒39), a 2018 expert panel recommended cholesterol-lowering therapy for those with LDL cholesterol over 160 mg/dL and a history of early-onset atherosclerosis in a close family member. For older adults, cholesterol-lowering therapy should be considered if one has diabetes, an LDL concentration ≥ 190 mg/dL, or increased risk as determined by a risk algorithm.51

Life Extension recommends a fasting blood triglyceride level under 80 mg/dL for anyone with any cardiovascular risk factors and under 60 mg/dL for people with a history of cardiovascular disease. The optimal target for non-fasting triglycerides is under 116 mg/dL. While triglyceride levels can be lowered with prescription medications, nutrient options include fish oil, niacin, green tea, and soy protein supplementation.52-56 Weight loss, caloric reduction, a diet rich in fruits and vegetables, and physical activity also promote cardiovascular health.

Please see Life Extension’s protocol on Cholesterol Management for more information.

High Blood Pressure

Blood pressure is the measurement of systolic pressure (maximum pressure during one heartbeat) over diastolic pressure (minimum pressure between heartbeats). Healthy blood pressure is less than 120/80 mm Hg, and Life Extension recommends an optimal target of 115/75 mm Hg. High blood pressure is an established risk factor for overall cardiovascular disease, and atherosclerosis in particular. Observational evidence suggests the risk of cardiovascular disease doubles for each increment of 20 mm Hg systolic and 10 mm Hg diastolic above 115/75 mm Hg.57

A large, randomized, controlled trial with over 9,300 subjects showed that non-diabetics at increased cardiovascular risk can substantially reduce their risk of cardiovascular events and death by lowering their blood pressure.58,59 One group of trial participants was intensively treated with blood-pressure-lowering medications to a target systolic blood pressure of less than 120 mm Hg. The other group received medications with a treatment goal of achieving systolic blood pressure of less than 140 mm Hg. The intensively treated subjects took, on average, one additional blood pressure medication compared with the standard treatment group. The trial was scheduled to last for five years, but was stopped after a median of only 3.3 years of follow-up because subjects who underwent more intensive blood pressure lowering had a dramatic 25% risk reduction for a composite of cardiovascular outcomes and a 27% lower risk of death from any cause compared with the standard-treatment group.59

Note: Blood pressure treatment goals may need to be adjusted based on baseline risk and health status (eg, diabetes status). See “Managing Blood Pressure” later in this protocol for a discussion of treatment goals in people with established cardiovascular disease or otherwise at high risk.

Antihypertensive medications may be prescribed to lower blood pressure levels, but nutrients such as garlic, coenzyme Q10 (CoQ10), fish oil, and vitamin C may also be used.60-63 In addition, modifying lifestyle factors such as adopting the Dietary Approaches to Stop Hypertension (DASH) diet, which includes a variety of fruits and vegetables and restricted salt intake, exercising, and quitting smoking also support healthy blood pressure levels.

More information, including summaries of several additional nutritional interventions to support healthy blood pressure, is available in Life Extension’s High Blood Pressure protocol.

High Blood Sugar, Insulin Resistance, and Diabetes

Research suggests fasting glucose levels over 85 mg/dL incrementally increase heart attack risk.64 Diabetes is a strong risk factor for atherosclerosis, and is associated with an accelerated form of the disease. Hyperglycemia (elevated blood sugar) activates inflammatory pathways in the body, increases the production of cell adhesion molecules, and reduces the production of nitric oxide, a naturally occurring biochemical that lowers blood pressure and increases blood flow.65

Insulin, a hormone that regulates blood sugar levels, allows the body to use or store glucose from food. Excess insulin in the blood (due to aging, genetics, poor diet, and/or physical inactivity) reduces the ability of cells to absorb and utilize glucose. When muscle, fat, and liver cells do not respond to insulin, the pancreas makes more, which further contributes to insulin resistance.66 Excess insulin is associated with an increased risk of heart attack, stroke, and cancer.67 Life Extension recommends target blood levels of fasting insulin under 5 µIU/mL.

Glucose control and insulin signaling can be improved through the use of pharmaceuticals such as metformin, increasing soluble fiber in the diet, supplements such as chromium, cinnamon, and L-carnitine, and adhering to healthy eating plans such as the Mediterranean diet.68-72

Please see Life Extension’s protocol on Diabetes and Glucose Control for more information

Periodontitis (Gum Disease)

Inflammatory gum disease is an established risk factor for atherosclerosis.73 Periodontitis allows bacteria into the bloodstream, resulting in an inflammatory response that contributes to atherosclerosis. Treatment of periodontitis has been shown to improve markers associated with cardiovascular health, such as hs-CRP blood levels and endothelial function.74

More information is available in Life Extension’s Oral Health protocol.

Other Health Conditions

Diseases that involve chronic inflammation can also increase risk of atherosclerosis and cardiovascular disease.75 Autoimmune inflammatory diseases like rheumatoid arthritis and systemic lupus erythematosus are associated with an increased risk of death from cardiovascular disease. The link between autoimmune diseases and cardiovascular disease is partly intuitive: inflammatory biochemicals that can promote inflammation in the blood vessel are elevated in autoimmune diseases. Additionally, HDL cholesterol is less protective in those with certain autoimmune diseases. HDL dysfunction has also been shown to occur in viral and bacterial infections in animal models.75

Unhealthy Microbiota

The collection of microbes (such as bacteria and viruses) that reside in the gastrointestinal tract, referred to as the gut microbiota, is important in overall human health and disease.76 Unhealthy changes in the gut microbiota have been linked to the development of atherosclerosis. Alterations of the gut microbiota can lead to increased permeability of the gut’s barrier to the bloodstream, allowing components such as lipopolysaccharide to enter the blood. Lipopolysaccharide can stimulate an inflammatory response that promotes atherosclerosis.77 An unhealthy microbiota itself can also produce deleterious metabolites that can trigger or worsen atherosclerosis. Research continues to evaluate whether and how manipulating the microbiota could modify cardiovascular risk. However, several studies suggest supplementation with Lactobacillus reuteri 30242 may support cardiovascular health.78-82 For more information, see Life Extension’s protocol on Maintaining a Healthy Microbiome.

Hormones and Cardiovascular Risk

Hormones are chemical messengers that serve critical roles in cellular communication throughout the body and help regulate various aspects of physiology and behavior. Maintaining a healthy balance among hormones, including progesterone, estrogen, dehydroepiandrosterone (DHEA), testosterone, and pregnenolone, is important for overall health.83 Hormone levels naturally decline as we age,83,84 and research suggests declining hormone levels may play a role in cardiovascular disease risk.

Hormonal health and CVD risk among men. Testosterone, the major male sex hormone, plays a role in sperm production, libido, and bone and muscle strength. Testosterone levels are at their highest in adolescence and early adulthood, and then they begin to gradually decline by the age of about 25.85 Low testosterone levels are associated with brittle bones, decreased libido, and irritability and depression.86 Life Extension suggests an optimal target level of free testosterone of 20‒25 pg/mL for most men.

Research suggests that low levels of testosterone are associated with an increase in all-cause mortality and cardiovascular risk, metabolic syndrome, and diabetes.87 Low levels of testosterone in men with coronary artery disease is associated with a poor prognosis.87 Testosterone replacement therapy has been shown to improve ischemia in men with coronary artery disease and improve exercise capacity in men with congestive heart failure.87

A recent meta-analysis examined the relationship between testosterone and cardiovascular risk in men. In all, 108 studies were examined, including randomized trials and epidemiological studies. The authors concluded that testosterone therapy reduced overall morbidity and mortality, particularly in obese patients.88 Another review concluded that low testosterone levels are a cardio-metabolic risk factor.89 A longitudinal follow-up study of 930 men with coronary disease found that testosterone deficiency was common and negatively affected survival.90 Other research in 79 males aged 33‒68 found that free and total serum testosterone levels are lower in men with acute myocardial infarction.91

While testosterone levels are important for a man’s overall health and well-being, other hormones, including DHEA, also play a role. DHEA is a steroid hormone that is metabolized into testosterone and estrogen. However, DHEA has many important functions in its own right. Some studies have suggested that DHEA supplementation supports cognitive function, energy levels, and a healthy body weight. A prospective population-based study in over 2,000 elderly men found that low levels of DHEA were predictive of the five-year risk of coronary heart disease.92 Life Extension suggests an optimal target level of DHEA-sulfate (DHEA-s) of 350‒500 µg/dL for men (and 275‒400 µg/dL for women).

A prominent study published in 2017 raised concerns about testosterone therapy and increased progression of coronary artery non-calcified plaque.93 However, a follow-up analysis published in late 2019 suggested that waist-to-hip ratio may modify the association between testosterone therapy and coronary plaque progression. The 2019 analysis found that as participants’ waist-to-hip ratio increased, so did coronary artery plaque progression among men assigned to testosterone therapy.94 More studies are needed to determine whether testosterone replacement therapy modifies coronary artery plaque progression in otherwise healthy men with a healthy waist-to-hip ratio.

Estrogen, the primary female sex hormone, also modulates sperm production and male libido. Although the role of estrogen in maintaining healthy bone mass in women is well known, men may not realize that estrogen plays an important role in maintaining bone health in males as well.95 Some evidence suggests keeping estrogen levels in a healthy range may benefit men’s cardiovascular health. In a prospective observational study involving 501 men with chronic heart failure, men with the highest and lowest amounts of estradiol had the highest mortality, while those in the middle group (with estradiol levels of 21.80‒30.11 pg/mL) had the fewest deaths. The researchers concluded that balanced estradiol levels are cardioprotective, perhaps due to protective effects of the heart tissue and vascular system.96 In another prospective cohort study of over 2,000 healthy middle-aged men, higher serum estradiol levels were associated with a lower risk of cardiovascular disease in older, but not younger, men.97 Life Extension suggests most aging men target an optimal estradiol blood level of 20‒30 pg/mL. Estradiol levels should be balanced with testosterone levels in men, and a healthy ratio of total testosterone to estradiol may be roughly 23:1 to 40:1.

More information is available in Life Extension’s Male Hormone Restoration protocol.

Hormonal health and CVD risk among women. The main sex hormones that guide female sexual function and reproduction are estrogen and progesterone. Declining hormone levels with menopause have been associated with several health conditions. Although the risks and benefits of hormone replacement therapy have been extensively debated, current evidence suggests initiating hormone replacement therapy near menopause offers cardiovascular benefits and minimal risks.98-100

In a large prospective cohort study of over 4,200 post-menopausal women, hormone replacement therapy was associate with lower all-cause mortality and less coronary atherosclerosis.101 In an open-label, randomized, controlled trial, over 1,000 women aged 45‒58 who were post-menopausal or had peri-menopausal symptoms were randomized to receive hormone replacement therapy or no treatment. After 10 years of intervention, the women receiving hormone therapy had significantly reduced risk of mortality, heart failure, and myocardial infarction, without an increased risk of cancer or stroke.102 Another study involving over 2,800 post-menopausal women found that higher estradiol levels were associated with a lower risk of cardiovascular disease.103

It is important for all aging individuals to monitor their hormone status. Comprehensive testing as well as regular physical examination by a doctor may help detect hormonal imbalances in aging individuals. Natural products including phytosterols may help promote healthy hormonal signaling. Bioidentical hormone replacement therapy, which uses hormones identical to those naturally made in the body, is the preferred method of hormone replacement therapy. Today, several FDA-approved bioidentical hormone replacement preparations are available.

More information is available in Life Extension’s Female Hormone Restoration protocol.

Nitric Oxide Deficit

Nitric oxide (NO) is a compound in the body that plays a role in cell signaling and helps facilitate healthy blood flow by promoting blood vessel relaxation. NO supports healthy arterial walls and allows arteries to maintain their elasticity. Age-related declines in NO may contribute to cardiovascular disease.104-106 Commercial blood tests for measuring NO levels in the body are currently not widely available.

Statin drugs may promote NO synthesis and can be taken at low doses with supplemental CoQ10.107,108 In addition, there are some dietary supplements that may help promote healthy NO levels. Arginine, an amino acid, is a precursor to the production of NO in the endothelium, and pomegranate also supports healthy NO synthesis and endothelial function.109,110

Elevated Homocysteine

Homocysteine is an amino acid present throughout the body. Excess homocysteine levels are implicated in atherosclerosis, through promotion of blood clotting factors and damage to the arterial lining.111 Many factors can contribute to elevated homocysteine levels, including insufficient intake of B vitamins, excess alcohol consumption, certain medications, and genetic variations that lead to inefficient folate metabolism. Life Extension recommends that homocysteine blood levels be kept below 8 µmol/L.

Elevated homocysteine levels can be lowered by medications such as Cerefolin. Natural therapies include supplementation with B vitamins, including methylfolate, vitamin B12, and vitamin B6, as well as trimethylglycine and N-acetylcysteine.112-114 Limiting alcohol consumption and consuming a diet low in meats (including beef, pork, chicken, and turkey) and high in fruits and vegetables and monounsaturated fats may also promote healthy homocysteine levels.

Refer to Life Extension’s Homocysteine Reduction protocol for more information.

Low EPA/DHA

Eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) are omega-3 fatty acids that promote healthy neural development, vision, cognitive function, cardiovascular health, and inflammatory response. The FDA announced in mid-2019 that EPA/DHA supplements can make the qualified health claim that they may reduce the risk of hypertension and coronary heart disease; although the agency described the evidence available at the time as “inconclusive.”115 Research suggests omega-3 fatty acids reduce inflammation and modulate blood clotting and may help prevent peripheral artery disease and major coronary events.116

It has long been noted that higher intakes and blood levels of omega-3 fatty acids (relative to omega-6 fatty acids) are associated with cardiovascular health, including lower rates of heart attack. Evidence suggests an ideal omega-6 to omega-3 ratio is less than 4:1. The best ways to enhance levels of EPA and DHA are through quality fish oil supplements and a diet that includes cold water fish at least twice a week. This includes mackerel, lake trout, sardines, tuna, sea bass, and salmon.116

Low Vitamin D

Vitamin D supports bone health and may help reduce the risk of some forms of cancer. It also promotes cardiovascular health by reducing chronic inflammation and promoting healthy vascular cell function.117,118 Life Extension suggests a target level of vitamin D between 50 and 80 ng/mL of 25-hydroxyvitamin D for most people, and blood levels should determine the necessary supplemental dosage, which is typically between 1,000 and 7,000 IU daily. Vitamin D is also synthesized by the skin in response to sunlight exposure, although excessive sun exposure is a major risk factor for skin cancer.

Inadequate Vitamin K Intake

Vitamin K is a fat-soluble family of vitamin compounds that play a role in blood clotting and bone metabolism. It is naturally found in leafy green vegetables.119 Importantly, adequate vitamin K intake is critical for helping maintain healthy calcium balance in the arteries and bones. In fact, the older anti-coagulant drug warfarin blocks the activity of vitamin K and is associated with increased vascular calcification.120 Conversely, vitamin K supplementation (especially K2 supplementation) slows the progression of coronary artery calcification in people with pre-existing coronary calcification and helps improve vascular stiffness.121-123

While there is no defined optimal blood level for vitamin K, vitamin K supplements containing both K1 and K2 (as MK-4, MK-6, MK-7, and MK-9) can help ensure healthy vitamin K intake.

Elevated Fibrinogen

Fibrinogen is a protein found in the blood that plays an important role in blood clotting. Excess fibrinogen is associated with vascular disease via its effects on blood viscosity and cellular adhesion in the arteries.124,125 Life Extension suggests a target blood level of 295–369 mg/dL for fibrinogen.

Some prescription medications, such as statins, may lower fibrinogen levels. In addition, supplements such as fish oil, vitamin C, and Nattokinase may help promote healthy fibrinogen levels.126-128

Elevated C-reactive Protein (CRP)

C-reactive protein (CRP) is a nonspecific blood marker that connotes inflammatory status in the body.9 It is produced in many cells in the body, but CRP produced by fat and liver cells increases the production of cell adhesion molecules and plasminogen activator inhibitor-1, a protein involved in blood clotting. CRP also inhibits an enzyme that produces NO.28,129

Life Extension’s suggested target blood levels of CRP are less than 0.55 mg/L for men and less than 1.0 mg/L for women. Statin drugs have anti-inflammatory properties and can lower CRP levels.130,131 Dietary supplements such as vitamin C, curcumin, fish oil, borage oil, and Irvingia gabonensis extract may also reduce CRP or suppress inflammation.132-136 Consuming soluble fibers may also reduce inflammation and lower CRP levels.137 Weight loss, through a healthful diet (eg, the Mediterranean diet) and increased physical activity, reduces inflammation. In addition, avoiding foods cooked at high temperatures may reduce inflammation and levels of CRP in the body by reducing exposure to advanced glycation end products (AGEs).138

Apolipoprotein E (ApoE) Risk Variants

Apolipoprotein E (ApoE) is a protein that plays a role in fat metabolism. There are three genetic variants of ApoE, and they exert differential influence on cardiovascular risk. ApoE2 is associated with lower risk under most circumstances and ApoE4 is associated with higher risk, whereas ApoE3 is considered roughly neutral. ApoE4 also increases risk of Alzheimer disease.139,140 ApoE2 exerts its protective effects by helping the liver clear harmful lipoproteins from the body more effectively than the E3 and E4 variants.141-143 However, among people with hyperlipoproteinemia, ApoE2 may be associated with increased cardiovascular risk.

Elevated Serum Amyloid A (SAA)

Serum amyloid A (SAA) is a group of proteins produced by the liver in response to infection, inflammation, or injury.144 Because SAA blood levels are often increased in those with atherosclerosis, blood measurements have been used to identify those with or at risk of developing the disease.145 There is now evidence that SAA proteins play a direct role in the development and progression of atherosclerosis.146,147 SAA can stimulate macrophages to secrete inflammatory biochemicals and cell adhesion molecules, and modify HDL, reducing its protective effects.148

Elevated Tumor Necrosis Factor-alpha (TNF-α)

Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that plays a role in the initiation and progression of atherosclerosis. Specifically, TNF-α promotes the production of inflammatory factors, leads to the overproduction of cell adhesion molecules, and depresses levels of NO. TNF-α also causes direct harm to blood vessel linings by accelerating cell death.28 Natural compounds that may promote healthy levels of this biomarker include curcumin and resveratrol.149,150

Elevated Resistin

Resistin is a peptide-hormone that is not completely understood, but is thought to play a role in insulin tolerance or resistance.151,152 Macrophages found in atherosclerotic plaque produce resistin, where it is believed to contribute to the formation of foam cells, increase the production of cell adhesion molecules, and cause endothelial dysfunction. Increased resistin levels are found in cases of heart attack and near heart attack, and it is likely released into the blood during plaque rupture.153

While an optimal healthy range for resistin is not known at this time, preliminary research suggests vitamin C and garlic may help reduce resistin levels.154,155

Elevated Leptin

Leptin is a hormone that regulates hunger. Normally, leptin inhibits hunger, but abnormally elevated levels can lead to the body becoming resistant to its effects, which promotes overeating and obesity. In atherosclerosis, leptin excess contributes to endothelial dysfunction, inflammation, and oxidative stress.156 Furthermore, irrespective of its role in inflammation, leptin can promote thrombosis.28

Leptin levels vary day to day and typically decline with age, and leptin is higher in women than in men. In one study, fasting leptin levels above 15 ng/mL were associated with insulin sensitivity issues,157 and in another study values above 23.75 ng/mL in women and 6.45 ng/mL in men were associated with cardio-metabolic abnormalities.158 While research is ongoing, a diet rich in monounsaturated fatty acids and low in excess fat, cholesterol, and calories is believed to support healthy leptin levels.159 In addition, 10 weeks of supplementation with Irvingia gabonensis extract has been shown to reduce leptin levels in overweight subjects.132

Elevated Lipoprotein (a)

Lipoprotein (a), also called Lp(a), is a subclass of lipoprotein particles composed of LDL-like particles bound to another particle, called apolipoprotein(a). Lp(a) is a known marker of cardiovascular risk; that is, elevated levels correlate with greater risk for cardiovascular disease. Lp(a) levels are mostly determined by genetics (as opposed to diet and lifestyle as with other blood lipid markers). Generally, Lp(a) levels above 50 mg/dL (~125 nmol/L) are considered to indicate high cardiovascular risk, whereas levels below 30 mg/dL (~72 nmol/L) are associated with low risk.160

Lp(a) levels should be interpreted in the context of other cardiovascular and lipid risk markers, and family history of cardiovascular disease is an indication for measurement of Lp(a). As of mid-2019, no reliable data from randomized controlled trials have shown that targeting Lp(a) reduction with medication is an effective risk-reduction strategy. As of this writing, the only intervention available that appears promising for lowering Lp(a) is lipoprotein apheresis.161 Lipoprotein apheresis involves the removal of lipoproteins from the blood via a blood filtration process used only in people with very elevated blood lipids despite maximal lifestyle and drug therapy. Thus, Lp(a) is primarily useful as a marker for identifying people who might benefit from adopting a more intensive overall cardiovascular risk reduction strategy.

Nevertheless, some intriguing interventions that target Lp(a), such as antisense oligonucleotides, are currently under development and may represent a novel intervention if research progresses as hoped, but further studies are needed.162-165

Estimating Cardiovascular Risk

A discussion about risk of developing heart disease can and should occur at any age, but for those age 40‒79 years, risk can be quantified through the use of a risk estimator calculator, such as the 10-year ASCVD (atherosclerotic cardiovascular disease) risk calculator developed by the American Heart Association and the American College of Cardiology. The calculator provides a percentage estimate of having a fatal or nonfatal heart attack or stroke over the next 10 years of life for an individual aged 40 to 79 years. It takes into account one’s age, gender, race, cholesterol levels, blood pressure, and the presence of hypertension, diabetes, and tobacco use.

The calculator assumes that an individual has not had a prior heart attack or stroke. If you have had a heart attack or stroke, or your LDL cholesterol levels are greater than 190 mg/dL, speak with your physician about aspirin or stain therapy. The American Heart Association/American College of Cardiology online ASCVD risk calculator is available here: http://static.heart.org/riskcalc/app/index.html#!/baseline-risk

The risk calculator is a useful tool, but it can overestimate or underestimate risk. If risk is estimated as borderline or intermediate, higher risk can be determined if someone has so-called risk-enhancing factors. These include a family history of atherosclerosis at a young age; metabolic syndrome; chronic kidney failure; chronic inflammatory disease; history of premature menopause or preeclampsia; South Asian ancestry; or elevated blood markers, such as CRP.

Coronary Artery Calcium

A test that is gaining popularity in helping to further define risk is the coronary artery calcium (CAC) score. As atherosclerosis progresses, fatty deposits in blood vessel walls become increasingly calcified. Autopsy studies have shown that degree of calcification in coronary arteries strongly correlates with the general extent of atherosclerotic disease.166

Your CAC score can be determined with a simplified computed tomography (CT) scan that measures the amount of calcium buildup in coronary artery plaques. The CT scan generates a number that corresponds with the amount of calcium detected. The higher the number, the greater the risk. The results are reported in risk categories, ranging from zero to greater than 400. A score of zero suggests no atherosclerosis, and a score of greater than 400 suggests severe atherosclerotic vascular disease (and a corresponding high risk of future heart attack).166 The CAC score is such a strong predictor that an elevated score moves your risk from the intermediate (as determined by a risk estimator) to high category.24,25

Because the CAC test uses computed tomography, the person undergoing the test is exposed to a low dose of radiation, comparable to the amount of radiation exposure associated with a mammogram.166

Carotid Artery Ultrasound

Carotid artery ultrasound detects atherosclerotic plaque in the arteries of the neck using ultrasound technology. Carotid artery plaque is closely associated with coronary atherosclerosis, and some advocate performing this relatively simple test to screen individuals at risk for ischemic heart disease in the primary care setting.167 The carotid ultrasound produces data that allow several evaluations (eg, carotid intima-media thickness [cIMT], carotid plaque score [cPS], and carotid total plaque area [cTPA]). Some of these measures correlate with risk of cardiovascular outcomes, especially in people at high cardiovascular risk.168,169

6 Atherosclerosis Prevention

In most cases, atherosclerosis is preventable because many factors that contribute to its development are modifiable. Assessing your risk and making appropriate dietary and lifestyle changes are key. This section outlines several considerations that can help you understand your risk of cardiovascular disease and the steps you can take to reduce it.

Atherosclerosis is a complex and multifactorial process. Please see Life Extension’s protocols on Cholesterol Management, High Blood Pressure, Homocysteine Reduction, Stroke, and Diabetes and Glucose Control for more information on cardiovascular health and disease prevention.

Adopt a Healthy Diet

A healthy diet contains plenty of vegetables, fruits, nuts, whole grains, and fish, and less processed foods, red meats, refined carbohydrates, and sweetened beverages. In addition, a diet rich in pro-inflammatory omega-6 fatty acids and deficient in anti-inflammatory omega-3 fatty acids promotes inflammation and oxidative stress, which has been linked to numerous age-related diseases.170,171,

A recent large meta-analysis that examined over 45 prospective studies determined that there is a large, strong, and consistent body of evidence to support the benefits of the Mediterranean Diet on cardiovascular health.172 The Mediterranean diet has consistently been shown to reduce the risk of atherosclerotic cardiovascular disease. This diet, which is low in animal products and saturated fat, and high in olive oil, legumes, fruit, vegetables, and fish has been shown to reduce the risk of heart attack, stroke, and dying from cardiovascular disease by about 30%.173

In a recent prospective cohort study of nearly 26,000 women in the United States, those with the highest intake of Mediterranean foods had a 28% reduction in risk of cardiovascular events. This was mostly attributed to reduced biomarkers of inflammation, glucose metabolism, insulin resistance, and adiposity.174

Research indicates that the ideal dietary ratio of omega-6:omega-3 fatty acids is 4:1; however, the typical Western diet has a ratio of 20:1.175 Most people have a diet deficient in omega-3s and too high in omega-6s as compared to the diet that humans evolved with.176 This change in dietary composition parallels the rise in overweight and obesity in Western society.177 Elevated levels of omega-6 polyunsaturated fatty acids and higher omega-6:omega-3 ratios promote many chronic diseases, including cardiovascular disease, cancer, asthma, and autoimmune disease.176

Be Physically Active

American adults average six to eight hours a day sitting, despite the well-known association between sedentarism and an increased chance of developing and dying from cardiovascular disease.178 Regular physical activity has been shown to be beneficial in those with atherosclerosis. Formal protocols called cardiac rehabilitation, supervised by medical practitioners either in a medical practice or at home, are encouraged, but do-it-yourself programs are also beneficial.

The American Heart Association recommends at least 150 minutes per week of moderate-intensity activity or 75 minutes of vigorous-intensity activity. Moderate intensity activities include brisk walking, biking at a speed of 5‒9 miles per hour, dancing, active yoga, recreational swimming, or any activity that puts one near, but not past, the point of being unable to speak a complete sentence without pausing for breath.179 Examples of vigorous activities are jogging, biking at speeds greater than 10 miles per hour, resistance training, and swimming laps. Resistance training includes muscle-strengthening tasks such as weightlifting or the use of elastic bands or one’s own body weight to improve body strength. In some cases, this type of activity improves lipid profiles beyond what aerobic activity alone can.179,180 In addition to a physical activity program, individuals should combat a sedentary lifestyle by increasing daily physical activity by keeping busy with household work, gardening, and taking the stairs instead of elevators, etc.

For more information, see the section titled “Lack of Physical Activity.”

Avoid Tobacco Use and Second-hand Exposure

Tobacco use is a major modifiable risk factor for many diseases, including cardiovascular diseases such as coronary artery disease, stroke, vascular disease, congestive heart failure, angina, and aortic aneurysms. Smoking cigarettes is a causative factor in approximately one in five deaths in the United States each year.181 It is known to damage the heart and blood vessels, and elevates cholesterol and blood pressure levels. It also prevents oxygen from adequately reaching all of the body’s organs and tissues.27 Research suggests cigarette smoke causes oxidative stress, vascular dysfunction and inflammation, platelet coagulation, and impairs the serum lipid profile in both active and passive smokers.

Those who use tobacco should strongly consider quitting. The process of quitting can be different for each person and should be individualized; however, successful quitting most often involves a combination of tobacco cessation counseling and nicotine replacement. Any level of exposure to tobacco smoke is harmful. Nonsmokers who are regularly exposed to second-hand smoke are at risk of developing cardiovascular disease and stroke,182 and even a brief encounter with smoke may be harmful.183

Limit Alcohol Intake

There is some evidence that light drinking may be heart-healthy. However, the evidence is relatively weak as it is based on observational studies and not controlled trials. It is not generally recommended to start drinking alcohol for any perceived benefit on atherosclerosis.5 For those who do partake, light drinking should be emphasized, limiting consumption to one drink (four ounces of wine or one ounce of liquor) per day for women and no more than two drinks per day for men.

Consider Medication to Lower Cholesterol

People with a very high LDL (greater than or equal to 190 mg/dL), diabetes, those between 40‒75 years of age, and those who have an elevated risk through cardiovascular risk estimation may require more aggressive cholesterol lowering strategies, including medication. Statins (eg, atorvastatin [Lipitor] and rosuvastatin [Crestor]) are the pharmaceuticals most often recommended for preventing cardiovascular disease. Statins inhibit the activity of HMG-CoA reductase, a key enzyme in cholesterol synthesis, and may also reduce CHD risk by other mechanisms, such as reducing inflammation.184

Reduction of total cholesterol and LDL cholesterol (and/or triglycerides) by drugs usually involves inhibiting cholesterol production in the body or preventing the absorption/reabsorption of cholesterol from the gut. When the availability of cholesterol to cells is reduced, they are forced to pull cholesterol from the blood (which is contained in LDL particles). This has the net effect of lowering LDL cholesterol. Therapies that increase the breakdown of fatty acids in the liver or lower the amount of VLDL in the blood also result in lower serum cholesterol levels. Often, complementary strategies (eg, statin to lower cholesterol production plus a bile acid sequestrant to lower cholesterol absorption) are combined to meet cholesterol-lowering goals.

Consider Aspirin (For Those at High-risk)

Aspirin has long been used to prevent heart attacks in those at risk of cardiovascular events due to its role in preventing thrombosis, the underlying cause of heart attacks. Recent large-scale studies have helped redefine the groups of people most likely to benefit from aspirin therapy. The European Society of Cardiology does not recommend aspirin or aspirin-like therapy for individuals without established cardiovascular disease,185 and the American Heart Association states that daily, low-dose aspirin might be considered as a preventative measure among select adults 40 to 70 years of age who are at higher ASCVD risk but not at increased bleeding risk.186 Current evidence suggests aspirin is not helpful for primary prevention of cardiovascular events among people at low baseline cardiovascular risk.

The American Heart Association indicates that daily low-dose aspirin should not be used on a routine basis to prevent heart disease in those older than 70 years and not at all as a preventative in adults of any age who have a history of abnormal bleeding (eg, in the stomach or intestine); stomach or intestinal ulcers; low blood platelets; those who use medications that increase bleeding, such as anticoagulants or other blood thinners; and those with certain other medical conditions. In addition, aspirin therapy is not appropriate for those who drink alcohol on a regular basis.

Recent research has demonstrated an increased risk of major bleeding episodes, and recent trials have failed to show that aspirin was effective at preventing major cardiovascular events, including heart attack and stroke.187 An observational study tracked over 33,000 people with atherosclerosis and found that aspirin was only slightly beneficial for those with a history of heart attack or stroke, but not beneficial for those with no such medical history.188

In another trial, adults with diabetes (but no cardiovascular disease) randomly received either 100 mg of aspirin per day or placebo. More than 15,000 subjects were followed for over seven years, with the primary endpoints being serious vascular event (such as stroke, heart attack, or death from vascular causes) or major bleeding event, such as serious bleeding or hemorrhage. The researchers found that aspirin prevented vascular events in those with diabetes but no cardiovascular history, but also caused major bleeding events.189

In another randomized, double-blind, placebo-controlled, multicenter trial, over 12,000 men aged 55+ and women aged 60+ with an average cardiovascular risk received either 100 mg aspirin or placebo daily. Researchers were not able to conclude that aspirin was more effective than placebo at preventing a major cardiovascular event such as cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischemic attack.190 In yet another randomized placebo-controlled trial involving over 19,000 people aged 70 years and older who received 100 mg aspirin for five years to determine if aspirin had an impact on death, dementia, or physical disability, researchers concluded that aspirin use did not prolong disability-free survival and led to a higher rate of major hemorrhage as compared with placebo.191

Do not take daily low-dose aspirin without the guidance of a physician, as the risk and benefits vary with each person. Aspirin can be used as part of a treatment plan for a person who has a history of stroke or heart attack. Follow only the treatment plan that your physician has established for you.

7 Atherosclerosis Treatment

The American Heart Association provides atherosclerosis treatment guidelines to health care providers and their patients.5 These guidelines are intended to prevent fatalities from atherosclerosis, nonfatal heart attacks, and damage to heart function, which could lead to heart failure.

As noted earlier, atherosclerosis is a complex and multifactorial process. Please see Life Extension’s protocols on Cholesterol Management, High Blood Pressure, Homocysteine Reduction, Stroke, and Diabetes and Glucose Control for more information on cardiovascular health and disease treatment.

One cornerstone of therapy for atherosclerosis is managing the underlying conditions that lead to its onset and progression (risk factor modification). This section summarizes several key targets for modification. In addition, Life Extension encourages people who wish to promote optimal cardiovascular health to take steps to manage all the risk factors described earlier in this protocol.

Managing Blood Lipids

A multifaceted approach is recommended to modify blood lipids. This includes lifestyle elements, nutritional supplements, and pharmaceutical treatment. Daily physical activity is advised, and weight loss is encouraged, as a 10-pound weight loss is associated with a lowering of LDL by 5‒8%.192 Intake of saturated fats should be limited to less than 7% of total calories and trans-fats should be avoided. Supplementation of plant stanols/sterols and viscous fiber have also been shown to reduce LDL.

Current guidelines generally recommend high-dose statin medications for most people with atherosclerosis, unless there are contraindications or intolerable side effects.51

For individuals with atherosclerosis who are identified as being at high risk, Life Extension recommends that the LDL level be kept below 70 mg/dL. This applies to those with multiple cardiovascular disease events or one cardiovascular event and multiple high-risk characteristics.51 Cardiovascular events include heart attack, near heart attack within the past 12 months, stroke due to plaque rupture, or any symptomatic peripheral atherosclerosis. High-risk characteristics include age older than 64 years, diabetes, high blood pressure, chronic kidney failure, current smoking, and heart failure, among others. If this goal cannot be reached with statins alone, then ezetimibe (Zetia) may be added to the medication regimen, followed by a PCSK9 inhibitor.

Managing Blood Pressure

In those who have atherosclerosis and high blood pressure, blood pressure control is paramount. Lifestyle modification alone can be attempted first to see if blood pressure can be controlled without medication. This involves weight control, increased physical activity, and a diet low in sodium with lots of fresh fruits, vegetables, and low-fat dairy products. However, medication is often needed as well.

The blood pressure treatment target may vary depending on the patient’s established risk factors and overall baseline risk. Life Extension’s High Blood Pressure protocol contains information about managing blood pressure effectively using lifestyle, diet, pharmaceuticals, and integrative interventions. Because different blood pressure treatment targets may be appropriate for different patients, you should consult with your physician before implementing a blood-pressure-lowering medication regimen.

A review of studies examining aerobic exercise found that regular moderate-intensity exercise can lower systolic blood pressure by about 3.84 mm Hg and diastolic blood pressure by 2.58 mm Hg.193 In people who are overweight, even modest weight loss (4‒8% of body weight) can lead to a 3 mm Hg drop in systolic and diastolic blood pressure.194 A review of studies that focused on the effects of excessive alcohol consumption on high blood pressure found that quitting drinking or limiting alcohol to one or two drinks per day resulted in a 3.3 mm Hg reduction in systolic blood pressure and a 2 mm Hg reduction in diastolic blood pressure.195 Reducing sodium intake can lower systolic blood pressure by 3.39 mm Hg and diastolic blood pressure by 1.54 mm Hg.196 A very effective lifestyle modification appears to be the DASH-sodium diet, which combines a reduced sodium diet with one that emphasizes vegetables, fruits, and low-fat dairy products. In one clinical trial, compared to participants in a higher sodium diet group, hypertensive participants in the DASH-sodium group experienced a reduction of 20.7 mm Hg for systolic blood pressure and 7.9 mm Hg for diastolic blood pressure.197

If a medication is needed to achieve the goal, then the most common pharmaceuticals employed are thiazide diuretics (hydrochlorothiazide, chlorthalidone, and others), beta blockers (metoprolol [Lopressor, Toprol XL], atenolol [Tenormin], and others), and ACE inhibitors (lisinopril, captopril, and others) or angiotensin receptor blockers (ARBs) (eg, telmisartan [Micardis]). Certain medications are preferred under certain conditions. For example, beta blockers are favored in those who have had a heart attack, and ACE inhibitors are the preferred treatment in individuals who have both high blood pressure and diabetes. Life Extension Magazine published a 2015 article on ancillary benefits of the ARB telmisartan, which may be a good choice for initial treatment in appropriately selected patients.

Managing Diabetes

In the context of atherosclerosis and cardiovascular disease, the official position of the American Heart Association on hemoglobin A1c (HbA1c) is that a goal of 7% or less is “reasonable” for certain patients, like “those with a short duration of diabetes mellitus and a long life expectancy.”5 However, because clinical studies have failed to show a clear advantage for intensive glucose control on cardiovascular events, the recommendations also state that a goal between 7% and 8% is reasonable in other instances, such as advanced age or a history of low blood sugar.

The main noninsulin agent used in the treatment of diabetes, metformin, has been shown to reduce the incidence of heart attack.198 Two or more medications are often necessary for optimal treatment, and not all medications are created equal in terms of cardiovascular risk. For example, rosiglitazone (Avandia), a member of a commonly-used class of medications called thiazolidinediones, has been associated with an increase in cardiovascular risk.5 Since the development of thiazolidinediones, two newer classes of medications for diabetes with clear cardiovascular benefits have been introduced.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors block the kidneys’ ability to bring glucose back into the blood after filtering it, which leads to increased excretion of glucose into urine. A clinical trial looking at the cardiovascular effects of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes demonstrated a reduction in death from cardiovascular causes and nonfatal heart attack and stroke.199 This benefit has been shown to extend to another medication in this class, canagliflozin.200

Glucagon-like peptide-1 (GLP-1) analogues are injectable medications that are useful in the treatment of diabetes because they stimulate the release of natural insulin. Notably, two members of this class of medications have been shown to reduce cardiovascular disease event rates, liraglutide 201 and semaglutide.202

Physical Activity

Regular physical activity has been shown to be beneficial in those with atherosclerosis. For more information on cardiovascular health and physical activity, please see the “Lack of Physical Activity” and “Be Physically Active” sections earlier in the protocol.

Body Weight

Body weight, body mass index (BMI), and/or waist circumference are often recorded as vital signs, along with blood pressure and pulse rate, at each health care provider visit. The goals from the American Heart Association are a BMI between 18.5 and 24.9 kg/m2 and a waist circumference less than 40 inches in men and 35 inches in women. Because even modest weight loss improves risk factors for atherosclerosis, for those for whom weight loss is advised, an initial goal of 5‒10% loss of body weight is appropriate.194

Previously many health care providers believed the so-called obesity paradox, which is the belief that being overweight or obese had a protective effect on certain cardiovascular risk parameters. This notion was originally supported by some scientific evidence, but subsequent large studies, including one published in the Journal of the American Medical Association in 2018, cast overwhelming doubt.203 The JAMA study, which pooled data from 10 separate studies involving nearly 200,000 patient encounters over 50 years, concluded that being obese (BMI of 30‒39.9) was associated with a shorter lifespan and a definite increase in cardiovascular disease incidence and death from cardiovascular disease. Those who were overweight (with a BMI of 25‒29.9) had a definite increased risk of cardiovascular disease compared to the group with a BMI of 18.5‒24.9.

Additional Medical Therapy

In 2014, the American Heart Association revised their guideline regarding two additional therapies.204

Chelation therapy. Chelation therapy refers to an intravenous infusion of a compound called disodium ethylenediamine tetraacetic acid (EDTA), which chelates or binds certain blood electrolytes, like calcium and cadmium. Once advocated by some to be helpful in the treatment of atherosclerosis, the promise of benefit was subsequently debunked by controlled studies. However, the thinking on chelation therapy has evolved again. In light of a new trial showing some benefit205 (but not enough to make a recommendation for its use), the American Heart Association said that the “usefulness of chelation therapy is uncertain” to reduce cardiovascular events in patients with stable ischemic heart disease.204 A large-scale randomized controlled trial to assess the benefits of chelation therapy plus a multivitamin in people with diabetes and a history of cardiovascular disease is underway as of the time of this writing (December 2019). The estimated completion date of the trial, called TACT2, is December 2022.

Enhanced external counterpulsation (EECP). EECP is a procedure that involves inflating pressure cuffs on the legs to aid lower extremity circulatory return. EECP was shown to improve cardiac output in a small study on eight patients with angina. The researchers speculated this effect may have arisen as a result of increased peripheral oxygen demand. EECP is typically administered over 35 treatment sessions spanning seven weeks, five days per week, for one hour per treatment session.206

EECP received FDA approval in 1995 for the treatment of angina pectoris when symptoms do not respond to most treatments. In 2014, the data was re-examined, and it was concluded that EECP may be considered for relief of refractory angina in patients with stable ischemic heart disease. The 2014 multi-society guidelines on the Management of Patients with Stable Ischemic Heart Disease concluded that most data were derived from small, heterogeneous studies, and more studies are needed to strengthen the recommendation for EECP.204

EECP has also been studied in the context of heart failure. The Prospective Evaluation of Enhanced External Counterpulsation in Congestive Heart Failure (PEECH) trial, published in 2006, found that EECP improved quality of life, NYHA functional classification, and exercise tolerance. However, in this study, EECP intervention satisfied only one of two pre-defined primary endpoints—it improved the percentage of subjects with a 60-second or more increase in exercise duration, but not VO2 max.207 In a randomized controlled trial published in 2015, EECP improved functional capacity significantly more than sham-EECP treatment among heart failure patients.208 Another study showed that EECP reduced myocardial oxygen demand by 19% in patients with left-ventricular dysfunction.209

EECP has also shown some potential for utility in other conditions in small, early studies as well. In a preliminary study, EECP was shown to be safe and feasible in patients with acute ischemic stroke, with minor improvements in blood flow velocity in the middle cerebral artery. The researchers called for further study.210 Intriguingly, EECP has also been shown to improve markers of glycemic control and glycation burden among diabetic patients, but this needs to be explored in additional studies.211,212

Because EECP is non-invasive and generally well tolerated, there is little downside to asking your health care provider whether EECP may benefit you. It will be important, however, to consider cost, as your insurance company may not cover EECP for conditions other than those for which it is FDA-approved.

Colchicine ‒ Potential Cardiovascular Benefits After Heart Attack

Inflammation plays a role in the development and progression of atherosclerosis and complications thereof, such as heart attack and stroke. Colchicine, an anti-inflammatory drug used to treat gout and familial Mediterranean fever, is often used off-label to treat pericarditis, a condition in which supportive tissue surrounding the heart muscle becomes inflamed.

A randomized controlled trial called the Colchicine Cardiovascular Outcomes Trial (COLCOT), published in late 2019, assessed the benefits of colchicine in people who had had a heart attack within the past 30 days.213 Participants received either 0.5 mg of colchicine or placebo daily and were followed-up for a median of nearly 23 months. A total of 4,745 participants were randomized in the study. The primary endpoint was a composite of death due to cardiovascular causes, resuscitated cardiac arrest, heart attack, stroke, or urgent hospitalization for chest pain leading to coronary revascularization. The composite outcome occurred less frequently among subjects randomized to colchicine. Specifically, the endpoint occurred in 7.1% of subjects taking placebo and 5.5% of those taking colchicine. The overall composite reduction with colchicine was driven largely by pronounced reductions in incidence of stroke and urgent hospitalizations for chest pain requiring coronary revascularization.

Because the results in the COLCOT trial were limited by a relatively short follow-up and are applicable only to people who have had a heart attack within 30 days prior to starting colchicine, many experts are awaiting more evidence before implementing post-heart-attack colchicine as a standard part of clinical practice. Weighing the risks and benefits is important because colchicine has been linked to myelosuppression and muscle toxicity at therapeutic doses, although these adverse effects appear to be relatively uncommon. Kidney or liver dysfunction may increase the risk of adverse effects with colchicine, and people taking colchicine should avoid grapefruit juice and certain drugs metabolized by CYP3A4 enzymes, such as cimetidine.214-216

Surgical Procedures and Interventions

In some cases, a more invasive atherosclerosis treatment plan may be advisable. For example, the best approach to the treatment of certain patients with atherosclerosis and ischemic heart diseases is to mechanically restore coronary artery blood flow with surgery or a catheter-based intervention.

With coronary artery bypass grafting (CABG) surgery, a heathy blood vessel from elsewhere in the body is stitched around a severe coronary artery plaque to bypass the plaque and restore blood circulation to the heart muscle. There are several variations to this surgery, but all involve significant risks and prolonged recovery periods.217

In a catheter-based intervention, the heart is accessed through a puncture in a wrist or groin artery to deliver a catheter to the coronary arteries. The inserted end of the catheter is equipped with a balloon, which is inflated in a procedure called angioplasty, thereby relieving a blood flow problem caused by significant coronary plaque. After removing the balloon, in most cases, a metallic stent is permanently implanted at the site of the angioplasty to prop open the artery and maintain blood flow.

These more invasive treatments are reserved for very severe and extensive coronary atherosclerosis because mechanical blood flow restoration has been shown to reduce the risk of death in these cases. In less severe cases, invasive treatments are employed if medications, lifestyle changes, and external procedures fail to adequately relieve chest pain, breathlessness, or fatigue that can be caused by ischemic heart disease.5

ISCHEMIA Trial – Invasive Approach May Not Be Better Than Optimal Medical Therapy in People with Stable Ischemic Heart Disease

Results of the large ISCHEMIA trial presented at the November 2019 meeting of the American Heart Association suggest that, for selected patients with stable ischemic heart disease with ischemia during stress testing, optimal medical therapy may be just as effective as a more aggressive, invasive approach using cardiac catheterization and revascularization. In the trial, 5,179 subjects were randomized to receive either optimal medical treatment plus lifestyle and diet advice, or lifestyle and diet advice, optimal medical therapy, plus an invasive revascularization procedure with either CABG or percutaneous coronary intervention.

The primary study endpoint was a composite of cardiovascular death, myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. The study revealed no significant differences in the primary study outcome between the invasive and conservative groups. There were also no differences between the groups in rates of cardiovascular death or heart attack. The researchers concluded that invasive procedures were no better than optimal medical therapy and lifestyle and dietary advice during the median follow-up of 3.3 years.218

8 Integrative Interventions

Monounsaturated Fatty Acids

Diets rich in monounsaturated fatty acids (MUFA) are associated with improvements in lipid profile and LDL oxidation, improving atherosclerosis risk. Non-lipid benefits of MUFA in the diet include a lower risk for abnormal heart rhythms and beneficial effects on blood pressure and heart rate, blood platelet activity, and clotting.219 Dietary sources of MUFA include olive oil and other cooking oils made from plants or seeds (canola, peanut, soybean, rice bran, sesame, or sunflower), almonds, cashews, peanuts, and avocados.

Conclusions about the effects of a MUFA-rich diet on cardiovascular events have been mixed. In the Nurses’ Health Study, a Harvard-conducted study of the health and well-being of over 100,000 registered nurses aged 30‒55 that were followed for over 20 years, revealed a positive effect of MUFA consumption on cardiovascular disease development.220 However, two other studies showed an increased association between cardiovascular disease and MUFA consumption.221,222 It is likely that these negative results were confounded by increased dietary saturated fat.219 Interestingly, a recent study in a mouse model of atherosclerosis showed that supplements containing long-chain monounsaturated fatty acids reduced atherosclerotic plaques by 40%, even though the mice were fed a Western diet high in saturated fats.223

Polyunsaturated Fatty Acids

Polyunsaturated fatty acids (PUFA) include omega-3 fatty acids found in seafood, fatty fish, fish oil, vegetable oils, and walnuts. As mentioned previously, the ideal dietary ratio of omega-6:omega-3 fatty acids is 4:1; however, the typical Western diet has a ratio of 20:1.175 Most people have a diet deficient in omega-3s and too high in omega-6s as compared to the diet that humans evolved with.176 This change in dietary composition parallels the rise in overweight and obesity in Western society.177 Elevated levels of omega-6 polyunsaturated fatty acids and higher omega-6:omega-3 ratios promote many chronic diseases, including cardiovascular disease.176

Three large controlled scientific studies have provided evidence that greater PUFA intake is associated with a reduction in the incidence of cardiovascular events in those with atherosclerosis.224-226 A 2019 meta-analysis found that greater omega-3 PUFA intake was associated with reduced cardiovascular risk in long-term studies that provided follow-up periods of 10 years. This finding suggests long-term, consistent intake of healthy PUFAs may be important for cardiovascular health.227

Regarding omega-3 supplementation in the context of cardiovascular outcomes, the controlled trials preformed to date have varied a great deal in their design and methods. Not surprisingly, study results and interpretations of the findings have been inconsistent. However, as of late 2019, the benefit of higher omega-3 dosages have become apparent. A meta-analysis published in the Journal of the American Heart Association pooled data from 13 randomized controlled trials involving nearly 130,000 participants. This analysis found a dose-response relationship between omega-3 supplementation and a reduction in risk of several cardiovascular outcomes. That is, higher doses of omega-3 supplementation were linked to greater risk reductions.228

Other studies suggest omega-3 supplementation may be particularly useful in certain subgroups of people. For example, a controlled trial involving approximately 7,000 patients with heart failure found that omega-3 supplementation reduced risk of death or hospitalization due to cardiovascular causes.229 One trial demonstrated that fish oil supplementation reduced the risk of death in people who suffered a heart attack within the past three months.225 The American Heart Association recently declared that PUFA supplementation is reasonable to help prevent cardiac death in patients with prevalent coronary heart disease and to help prevent outcomes in those with heart failure.230

More recently, a large multicenter trial randomized over 8,000 patients with (or at risk for) atherosclerosis and mildly elevated blood triglycerides to supplementation with a highly purified form of the omega-3 fatty acid eicosapentaenoic acid (EPA, as icosapent ethyl) or placebo. The EPA group had a significant drop in risk of heart attack, stroke, and death from any cardiovascular cause.231 Additionally, a review of 16 controlled human trials concluded that omega-3 fatty acid supplementation beneficially affects vascular endothelial function.232

Dietary Fiber

The term dietary fiber applies to a group of nondigestible elements that are not absorbed by the human body after eating. Insoluble fiber passes through the digestive tract unaltered, and soluble fiber can be fermented by intestinal microbes and broken down to short-chain fatty acids.233 Insoluble fiber is found in whole grains, wheat, bran, nuts and seeds. Soluble fiber is found in vegetables, fruits, legumes, oats, barley, and is the main type of fiber in fiber-based laxatives.

Numerous studies that observe cohort data over time have linked increased dietary fiber with a reduced risk of atherosclerosis, stroke, and peripheral vascular disease.219 In 2013, a review of 22 such studies spanning two decades and three continents found a significantly lower risk of atherosclerosis with greater intake of insoluble, cereal, fruit and vegetable fiber. The risk was lower with soluble fiber as well, but the association was not statistically significant.234

Randomized controlled studies involving fiber have focused mostly on cardiovascular disease risk factors. For example, a 2016 study randomized 60 post-menopausal women with elevated LDL cholesterol to receive brown rice extract supplements or placebo. At six months of treatment, those receiving the supplements had significantly lower levels of LDL cholesterol and TNF-α, a pro-inflammatory biochemical. Moreover, the rice bran extract also improved flow-mediated dilatation, a measure of vascular endothelial function.235

Polyphenols

Polyphenols, naturally occurring compounds found in tea, vegetables, fruits, and wine, are thought to counteract atherosclerosis by decreasing LDL oxidation, promoting NO levels, and inhibiting blood clot formation by reducing platelet clumping.219

In addition to being a source of monounsaturated fat, olive oil also contains polyphenols. A recent study examined the role of polyphenols in the protective effect of olive oil by providing participants with either olive oil enriched with its own polyphenols or regular olive oil. A small sample of individuals with mildly elevated blood pressure were given a single dose of either “boosted” or plain olive oil in a randomized blinded fashion. Those who received the “boosted” supplement saw an almost immediate improvement in endothelial function.236

Flavonols are another type of polyphenol found in fruits, vegetables, green tea, and cocoa. A major flavonol found in green tea and cocoa is catechin, which is thought to have a direct anti-inflammatory effect on vascular endothelial cells.237 In a small trial involving patients with heart failure, eating flavonol-rich chocolate led to an almost immediate improvement in vascular endothelial function when compared with plain chocolate, and sustained improvement after four weeks of daily consumption.238 Similarly, when 30 overweight men and women were given dark chocolate and a sugar-free cocoa beverage, vascular endothelial function improved compared with those given a low-flavonol chocolate bar and a cocoa-free beverage. The women in the study also saw an improvement in arterial stiffness with the administration of dark chocolate and cocoa.239

This effect may extend to black tea as well, which contains the polyphenols thearubigins and flavonoids. In a 2015 study, participants with high blood pressure drank a hot beverage containing a controlled amount of black tea-derived polyphenols. The researchers found that the polyphenol beverage dose-dependently improved blood pressure and arterial stiffness.240

Pine bark extract (Pycnogenol). Pycnogenol is obtained from the French maritime pine tree (Pinus pinaster). Between two-thirds and three-quarters of Pycnogenol is made up of catechins and their chemical cousins epicatechins.241,242 Pycnogenol benefits cardiovascular health through a variety of mechanisms. It has been demonstrated to inhibit inflammation and clotting, and improve endothelial function.243

In a randomized placebo-controlled trial, individuals with atherosclerosis received 200 mg Pycnogenol daily for eight weeks followed by placebo or vice versa. Treatment with Pycnogenol resulted in a significant reduction in oxidative stress and a 32% increase in a standardized measure of blood flow and vasodilation, a powerful indicator of endothelial function.244

Quercetin. Quercetin, a polyphenol found in apples, onions, cherries, and grapes, is known to possess anti-inflammatory and antioxidant properties, as well as a beneficial effect on diabetes and obesity.245 A controlled trial that tested quercetin supplements in 37 individuals with elevated blood pressure found improved measurements of inflammation linked to atherosclerosis as compared with placebo.246

Resveratrol. Resveratrol is another polyphenol found in grapes, berries, and peanuts. Historical studies have suggested it may have a positive treatment effect on atherosclerosis and high blood pressure.245 Resveratrol may inhibit the formation of foam cells and inhibit the uptake of ox-LDL.237 One animal study found that in mice fed a cholesterol-rich diet with and without resveratrol for 14 weeks, mice given resveratrol had atherosclerotic plaque regression and decreased plasma cholesterol levels.247

A study randomized 50 diabetic patients to receive either supplemental resveratrol or placebo for 12 weeks, then measured a number of physiologic and metabolic parameters and compared them to parameters determined at baseline. The study concluded that resveratrol not only improved blood pressure and body weight, but also reduced arterial stiffness, a common surrogate for atherosclerosis.248

Hesperidin. Hesperidin is a polyphenol that occurs in citrus fruits, especially their peels.249,250 Digestion of hesperidin produces a compound called hesperetin, along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity.251,252

In a randomized, placebo-controlled, crossover trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its cardiovascular benefits. Hesperidin supplementation also led to a 32% reduction in CRP, as well as significant decreases in levels of total cholesterol, apolipoprotein B, and markers of vascular inflammation, relative to placebo.253

Hydroxytyrosol. Hydroxytyrosol, the main phenol found in olive oil, is a potent antioxidant and anti-inflammatory agent that may inhibit LDL oxidation, platelet aggregation, and atherosclerosis progression.237,254 In one randomized crossover trial involving 200 healthy males, participants received 25 mL of three olive oils (one with 2.7 mg/kg of phenolic compounds, one with 164 mg/kg of phenolic compounds, and one with 366 mg/kg of phenolic compounds) for three weeks, followed by a two week washout period between treatments. HDL cholesterol levels increased and triglyceride levels decreased in all groups, and oxidative stress markers decreased linearly depending on phenolic content of the oil. Researchers concluded that the benefits of olive oil were greater than its monounsaturated fatty acid content, and that phenolic compounds in the oil may benefit plasma lipid levels and help prevent oxidative damage.255

In another randomized, double-blind, crossover study involving 13 early-stage hypertensive patients, subjects received 30 mg of functional olive oil enriched with its own polyphenols or standard virgin olive oil. Markers of endothelial function were followed for five hours after oil consumption. The enriched oil demonstrated greater benefit than the standard oil.236

Phytosterols

Phytosterols, plant compounds similar in nature to cholesterol, help support healthy LDL levels by competing with cholesterol for uptake into cells. As previously highlighted, cholesterol plays a role in the development of cardiovascular disease and atherosclerosis.237 Phytosterols can be found in rice bran, wheat germ, corn oils, soybeans, and peanuts.

In a randomized, double-blind, placebo-controlled trial, 232 men and women with elevated cholesterol levels consumed 20 grams per day of a low-fat spread with or without plant sterols (3 grams per day) for 12 weeks. Serum LDL levels were reduced with phytosterol supplementation.256 In a meta-analysis of 20 randomized controlled trials involving over 1,300 subjects, there was a clear association between phytosterol intake and reduced serum LDL cholesterol levels.257 In an older cross-sectional study of over 22,000 men and women aged 39‒79, researchers concluded that a high intake of plant sterols was associated with lower total and LDL cholesterol levels.258

Beta-sitosterol is a plant sterol associated with healthy cholesterol levels and optimal cardiovascular health. It is also believed to combat obesity-related inflammation, and may help treat metabolic diseases.259 Research in hypertensive rats with renal damage suggests treatment with beta-sitosterol (at a dose between 1.3‒2.3 mg/kg) for two weeks decreased atherosclerotic markers, including total cholesterol, LDL, and triglyceride levels.260

Vitamins

B vitamins. The family of B vitamins includes eight compounds: thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9) and cobalamin (B12). They play a role in energy production and cellular health, and are found in fish, leafy greens, and liver.261 Data suggest the B vitamin family plays a role in maintaining optimal cardiovascular health. In a randomized controlled study involving over 300 people, subjects with the highest intake of a variety of micronutrients, including vitamin B6, folate, and antioxidants, had the lowest risk of stroke and cerebral atherosclerosis.262

In another trial involving 81 people with mild-to-moderately high blood pressure who were not on blood pressure medication, a combination of L-arginine (2.4 grams) and vitamin B6 (3 mg), folic acid (0.4 mg), and vitamin B12 (2 mcg) improved vascular function (including blood pressure, endothelial health, and homocysteine levels) compared with placebo.263

Niacin (vitamin B3), which is involved in energy production and cellular communications and function, is found in poultry, meat, and fish.264 Research has long suggested that niacin plays a role in maintaining cardiovascular health, including decreasing coronary artery disease and strokes.265,266 Animal research suggests niacin inhibits atherosclerosis and decreases levels of inflammatory cytokines.267 A randomized placebo-controlled study of over 300 patients with coronary heart disease (with LDL cholesterol levels less than 100 mg/dL and HDL cholesterol levels less than 50 mg/dL) on statins found that 2,000 mg per day of niacin was more effective than 10 mg/day of ezetimibe at reducing carotid thickness after 14 months.268

Vitamins C and E. Vitamin C, a potent antioxidant and water-soluble vitamin that helps synthesize collagen, metabolize protein, and heal wounds, is found naturally in broccoli and oranges.269 Vitamin E, a fat-soluble vitamin found naturally in nuts, seeds, and vegetable oils, is a potent antioxidant that plays a role in immune function and cell signaling.270 Vitamin E is actually a family of eight different compounds, including four tocopherols and four tocotrienols. Research suggests it may be cardioprotective and exert control over the atherosclerotic process via microRNA regulation.271

Older cellular and animal models demonstrate that vitamin C improves endothelial function.237 A population-based prospective study involving over 20,000 people suggests vitamin C concentrations are associated with a decreased risk of stroke.272 In an older trial, 520 men and post-menopausal women (including smokers and non-smokers) took 136 IU vitamin E and 250 mg of slow-release vitamin C. At the three year follow-up, supplementation slowed the progression of atherosclerosis in men, and at the six year follow-up, a similar result was seen in both genders (but more significantly in males).273

While clinical trials involving vitamin E’s cardioprotective abilities have been mixed, some scientists believe this is the result of type of tocopherol compounds studied, particularly the lack of gamma-tocopherol, which has potent antioxidant and anti-inflammatory effects. Further research, particularly in the form of randomized clinical trials, is warranted for both vitamins.274

Vitamin K. Vitamin K, a fat-soluble family of vitamin compounds, plays a role in blood clotting and bone metabolism. It is naturally found in leafy green vegetables.119 Importantly, adequate vitamin K intake is critical for helping maintain healthy calcium balance in the arteries and bones. In fact, older anticoagulant drugs, such as warfarin, block the activity of vitamin K and are associated with increased vascular calcification.120 Conversely, vitamin K supplementation (especially K2 supplementation) slows the progression of coronary artery calcification in people with pre-existing coronary calcification and helps improve vascular stiffness.121-123

In a recent study, 42 people with chronic kidney disease took either 10 mcg cholecalciferol (vitamin D3) or a combination of 90 mcg menaquinone (vitamin K2) and 10 mcg cholecalciferol for 270 days. The group taking the combination showed lower carotid arterial thickness, suggesting it slows the progression of atherosclerosis.275

Coenzyme Q10

Coenzyme Q10 (CoQ10) is a naturally occurring antioxidant that plays an important role in cellular energy metabolism. Statin therapy significantly lowers blood CoQ10 levels,276 and for this reason many health care providers recommend CoQ10 supplementation for those taking statins.

CoQ10 deficiency is associated with an increased risk of cardiovascular disease. Several publications suggest that CoQ10 has beneficial effects on CRP and levels of pro-inflammatory biochemicals.277 After one year of supplementing with CoQ10 and aged garlic extract, a small trial of healthy, nonsmoking firefighters found an improvement in measures of arterial stiffness and endothelial function compared with placebo.278 In this same group, calcium artery scores were used to estimate risk of atherosclerosis. Before treatment, the average calcium score was in the moderate range. Supplementation slowed the rate of increase of the average calcium score by a statistically significant amount, suggesting the combination of CoQ10 and aged garlic extract may slow the progression of atherosclerosis before it becomes clinically evident.279

A review of five well-controlled studies established that CoQ10 supplementation improved vascular endothelial function in patients with known atherosclerosis or significant risk factors for atherosclerosis, like high cholesterol and diabetes.280 Macrophages isolated from the blood of healthy volunteers that were given 100 mg CoQ10 for one week proved resistant to foam cell formation compared with those from people who received placebo through increased cholesterol removal from cells.281 A recent cellular study found that CoQ10 may play a role in reducing atherosclerotic plaques by inhibiting a platelet signaling pathway.282

Magnesium

Magnesium plays several important roles in cardiovascular health.283 Accordingly, magnesium deficiency can contribute to several problems with cardiovascular physiology.283 Clinical studies have shown that magnesium supplementation can favorably modulate parameters related to cardiovascular health, including blood pressure,284 endothelial function,285 arterial stiffness and calcification,286,287 and hs-CRP levels,288 among others. Observational evidence suggests greater magnesium intake is associated with lower mortality among people at high risk of cardiovascular disease.289

Propionyl-L-carnitine

Propionyl-L-carnitine has received attention for its ability to decrease the severity of atherosclerotic lesions in animals.290 Propionyl-L-carnitine is a chemical made in the body that rapidly passes into cells across the mitochondrial membrane to supply free carnitine, a much-needed factor for energy production.291 Carnitines are essential for mitochondrial fatty acid transport and energy production, which is important because endothelial cells and heart muscle cells mostly burn fatty acids as their source of energy.292

Animal studies suggest propionyl-L-carnitine may help prevent or decrease the severity of vascular disease. In rabbits fed a high-cholesterol diet, which normally induces endothelial dysfunction and subsequent atherosclerosis, supplementation with propionyl-L-carnitine resulted in reduced plaque thickness, markedly lowered triglyceride levels, and reduced proliferation of foam cells.290 In a rat study, propionyl-L-carnitine accelerated wound healing, reduced oxidative stress, and improved vascular function.293 In human studies, propionyl-L-carnitine produced significant improvement in maximum walking distance in those with claudication (pain while walking due to atherosclerosis in the legs), with no major side effects.294

Carnosine

Carnosine is an antioxidant that naturally occurs in meat sources, and therefore is often lacking from a vegetarian diet. Carnosine is a dipeptide (two amino acids linked together) composed of the amino acids L-histidine and beta-alanine. In the body, carnosine can counteract oxidative stress and improve muscle contractions.295

In the laboratory, when added to cultures of human macrophages, carnosine inhibited the formation of foam cells.296 Animal research suggests the antioxidant, anti-inflammatory, and chelating properties of carnosine make it potentially therapeutic for cardiovascular and metabolic disorders.297 A pilot study in overweight individuals demonstrated improved insulin resistance after three months of carnosine supplementation, leading some experts to hypothesize that carnosine may prove to be useful in controlling atherosclerosis risk factors, particular in diabetes.237,298

Lipoic Acid

Lipoic acid, a naturally occurring antioxidant, serves as a coenzyme in energy metabolism of fats, carbohydrates, and proteins. It can regenerate thioredoxin (an antioxidant protein), vitamin C, and glutathione, which in turn can recycle vitamin E. Lipoic acid also helps manage proper serum glucose levels in diabetic patients.299 Research suggests that lipoic acid decreases oxidative stress, which may promote optimal cardiovascular health.300

In a rabbit model of atherosclerosis, rabbits were fed a high cholesterol diet with and without lipoic acid supplements for three months. Those that received the supplements demonstrated a reduction in atherosclerotic plaque formation as determined by MRI of their abdominal aortas.301 In a randomized placebo-controlled clinical trial in 58 patients with metabolic syndrome, one month of lipoic acid supplementation improved vascular endothelial function and reduced levels of pro-inflammatory biochemicals.302

Glucosamine

Known best as a supplement for combating osteoarthritis and joint pain, glucosamine may have benefits above and beyond these indications. In a recent randomized controlled trial, 3,000 mg glucosamine for four weeks improved vascular endothelial function.303 In another questionnaire-based study of nearly 78,000 people from Washington state found that regular glucosamine use was associated with a non-significant 12% reduced risk of death from cardiovascular disease, as well as significantly associated with a reduced risk of death from cancer, respiratory illness, and all other causes.304

Findings from the United Kingdom’s health resource databank, UK Biobank, published in early 2019 suggested people taking glucosamine supplements for arthritis have a lower risk of death from cardiovascular disease, atherosclerosis, and heart attack and stroke, even after statistically adjusting the data to remove influence from age, gender, BMI, race, lifestyle factors, dietary intake, drug use, and other supplement use.305

Selenium

Selenium, an antioxidant and trace mineral naturally found in seafood and organ meats, is essential for DNA synthesis, reproduction, and protection from oxidative damage.306 Animal research suggests selenium supplementation may be cardioprotective, and that it prevents atherosclerosis by inhibiting oxidative stress, suppressing endothelial dysfunction, and modulating inflammation.307

In a controlled study involving mice, animals fed a diet fortified with selenium (0.3 mg/kg) had reduced plaque lesion formation.308 A cellular model of atherosclerosis demonstrated that selenium and vitamin D attenuated monocyte adhesion to endothelial cells.309 This suggests these nutrients may play a role in modulating the atherosclerotic process. However, further study is necessary to confirm the role selenium plays in preventing atherosclerosis.

L-Arginine

L-arginine, typically found in meat, fish, and soy, is an amino acid that has attracted attention for its ability to improve endothelial function and dilate blood vessels. L-arginine serves as the precursor of NO in the endothelium.310,311 Cell line and animal studies suggest L-arginine decreases inflammation and reduces vascular dysfunction.312-314 In a human study looking at the effects of oral L-arginine in patients with stable coronary artery disease, 10 grams L-arginine daily improved brachial artery dilation, a measure of endothelial function, and reduced LDL oxidation.315

Arginine Silicate

Arginine silicate, a specialized form of arginine stabilized with inositol, has been shown to boost NO levels and may represent a novel form of arginine with potential benefits in cardiovascular health.316 Interestingly, arginine silicate has also been shown to improve some aspects of cognitive function in a clinical trial in healthy young men. These results were postulated to be related to improved blood flow.317 In a rat model of kidney and cardiovascular disease, arginine silicate improved some measures of vascular function and manifestations of kidney damage.318

Aronia melanocarpa

Aronia melanocarpa, also called black chokeberry, is a member of the rose family. It produces small berries rich in polyphenols. In a clinical trial, 66 healthy male adults consumed an aronia extract containing 40% total polyphenols daily for 12 weeks. The aronia extract led to a significant improvement in flow-mediated dilation, a measure of vascular function. Aronia extract supplementation also led to potentially beneficial modifications of the gut microbiota. The authors of the study concluded that “…daily consumption of aronia berry polyphenols…has the potential to maintain cardiovascular health in healthy individuals at low risk of cardiovascular disease.”319 In a pre-clinical study, aronia extract, at relatively low concentrations, increased NO production by bovine endothelial cells.320

Red Yeast Rice

Red yeast rice is a fermented type of rice that contains naturally occurring compounds called monacolins that reduce LDL cholesterol with the same mechanism as statins. In those who cannot tolerate the side effects of statins, red yeast rice can be considered as an acceptable substitute.321 One well-controlled clinical trial using red yeast rice extract in individuals with prior heart attack and not taking any cholesterol-lowering medication showed that the supplement cut the incidence of heart attack and cardiovascular death by nearly one-half.322

Notably, there is evidence that red yeast rice supplements can be appropriate for adults of all ages, including the elderly.219 Also, the LDL-lowering effects can be appropriate for younger individuals, based on a controlled trial that showed a supplement containing red yeast rice to be safe and effective in LDL-lowering in people as young as 18 years old.323

In a recent animal study, red yeast rice decreased plaque formation and cholesterol levels in mice with atherosclerosis on a high-fat diet. The red yeast rice structurally changed the intestinal microflora, improved intestinal barrier function, and mediated inflammatory signaling pathways. The authors concluded that red yeast rice could alter gut microflora, which was protective against atherosclerosis.324

Garlic

Allicin is a naturally occurring substance that is released when fresh garlic is crushed. The chemical reaction creates hydrogen sulfide, which may have properties that counteract atherosclerosis.237 Aged garlic extract also contains similar sulfur-based compounds that have antioxidant effects protective against vascular endothelial damage.325

Garlic powder supplements were found to decrease atherosclerosis plaque progression in a placebo-controlled trial of 152 people with advanced carotid and/or femoral plaque as determined by ultrasound.326 In a thorough review of randomized controlled trials and meta-analyses, garlic supplementation was found to help reduce blood pressure and cholesterol levels. Aged garlic extract was especially effective at improving CRP and coronary artery calcification.61

Curcumin

Curcumin is an active ingredient in turmeric, a spice commonly used in curry. Because of its antioxidant properties, it has been studied in human atherosclerosis trials. A study of 32 healthy but sedentary post-menopausal women compared curcumin supplementation to exercise, which is known to improve vascular endothelial function. After eight weeks, the supplement group displayed an improvement in endothelial function that was as good as a supervised moderate aerobic exercise program. A control group which received neither curcumin supplements nor an exercise program showed no change in endothelial function.327 Recent animal research suggests a novel, soluble form of curcumin promotes plaque stability and reduces the development of atherosclerosis.328

In a trial of 240 men and women with type 2 diabetes and a low incidence (6%) of established atherosclerosis that received curcumin supplementation for six months, researchers found an improvement in endothelial function in the group receiving supplements compared with the placebo group. Interestingly, curcumin supplementation led to a significant decrease in leptin levels in the blood as well.329 As noted elsewhere, excess levels of leptin resulting from leptin resistance causes endothelial dysfunction, inflammatory stress, and promotes thrombosis.328

Lycopene

Lycopene, an antioxidant carotenoid found in tomatoes and other fruits and vegetables, has been studied as a protective compound against atherosclerosis. Its potential protective mechanisms include the ability to reduce inflammation, decrease cholesterol production, and inhibit smooth muscle proliferation.330 In a controlled trial involving patients with stable cardiovascular disease, adding lycopene to existing statin therapy led to a significant improvement in endothelial function. No effect on endothelial function was observed in age-matched healthy controls.331

Lycopene’s capacity to reduce inflammation was highlighted in a 2016 controlled “feeding” trial in 40 healthy volunteers. The results showed that a single meal of tomatoes or tomato sauce reduced blood levels of inflammatory biochemicals, and this effect was enhanced when refined olive oil was added to the meal.12 In a study involving type II diabetic rats, 10 mcg/mL of lycopene improved vascular cell proliferation and promoted endothelial progenitor cells, which are involved in the repair of the vascular endothelium.332

Saffron

Known best as a cooking spice and natural coloring agent, saffron has also been used as a medicinal plant for its pain-relieving and anticancer properties. Because of some promising animal studies showing an improvement in atherosclerosis plaque formation, there is interest in studying saffron as a treatment for atherosclerosis.333 A controlled trial involving 105 participants with the constellation of heart disease risk factors called metabolic syndrome found that saffron supplementation reduced amounts of antibodies to heat shock proteins.334 These antibodies are thought to have a role in accelerating the atherosclerosis disease process,335 and reducing them may therefore have a protective effect. In a randomized double-blind clinical trial, 63 people with atherosclerosis received either 100 mg saffron or placebo daily for six weeks. Those in the treatment group showed altered expression of the microRNAs that regulate gene expression of biomarkers of cardiovascular disease.336

Capsaicin

The ingredient in hot peppers that provides heat to the spice has also been shown in animal models to have beneficial effects on vascular endothelial function and atherosclerosis progression.337 Interestingly, according to a small but well-controlled study, applying a capsaicin patch on individuals with atherosclerosis prior to an exercise stress test enhanced blood NO levels.338 As mentioned elsewhere, NO is a naturally occurring biochemical that lowers blood pressure and increases blood flow. In individuals with low levels of the protective HDL cholesterol, three months of capsaicin supplements raised HDL levels and decreased triglyceride and CRP levels compared with placebo.339 In a randomized animal model study, guinea pigs fed a high-fat diet that received 2.5‒10 mg/kg capsaicin demonstrated reduced oxidative stress and improved endothelial function. All doses of capsaicin decreased total cholesterol and triglyceride levels and increased HDL cholesterol levels.340

Centella asiatica

Centella asiatica (commonly known as Gotu Kola) is a perennial herbaceous plant used in traditional Ayurvedic and Chinese medicine for thousands of years.341 The most important bioactive components in C. asiatica are triterpenes, which may have plaque-stabilizing abilities.342 Centella’s benefit to the vascular endothelium appears to be related, at least in part, to anti-inflammatory activity, modulation of collagen formation, and oxidative stress reduction.343

In two randomized controlled trials in patients with atherosclerosis, supplementation with 60 mg of a triterpenoid extract of C. asiatica three times daily for 12 months stabilized atherosclerotic plaques in femoral and carotid arteries.342,344 In another study that followed over 300 people with asymptomatic atherosclerosis for four years, the use of a C. asiatica and Pycnogenol extract (100 mg of each) was better than diet and exercise or Pycnogenol supplementation (100 mg) alone at reducing plaque progression and oxidative stress.345 The authors concluded that the results are promising and warrant a larger study.

Ginkgo Biloba

Ginkgo biloba is an extract from leaves of the tree of the same name (also known as the maidenhair tree). This extract has traditionally been used for thousands of years to promote cardiovascular health, relax the lungs, and as a circulatory system tonic.346 Several in vitro studies have shown that ginkgo may favorably alter endothelial function and reduce levels of ox-LDL.347-349

In a study involving eight patients who had recently undergone coronary artery bypass surgery, supplementation with ginkgo biloba extract, at 120 mg twice daily, was shown to reduce atherosclerotic plaque formation. Furthermore, ginkgo increased levels of endogenous antioxidant enzymes and reduced levels of ox-LDL.350 Studies of ginkgo biloba supplementation in humans have also demonstrated an improvement in claudication (pain while walking due to atherosclerosis in the legs).351 For this reason, ginkgo biloba is used commonly in Europe for symptoms of peripheral arterial disease.

Policosanol

Policosanol is an extract from the waxy coating of sugar cane. Research in rats with high cholesterol levels indicates that policosanol increased fecal cholesterol content and inhibited cholesterol biosynthesis and LDL cholesterol uptake.352 A randomized controlled study of hypertensive rats found that after eight weeks, policosanol (at doses of 20, 100, and 200 mg/kg) reduced blood pressure levels in a dose-dependent manner. Markers of hepatic inflammation and triglyceride levels were decreased and HDL cholesterol levels were elevated in the treatment groups.353

An older prospective, randomized, double-blind, placebo-controlled trial involved nearly 590 people with high cholesterol and blood pressure levels taking either 5 mg policosanol or placebo daily for 12 months. After six months, the policosanol dosage was doubled in those with cholesterol levels greater than 6.1 mmol/L. Policosanol decreased blood pressure, cholesterol, and increased HDL cholesterol levels compared with placebo.354 Further research is warranted to determine how policosanol impacts cardiovascular health.

Guggul

Guggul is a plant extract traditionally used to ameliorate arthritis, urinary tract disorders, and skin conditions.355 An animal study concluded that 3.5 mg/kg of guggul, alone and in combination with 3.7 mg/kg of atorvastatin, lowered cholesterol, LDL, VLDL, and triglyceride levels compared with control rabbits fed a high-fat diet.356 In another study involving mice fed a high-fat diet for 16 weeks, a combination of Curcuma longa, silymarin, guggul, chlorogenic acid, and inulin altered inflammatory activity and lipid metabolism, which may play a role in modulating atherosclerotic development.357 Older human research suggests guggul may support healthy cholesterol levels,358 but more clinical research is warranted.

Hawthorn

Hawthorn, a flower shrub of the rose family, has traditionally been used to treat heart, digestive, and kidney problems, and to combat anxiety.359 A mouse study found that 50 mg/kg hawthorn extract daily for 16 weeks decreased inflammatory markers as well as triglyceride, total cholesterol, and LDL cholesterol levels and increased HDL cholesterol levels.360 Another animal model study found that hawthorn attenuated atherosclerotic lesion area, inhibited foam cell formation, and altered the expression of genes involved with antioxidant activities. This is suggestive of hawthorn’s potential therapeutic use in preventing atherosclerosis.361

Potassium

Potassium, found naturally in fruits, vegetables, legumes, and potatoes, is an essential nutrient that is vital to cellular functioning.362 A recent animal study indicates that reduced dietary potassium intake was associated with arterial stiffness and atherosclerotic vascular calcification. The authors postulated that reduced potassium concentrations increased intracellular calcium levels.363 Further research is warranted to determine how dietary potassium intake influences cardiovascular health.

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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