What is Atherosclerosis?

Atherosclerosis is a chronic progressive condition of the arteries marked by characteristic lesions known as atheromas or atherosclerotic plaques. It is the main cause of heart attack, stroke, serious peripheral artery disease events, and cardiovascular death.^1,2 Atherosclerosis is generally caused by a combination of endothelial dysfunction, inflammation, and oxidative stress, which may be induced by a range of conditions such as smoking, unhealthy lifestyle, abnormal lipid levels, insulin resistance, obesity, and high blood pressure.³

As atherosclerosis progresses, plaques can expand within arteries, obstructing blood flow to tissues and sometimes causing site-specific symptoms. A plaque can also become highly inflamed and prone to rupture. Plaque rupture leads to formation of a blood clot that can block blood flow or break off into circulation and obstruct smaller vessels, sometimes resulting in major, life-threatening, catastrophic cardiovascular events.² Blood clot formation can also be triggered by erosion of the cells covering a plaque. Plaque erosion is a less common but important cause of major cardiovascular events, frequently in people without classic cardiovascular risk factors, but is associated with a better prognosis than plaque rupture.⁴

What are Risk Factors for Atherosclerosis and Cardiovascular Disease?

There are many conditions associated with atherosclerosis and cardiovascular risk. Some important risk factors include^5,6:

• Older age
• Family history
• Unhealthy diet and sedentary lifestyle
• Smoking
• Dyslipidemia (imbalanced levels of cholesterol and triglycerides)
• Hypertension
• Elevated glucose and insulin levels
• Chronic kidney disease
• Obesity
• High homocysteine levels
• A range of chronic inflammatory conditions
• Chronic infections such as human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)

It is important to note that a growing proportion of cardiovascular events, including heart attacks, are now occurring in people without well-established risk factors.^7,8

What are the Signs and Symptoms of Atherosclerosis?

Atherosclerosis is generally asymptomatic until very late stages. It is therefore critical for all susceptible individuals to take preventative measures and monitor their cardiovascular health.

What are the Treatments for Atherosclerosis?

• Cholesterol-lowering drugs
• Anti-platelet drugs, including aspirin
• Blood pressure-lowering drugs
• Blood glucose-lowering drugs
• Surgeries, such as coronary artery bypass and percutaneous coronary intervention (angioplasty)

What Dietary and Lifestyle Changes Can Benefit Atherosclerosis?

• Eat a balanced, plant-based diet rich in fruits and vegetables (eg, a Mediterranean-style diet)
• Include heart-healthy foods like extra virgin olive oil, cold water fish, and fiber-rich whole grains
• Exercise regularly
• Get adequate sleep (duration and quality)
• Build healthy social networks
• Do not smoke
• Limit or avoid alcohol intake

What Nutrients May Counteract Atherosclerosis?

• Omega-3 fatty acids. Omega-3 fatty acids help prevent the development and progression of atherosclerosis through multiple mechanisms, including reducing inflammation, lowering triglyceride levels, improving endothelial function, and inhibiting blood clot formation.⁹
• Coenzyme Q10 (CoQ10). Treatment with CoQ10 can improve vascular endothelial function and lipid profiles in patients with atherosclerosis, in part through decreasing oxidative stress and inflammation.^10,11 In combination with selenium, CoQ10 decreased cardiovascular mortality in a long-term clinical trial.¹²
• B vitamins. Folate and other B vitamins have been found to lower the risk of stroke, largely by reducing homocysteine levels.¹³
• Curcumin. Clinical trials have shown curcumin can promote metabolic health, support weight loss, improve lipid levels, and lower high blood pressure, oxidative stress, and inflammation.¹⁴
• Lipoic acid. Lipoic acid has been found to improve endothelial function by reducing oxidative stress and inflammation and increasing endothelial nitric oxide synthesis.¹⁵
• Lycopene. In clinical trials, lycopene has demonstrated anti-atherogenic effects such as improvement in lipid profiles, blood pressure, and endothelial function, and reduction of inflammation and oxidative stress.¹⁶
• Garlic extracts. Garlic and its extracts, in various preparations, have been shown to exert broad anti-atherogenic effects through lipid- and blood pressure-lowering effects, as well as lowering inflammation, homocysteine, and protecting against coronary artery calcification.¹⁷
• Polyphenols. This broad class of plant-derived molecules includes an array of anti-atherogenic compounds including resveratrol, quercetin, hesperidin from citrus peel, catechins from tea, flavanols from cocoa, proanthocyanidins from grape seeds, French maritime pine bark, arjuna bark, aronia and hawthorn berries, and more. Their beneficial effects are attributable in large part to combatting oxidative stress and inflammation, reducing blood pressure and atherogenic lipids, and promoting healthy endothelial function.^18,19
• Other natural interventions that may help counteract some of the processes that contribute to atherosclerosis and its progression include ginkgo biloba, lutein, magnesium, L-arginine, vitamins K and E, and more.

Atherosclerosis is a chronic inflammatory disease process characterized by plaque lesions in the arterial walls.²⁰ Plaque is made up of fatty substances, immune cells, smooth muscle cells, and dead and dying cell debris, enclosed under a fibrous cap. A growing plaque may restrict blood flow and cause symptoms of ischemia (reduced blood flow). As atherosclerosis progresses, it may trigger the formation of a blood clot, which can lead to serious complications such as a heart attack or stroke.²¹

Atherosclerosis is often categorized by the area affected. Some of the more clinically important types of atherosclerosis are^22-24:

• Coronary artery disease, which affects the arteries of the heart
• Peripheral artery disease, which usually affects the arteries in the legs, but may involve arteries in the arms or pelvis
• Cerebrovascular disease, which involves the arteries that supply blood to the brain
• Aortic atherosclerosis, affecting the large artery (aorta) leading away from the heart
• Renal artery stenosis, which involves narrowing of the arteries that bring blood to the kidneys
• Mesenteric artery ischemia, which is a lack of blood flow to the intestines due to atherosclerosis

Coronary artery disease is the most common type of heart disease, affecting over 20 million American adults, and is the leading cause of death in the United States.^25,26 The prevalence of coronary artery disease increases with age: almost 11% of U.S. adults aged 45 years and older and 17% of those aged 65 years and older have coronary artery disease.²⁵ Nevertheless, it is important to note that the atherosclerotic process often begins in childhood, particularly in children with overweight and obesity and those with high blood glucose levels.²⁷

The consequences of other types of atherosclerosis are also tremendously significant. For example, cerebrovascular disease is a cause of stroke, and peripheral artery disease can restrict activities and result in loss of limbs.²⁰

Many factors contribute to the development of atherosclerosis, some of which are modifiable. These include smoking, poor diet, physical inactivity, and excessive alcohol consumption, as well as conditions such as high blood pressure, high cholesterol and/or triglycerides, diabetes and insulin resistance, obesity, sleep disorders, air pollution exposure, imbalanced gut microbiome, and certain bacterial and viral infections.^21,25 In addition, elevated blood levels of homocysteine and high-sensitivity C-reactive protein (hs-CRP) have consistently been found to be correlated with increased atherosclerosis risk.^28,29 Tracking risk factors through periodic blood testing can help monitor overall vascular health and plan diet, lifestyle, and nutrient supplementation regimens 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 supplements, can help support overall cardiovascular health.

Endothelial cells form a single-cell layer on the inside of blood vessels that facilitates blood flow, communicates with various blood cells, and acts as a barrier between the blood and the vessel wall. Endothelial cells are connected by tight junctions; however, in the initial stage of atherosclerosis, turbulent blood flow interrupts these connections, making them more permeable, or leaky, and allowing lipoproteins to penetrate into the space under the endothelial cells, known as the intima. Sites of turbulent blood flow—generally at branch points in the major arteries—are where the atherosclerotic process usually begins and are the most common sites of arterial plaques.^2,21

Nitric oxide (NO) affects vascular function and health by promoting blood vessel relaxation, regulating endothelial permeability, inhibiting blood clotting, and controlling vascular smooth muscle cell proliferation.³ NO is produced via the action of an enzyme made by endothelial cells, called endothelial nitric oxide synthase (eNOS), on the amino acid L-arginine.^3,30 It can also be synthesized from dietary nitrates, such as those found in beets and green leafy vegetables.³¹ Healthy endothelial cells regulate vascular tone in response to a complex network of signals by modulating their production of eNOS.³² Malfunction of the eNOS pathway, such as due to aging, inflammation, oxidative stress, and nutrient deficiencies, results in a cycle of endothelial NO deficiency, dysregulated vascular tone, and endothelial damage.^3,30 Endothelial dysfunction is characterized by reduced endothelial NO synthesis and is a defining feature of atherosclerosis.^3,32

Figure 1: Blood vessel anatomy. Credit: Double Brain, Shutterstock

Endothelial dysfunction, inflammation, and oxidative stress are key contributors to atherosclerosis initiation, as well as its progression. When endothelial cell functions are compromised, lipid and immune cells infiltrate the deeper layers of the vessel wall, triggering inflammation and free radical production. In a vicious cycle, this leads to more endothelial damage.² Factors such as aging, dyslipidemia, high blood pressure, diabetes, obesity, unhealthy diet, lack of exercise, and smoking help initiate atherosclerosis by promoting endothelial dysfunction, oxidative stress, and inflammatory pathways.³

Once trapped in the intima, lipoproteins undergo various changes, including aggregation and oxidation. It is thought that signals from oxidized lipids and other factors in the vessel wall trigger activation of endothelial cells, resulting in expression of cell surface proteins that attract and adhere to circulating immune cells called monocytes. These monocytes enter the intima of the blood vessel wall and undergo transformation into macrophages, specialized cells whose role is to engulf and destroy infectious agents, cancer cells, or other unhealthy substances.³³ Within the vessel wall, macrophages take up the excess aggregated and oxidized lipoproteins. In their lipid-laden state, they are known as foam cells. Accumulating foam cells frequently die and break down, releasing pro-inflammatory molecules, pro-clotting factors, enzymes, cholesterol, and cellular debris, forming the necrotic core of an atherosclerotic plaque.^2,21 Interestingly, other macrophages in atherosclerotic plaques take on the role of resolving inflammation. Pro-resolving macrophages are believed to contribute to plaque and atherosclerosis regression.³³

Vascular smooth muscle cells normally make up a layer of the blood vessel wall known as the media, and are responsible for contraction and relaxation of blood vessels.² As plaques develop and grow, smooth muscle cells migrate into the intima, where they can undergo transformation to become more like macrophages and, ultimately, foam cells. Other migratory smooth muscle cells proliferate and secrete collagen and other structural molecules that form a fibrous cap under the endothelial cell layer, which helps stabilize the plaque against rupture.²¹

Immune cells known as T cells and B cells play a nuanced role in atherosclerotic plaques. T cells within plaques release cellular messengers known as cytokines that regulate inflammatory processes. B cells produce antibodies to low-density lipoprotein (LDL), oxidized LDL, apolipoprotein B (ApoB), cellular debris, and even certain pathogens. These antibodies can promote or inhibit atherosclerosis by modulating the immune response.^21,34,35

Atherosclerosis Progression

Figure 2: Phases of atherosclerosis. Credit: TimeLineArtist, Shutterstock

Atherosclerosis develops over many years. During the course of the disease, affected arteries undergo changes to their composition and structure.³⁶ Classic rupture-prone plaques progress in recognizable ways and are the leading cause of fatal heart attacks and sudden death. However, plaques without characteristic high-risk features are responsible for a significant proportion of major coronary events due to plaque erosion or, rarely, eruptive calcified nodules.¹

Fatty streak formation. Atherosclerosis begins with accumulation of modified lipoproteins, smooth muscle cells, and extracellular matrix (non-cell components of body tissue) in the intimal layer of the vessel wall due to endothelial dysfunction. Immune cells then enter the vessel wall, leading to increased inflammatory signaling and the accumulation of foam cells. As foam cells coalesce, a visible fatty streak forms. Fatty streak formation can begin as early as childhood.^2,21

Advanced atherosclerosis. The progression of atherosclerotic plaque is defined by three key features: the formation of a fibrous cap that covers the lesion under the endothelial cell layer, development of a necrotic core, and calcification.²

The fibrous cap is made by smooth muscle cells that migrate to the endothelial region and secrete collagen and other extracellular materials. The cap can be thought of as a structural support that protects against rupture. Its ability to stabilize the plaque depends on its thickness and collagen content.^2,21

Foam cells, lipids and lipoproteins, and immune cells can continue to accumulate under the fibrous cap. As the foam cells die, a necrotic core filled with cholesterol and cellular debris may form. A growing necrotic core can cause a plaque to expand into the lumen (the opening of the vessel where blood flows) and impede blood flow.^2,21

Vascular calcification is another important feature of advanced atherosclerosis. Calcium is released from dying smooth muscle cells and macrophages in the deeper layers of the vessel wall, forming microcalcifications under the necrotic core that can evolve into larger calcifications.^2,21 Calcified plaque is generally more stable than non-calcified plaque; nevertheless, coronary artery calcification has been closely correlated with the risk of cardiovascular events and mortality, probably because it reflects overall atherosclerosis burden.^37,38

Plaque stability. A highly calcified plaque with a small core and a thick fibrous cap tends to be more stable, while one with microcalcifications and a large inflamed necrotic core is more prone to rupture. Macrophages contribute to vulnerability by ramping up inflammation and releasing enzymes called matrix metalloproteinases (MMPs) that break down the fibrous cap. T-cell infiltration of the cap has also been implicated in destabilizing plaque.^21,39

Importantly, the size of a plaque and its obstruction of a vessel opening are unrelated to its stability.³⁸ For instance, when a plaque obstructs 70–80% of a coronary vessel, shortness of breath and chest pain (angina), especially with exertion, may occur. Over time, restricted coronary blood flow can weaken the heart muscle. On the other hand, rupture of an unstable plaque can give rise to an acute catastrophic cardiovascular event.²³

Plaque destabilization and thrombosis. Plaque destabilization results in thrombosis (the formation of a blood clot) in the blood vessel. Plaques can become destabilized through rupture, erosion, or eruptive calcified nodules. Plaques that rupture and plaques that erode have very different compositions and characteristics, tend to be located in different regions of arteries, and tend to occur in different populations.^4,7

• Plaque rupture. The fibrous cap of a highly inflamed lipid-rich plaque is vulnerable to rupture, allowing blood to come in contact with the necrotic core, triggering thrombosis. Plaque rupture is the cause in the majority of serious cardiovascular events, including heart attacks, strokes, critical peripheral artery disease events, and cardiovascular deaths.^1,2
• Plaque erosion. A very different type of plaque is susceptible to erosion rather than rupture.⁴⁰ Plaque erosion is implicated in roughly 30–40% of acute coronary events.^4,7 Plaque erosion-related blood clots and acute coronary events result from a breach in the endothelial barrier covering an erosive-type plaque, exposing the intact fibrous cap to blood flow.¹ Circulating platelets become activated by exposed smooth muscle cells and the non-cellular matrix of the cap, triggering thrombosis. Cytotoxic T cells and white blood cells called neutrophils are attracted to the site of endothelial erosion and play a role in this process.^1,4

Compared to rupture-prone plaques, plaque erosion tends to occur in younger individuals, in women more than men, and in people with a milder extent and severity of atherosclerosis.^40,41 In addition, eroded plaques are less inflamed, with less or absent lipid-laden and necrotic core, and have a higher concentration of vascular smooth muscle cells in a thick intact fibrous cap compared with plaques that rupture.¹ People with plaque erosion have better outcomes than those with plaque rupture, possibly because they have a lower overall atherosclerosis burden and fewer traditional cardiovascular risk factors.^4,42

• Eruptive calcified nodules. A third mechanism of plaque destabilization known to cause cardiovascular events involves eruption of calcified nodules through the vessel lining and into the lumen, leading to blood clot initiation.⁴³ Although the cause of calcified nodule formation is not fully understood, mechanical stress on the endothelium is thought to contribute. Eruptive calcified nodules are a relatively rare cause of acute coronary thrombosis often associated with extensive coronary artery calcification and advanced age.¹

Plaque destabilization and thrombosis can lead to life-threatening events.³⁹ A blood clot can grow and block blood flow where it forms or may break off and travel in the bloodstream as an embolism. An embolism poses the threat of becoming trapped in a small vessel and obstructing blood flow elsewhere in the body. Blood clots that block heart or brain blood flow are especially dangerous because they result in heart attack or stroke, respectively.²

Plaque healing. associated with catastrophic outcomes, the eventual outcome in most cases is repair. As healing occurs, the thrombus is stabilized by a structural protein called fibrin. Vascular smooth muscle cells infiltrate and further stabilize the site, and a new endothelium is eventually generated. Some healed plaques do not cause any clinical events, but others undergo structural changes over a period of days to weeks that eventually occlude the vessel, resulting in an acute ischemic event (eg, a heart attack) long after the initial plaque destabilization.⁴ Another possible outcome is multiple cycles of asymptomatic plaque rupture and healing, with continued atherosclerosis progression and narrowing of arteries.^23,39

Refer to Life Extension’s protocol on Blood Clot Prevention for more information.

Atherosclerosis often causes no symptoms until there is severe and potentially deadly arterial blockage. This is why early monitoring of cardiovascular risk factors through preventive blood testing and adhering to a healthy diet and lifestyle are important. When symptoms do occur, they vary depending on the location of the blockage and whether the obstruction is chronic or acute.

Coronary artery disease can cause a type of chest pain or discomfort known as angina. Angina usually occurs when blood flow to the heart muscle is chronically restricted due to narrowing of one or more coronary arteries. It may be described as heaviness, pressure, or a squeezing sensation on the left side or center of the chest and may be accompanied by shortness of breath, fatigue, nausea, a heartburn-like sensation, a lump in the throat, or other symptoms. In stable angina, symptoms are triggered by exertion or stress and resolve with rest, whereas in unstable angina—an acute medical emergency—symptoms come on unpredictably and do not respond to rest. Sweating, fatigue, breathlessness, and nausea even in the absence of chest pain are considered angina-equivalent when they occur in people with a high cardiovascular risk.^44,45

Acute coronary syndrome is a life-threatening event that occurs when blood flow to the heart muscle is suddenly severely decreased. This includes unstable angina and heart attack. Acute coronary syndrome is often accompanied or preceded by chest pain, or pain or discomfort in the arm, jaw, or back.⁴⁶ Other symptoms that may herald acute coronary syndrome include shortness of breath, unusual fatigue and weakness, sleep disturbance, nausea, digestive upset, lightheadedness, sweating, headache, and anxiety. Such symptoms have been reported anywhere from three months to two days before acute coronary syndrome.⁴⁷

Peripheral artery disease may cause pain in the extremities (usually the legs) due to chronic blood flow restriction. This pain, known as claudication and frequently felt in the calf, is typically triggered by exertion and relieved with rest; however, in more advanced disease with greater blood flow restriction, symptoms are more persistent.⁴⁷

Cerebrovascular atherosclerosis affecting the intracranial, vertebral, and carotid artery systems in the neck and skull can give rise to clots that cause sudden obstructive events such as strokes and transient ischemic attacks (TIAs).²⁴ Neurological symptoms such as weakness, numbness, confusion, speech problems, dizziness, loss of coordination and balance, and vision problems mark these events.^47,48 In addition, it is now thought that early-stage carotid artery disease, once referred to as asymptomatic, may be marked by “age-related” cognitive decline and impairment resulting from chronic restriction in brain blood flow.⁴⁸

Renal artery stenosis can restrict blood flow to one or both kidneys, which, over time, contributes to high blood pressure and chronic kidney disease (CKD).^49,50

Atherosclerosis tends to affect multiple locations within an individual. For instance, people with peripheral artery disease often have carotid and coronary artery diseases.^51,52

Diagnosis

Atherosclerosis can be diagnosed in the absence of symptoms, with non-urgent symptoms, or in an acute or emergency setting. Exam and diagnostic testing will vary, depending on the context.

In a non-emergency setting, diagnosis of atherosclerosis begins with a complete history and physical exam. Risk factors related to lifestyle, personal medical history, and family history can be assessed and blood pressure can be measured.²² This should be followed by laboratory assessment of the lipid profile and glucose metabolism. Laboratory tests include a full lipid panel with total cholesterol, LDL-cholesterol, high-density lipoprotein (HDL) -cholesterol, and triglyceride levels. Test results may also provide calculated values for non–HDL-cholesterol and a total-to-HDL-cholesterol ratio, which appear to be more closely correlated with cardiovascular risk than total or LDL-cholesterol levels.⁶⁸ Testing for additional important cholesterol fractions, including oxidized LDL and LDL particle size and count, should also be considered. Basic glucose metabolism testing would begin with fasting blood glucose and hemoglobin A1C (HbA1c).

In some cases, such as in individuals at higher risk and those presenting with symptoms, additional diagnostics may be ordered, including:

• Electrocardiogram (EKG or ECG) detects abnormalities in the heart’s electrical activity and can identify a current or past heart attack²²
• Coronary artery calcium (CAC) scoring (see below)^69-71
• Other heart and vessel imaging tests, such as²²:
  • angiography, a type of X-ray that uses a dye to visualize arteries
  • cardiac magnetic resonance imaging (MRI) to detect tissue damage or altered coronary blood flow
  • cardiac positron emission tomography (PET) to help visualize blood flow in the small arteries of the heart
  • ankle-brachial index (ABI) test to diagnose peripheral artery disease
  • stress test to assess the heart’s ability to respond to and recover from physical stress, such as exercise

Cardiovascular risk assessment is a crucial part of cardiovascular health maintenance. Established cardiovascular risk factors like high blood pressure and obesity can provide substantial insight into your cardiovascular health and can be diagnosed in a basic physical exam. Accessible inexpensive blood tests, including a standard lipid (cholesterol) panel and glucose level, provide information about other traditional risk factors. Additional blood tests, such as hs-CRP and ApoB, may add predictive value to an overall assessment. These biomarkers can also be helpful in monitoring the effects of lifestyle, nutritional, and medical interventions.

The following section explores many factors that can be part of a comprehensive cardiovascular risk assessment. Everyone interested in maximizing their healthspan should be sure to regularly monitor their risk with periodic lab testing, biomarker assessment, and overall health evaluations with their health care provider.

Understanding Cardiovascular Risk

Many decades of medical research have clarified the associations between various risk factors and cardiovascular disease. Some of these risk factors, like age and family history, are beyond our control. These are said to be “non-modifiable” risk factors. On the other hand, risk factors like high blood pressure and elevated LDL-cholesterol are “modifiable,” since therapies or diet and behavior adjustments can modulate the risk associated with these factors.

The level of certainty that specific factors influence cardiovascular risk and atherosclerosis development varies. Some risk factors are very clearly linked to cardiovascular disease and have been demonstrated to be important in rigorous research. These are described in this Protocol as “established cardiovascular risk factors.”

On the other hand, some risk factors appear to influence cardiovascular risk, but the research is not as robust and conclusions about the influence of these risk factors are not as certain. We describe these as “emerging cardiovascular risk factors.”

Generally, a prudent approach for most people who want to maximize their healthspan is to first ensure that they are aware of risk conferred by non-modifiable factors like age, race, and family history. Then, established modifiable cardiovascular risk factors should be assessed and optimized to the extent possible. Lastly, attention should be given to emerging modifiable risk factors.

Estimating Cardiovascular Risk

Over the years, the American Heart Association has developed risk calculators to estimate an individual’s chance of a cardiovascular event. PREVENT (Predicting Risk of Cardiovascular Disease EVENTs), launched in 2023, is an American Heart Association tool for cardiovascular disease risk assessment. The PREVENT tool takes into account markers of cardiovascular, metabolic, and kidney health, and can be used by those 30‒79 years of age without known cardiovascular disease to quantify their 10- and 30-year risks of heart attack, stroke, and heart failure. The calculations are based on age, gender, cholesterol levels, systolic blood pressure, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoker versus non-smoker status, and current use of blood glucose-lowering, blood pressure-lowering, and cholesterol-lowering drugs. Optional information about one’s urine albumin-to-creatinine ratio (a marker of kidney function), hemoglobin A1c (HbA1c, a marker of blood glucose control), and zip code (a marker used to estimate social determinants of health) can be added to improve accuracy when these numbers are relevant and available.⁷²

The risk calculator can be accessed here: PREVENT Online Calculator.

PREVENT has been found to be accurate across a large population of U.S. adults.⁷² Nevertheless, it does not assess known cardiometabolic risk factors such as stress, social isolation, and physical inactivity, and does not incorporate information about family history, mental health and sleep disorders, and other non-metabolic/non-renal chronic inflammatory conditions. This can lead to inaccuracies in estimating an individual’s risk. Furthermore, while PREVENT has demonstrated usefulness in the United States, it may not be an accurate or precise tool for assessing risk in populations in other world regions.⁷³ Also, it is intended for estimating risk in those without a history of heart disease, stroke, or heart failure.

Importantly, as of early-2025, the PREVENT calculator is still a relatively new tool. As such, the implications of particular risk estimates based on PREVENT are still being ironed out by researchers. For example, the threshold risk estimate at which to initiate statin therapy is still being refined in the medical literature.⁷⁴ Therefore, it is necessary to view the risk estimates generated by the PREVENT calculator as an informative tool in shaping discussions about whether specific therapies are appropriate, and the PREVENT risk estimates should not be used in isolation to make intervention decisions.

Non-Modifiable Risk Factors

Age & Genetics

Atherosclerosis mainly afflicts older individuals, in part due to cumulative molecular and epigenetic effects from modifiable risk factors that result in changes in vascular structure and function.⁷⁵ Most heart attacks and strokes, especially ones involving plaque rupture, occur in those over 55 years of age.^7,21,25 A phenomenon known as inflammaging, chronic low-level inflammation that often accompanies aging, is an important driver of atherosclerosis.⁷⁶

 

Family History

Family history is an important risk factor for atherosclerosis. Evidence points to both genetics and shared environmental conditions as explanations for the link between an individual’s risk and the vascular disease history in their immediate family.⁸¹

Apolipoprotein E (ApoE) Variants

Apolipoprotein E (ApoE) is a type of lipoprotein fraction that plays a role in lipid transport and distribution to tissues, as well as in modulating inflammation.⁸² ApoE plays a critical role in the removal of triglyceride- and cholesterol-laden lipoproteins such as LDL from circulation.⁸³ There are three known genetic variants of ApoE, and they influence atherosclerosis risk differently. ApoE3 is the most common variant, occurring in approximately 70–80% of people, and is considered neutral with no strong influence on atherosclerosis or dementia risk. ApoE4, occurring in about 14% of people, is associated with a higher risk of cardiovascular disease. ApoE2 occurs in roughly 5–10% of people and is generally associated with a lower risk of coronary artery disease—although it may increase the risk of atherosclerosis in certain cases.^82,83 In addition, ApoE2 and ApoE4 are closely associated with decreased and increased risk, respectively, of Alzheimer disease, and may play a role in cancer progression.^82,84 Genetic testing for ApoE variants may help an individual better understand the genetic contribution of their ApoE status to their risk for atherosclerosis.

Gender

Coronary atherosclerosis develops approximately seven to 10 years later in women than men, and men have a three-fold higher risk of acute coronary syndrome (heart attack or unstable angina) than women before the age of 60. The gap in atherosclerosis risk between genders narrows after 60 years and disappears at around 75 years of age. This can be explained in part by the cardio-protective effects of pre-menopausal estrogen levels, since estrogen has positive effects on lipid profiles and inhibits blood clotting mechanisms.⁸⁵

Race

The relationship between race and atherosclerosis risk is complex and not fully understood. While non-Hispanic White individuals have been reported to have a higher incidence of coronary artery disease than other racial groups, Black individuals have higher risks of fatal heart attack or stroke than White individuals. Hispanic individuals, particularly those of Mexican descent, have a lower incidence of coronary artery disease than other racial groups, despite being more likely to have adverse risk profiles. Asian people overall have lower risks of coronary artery disease and cardiovascular events; however, Asian-Indian and Filipino individuals have been found to have higher risks than other racial groups. The reasons for these differences are multifactorial, including genetic differences that affect susceptibility and disparities in social and economic conditions.^81,86

Established Modifiable Risk Factors

Atherosclerosis and the early phases of cardiovascular disease often begin early in life and progress slowly over decades. Developing healthy habits early and maintaining them throughout life can go a long way toward preserving cardiovascular health.

The following table includes established risk factors that can be influenced, for example, by adopting a healthy diet and lifestyle, intervening with targeted nutrients, and using medications when appropriate.⁸⁷ The importance of being aware of your risk profile as it relates to established, modifiable risk factors cannot be overstated. In fact, modifiable risk factors account for the majority of all cardiovascular events and deaths due to cardiovascular causes.⁸⁸

Atherosclerosis prevention relies on addressing modifiable risk factors. 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.

Adopt a Healthy Diet

A heart-healthy diet can be achieved through the following strategies:

Eat more plant foods and move towards a Mediterranean eating pattern. Healthy plant-based dietary patterns have been associated with lower cardiovascular risk and mortality and may protect against atherosclerosis by reducing inflammatory signaling, lowering associated risk factors like diabetes and hypertension, and supporting a healthy gut microbiome.⁸⁹ The Mediterranean diet in particular has the strongest evidence of benefit in terms of reducing risks of heart attack, stroke, cardiovascular death, and all-cause death.²²⁹ It is characterized by a high intake of olive oil, vegetables, fruits, whole grains, legumes (beans and lentils), and nuts and seeds, and may include modest amounts of seafood, dairy products, eggs, and lean poultry and meats. In clinical trials, Mediterranean diet interventions have consistently been shown to reduce plaque and improve biomarkers of atherosclerosis.²³⁰

Avoid processed foods. Processed meats and other highly processed foods, many of which are high in added salt, sugars (including sweetened beverages), and trans fats, have been linked to increased coronary artery disease risk and are generally not part of a healthy diet.^231-234

Reduce sodium and increase potassium intake. While sodium intake has been correlated with increased risk of coronary and carotid artery atherosclerosis,²³⁵ potassium (found naturally in fruits, vegetables, legumes, and potatoes) improves vascular health and function.²³⁶ Increasing potassium intake and reducing sodium intake, such as by replacing table salt with a salt substitute containing 25% potassium chloride, has been associated with reduced cardiovascular risk.²³⁷

Increase fiber intake. Numerous observational studies have linked increased dietary fiber with reduced risks of atherosclerosis, stroke, and peripheral vascular disease.²³⁸ Dietary fibers are indigestible or partially-digestible carbohydrates and lignins (structural components of plants) in plant foods. Soluble fibers are characterized by their ability to interact with water to form a thick solution or a gel. Many soluble fibers are readily fermented by intestinal bacteria and converted into anti-inflammatory compounds called short-chain fatty acids. Both soluble and insoluble fibers are important for health, and plant foods generally contain both, in varying proportions. High-fiber foods include legumes, whole grains, brans, nuts and seeds, vegetables, and fruits.²³⁹

Eat healthy fats. Saturated fat has long been considered unhealthy, and indeed it directly contributes to the formation of LDL-cholesterol. Replacement of dietary saturated fat with polyunsaturated fats (eg, from fish, safflower, and sunflower oils) and monounsaturated fats (eg, from olive oil, canola oil, avocados, and some nuts) has been found to reduce both LDL-cholesterol levels and cardiovascular events.²⁴⁰ It is important to note that when carbohydrates and sugars have been used as fat replacements, no cardiovascular benefit has been observed, and overall mortality may have increased.^240,241 Perspectives on dietary fats are evolving, as evidence suggests the context may partly determine its quality. For example, saturated fat from whole foods may be less harmful than those in ultra-processed foods.^241,242 Nevertheless, most sources continue to recommend restricting saturated fat intake and replacing those calories with unsaturated fats.²⁴²

Eat cold water fish. A meta-analysis of 25 observational studies with a total of more than 2 million subjects found that higher fish consumption and greater intake of omega-3 fatty acids (found in high concentrations in cold water fish [eg, salmon, herring, and trout]) were each associated with lower risk of death due to cardiovascular causes. Based on the data, the risk reduction was calculated to be 4% per 20 grams of fish eaten per day or 80 mg of omega-3 polyunsaturated fatty acids consumed per day.²⁴³

Use extra-virgin olive oil. Extra virgin olive oil has been intensively studied for its health benefits both on its own and as a component of the Mediterranean diet. Olive polyphenols, such as hydroxytyrosol and oleuropein, have demonstrated anti-inflammatory, antioxidant, anti-hypertensive, anti-diabetic, anti-thrombotic, HDL-raising, and anti-atherosclerotic effects in preclinical research.²⁴⁴ Meta-analyses of observational studies and randomized controlled trials have confirmed a link between olive oil consumption and reduced risks of cardiovascular disease and all-cause mortality. These studies suggest 20 grams (about 1.5 tablespoons) of olive oil daily may confer the maximum benefit.^245,246

Reduce calorie intake. Another essential feature of a healthy diet is balanced calorie intake and energy output, since overeating can contribute to metabolic disturbance and increased cardiovascular risk.^233,247 Calorie restriction increases endothelial NO synthesis and improves vascular function, and clinical trials have shown that a 25–30% reduction in calorie intake can lower blood pressure and reduce cardiovascular and metabolic disease risk in people with and without obesity.^248-250 Intermittent fasting reduces calorie intake by restricting eating to a limited time period each day or through alternate day fasting. Clinical evidence indicates intermittent fasting can promote improvements in cardiovascular and metabolic health parameters, but is not more effective than continuous calorie restriction.^251-253 Observational studies have found that not eating breakfast is associated with greater cardiovascular risk and cognitive decline,^254-256 which is consistent with other lines of evidence that show a benefit to cardiometabolic risk factors when energy intake takes place earlier in the day.²⁵⁷

Enjoy filtered coffee. Coffee may be best known as a source of caffeine, a nervous system stimulant, but coffee beans are also rich in free radical-scavenging and anti-inflammatory compounds, especially chlorogenic acids. Preclinical and clinical evidence indicate chlorogenic acids may improve lipid and glucose metabolism, endothelial function, and blood pressure.^258-260 Roasting reduces the chlorogenic acid content of coffee beans, such that dark roasted coffee beans have the least and green (unroasted) coffee beans have the most chlorogenic acids and other polyphenols.²⁵⁸

Numerous observational studies have reported a link between moderate coffee consumption (possibly including decaffeinated coffee) and lower risks of cardiovascular disease, type 2 diabetes, and some cancers, with the greatest benefits seen in those drinking 3–4 cups (at about 4 ounces per cup) daily.^261,262 Even in patients with existing cardiovascular disease, drinking four or more cups of coffee daily has been associated with lower mortality.²⁶³ Some research suggests only coffee brewed with a filter has cardio-protective effects, whereas unfiltered coffee (such as boiled coffee or espresso) can worsen lipid profiles and has been correlated with increased mortality risk.^264,265 Notably, occasional coffee drinking may increase the risk of atrial fibrillation and temporarily raise blood pressure, but habitual moderate coffee consumption has not been correlated with hypertension or atrial fibrillation risk.^266,267

Be Physically Active

The Physical Activity Guidelines for Americans recommends at least 150 minutes per week of moderate-intensity or 75 minutes of vigorous-intensity aerobic activity spread out across two or more days, plus muscle strengthening activity on at least two days, every week. Importantly, the document acknowledges any amount of physical activity is better than none.²⁶⁸ Regular physical activity has been shown to suppress inflammatory processes that promote atherosclerosis and reduce cardiovascular risk.^269,270 Exercise is well known to improve lipid profiles, and emerging research suggests it may indirectly lower Lp(a) levels as well.^271,272

Moderately intense aerobic activities include brisk walking, biking on level ground or slightly hilly terrain, water aerobics, yard work, or playing doubles tennis. As a general rule, you will be able to talk, but not sing the words to a song, when engaged in moderate-intensity activity. Examples of vigorous activities are jogging, swimming laps, biking fast or on hilly terrain, vigorous dancing, and playing basketball. Muscle-strengthening activities like heavy gardening, some types of yoga, and exercises that involve weightlifting, the use of elastic bands, and using one’s own body weight (eg, push-ups or sit-ups) are also important.²⁶⁸ One observational study that included data from 216,339 older adults (average age 69.9 years) participating the in the National Health and Nutrition Examination Survey found only 25% engaged in any amount of weight training, and those who did had lower risks of cardiovascular and all-cause death than those who did not. Interestingly, the benefit of weight training was only seen in those who also engaged in aerobic activity.²⁷³ Other research has shown exercise programs that include both aerobic and strength training may result in greater cardiovascular and mortality benefits than aerobic exercise alone.^269,274

Although prolonged sedentary time is independently associated with cardiovascular harm, getting 60–75 minutes per day of moderate- to vigorous-intensity activity appears to overcome this effect.²⁷⁵ Furthermore, engaging in light-intensity activities has been associated with reduced arterial stiffness and can also reduce sedentary time and its negative effects.²⁷⁶

People with existing atherosclerosis can benefit from increasing their physical activity. Formal protocols called “cardiac rehabilitation” have been shown to improve cardio-respiratory fitness and increase walking distance, duration, and pace in patients with coronary artery disease, peripheral artery disease, or both.²⁷⁷

Maintain a Healthy Body Weight

Body weight and waist circumference are often recorded as vital signs, along with blood pressure and pulse rate, during health evaluations. The goals from the American Heart Association are a BMI (calculated using body weight and height) between 18.5 and 24.9 kg/m² and a waist circumference less than 40 inches in men and 35 inches in women.²⁷⁸

An interesting phenomenon called the obesity paradox has emerged in some observational research showing reduced mortality in individuals whose BMIs indicate overweight or mild obesity compared with those whose BMIs indicate normal weight.^279-281 While the reason for this paradox is uncertain, one proposed explanation is that body composition and fitness are not measurable using BMI.^279,281 Sarcopenic obesity, in which age-related muscle loss is combined with excess fat accumulation, is associated with increased risks of a range of health problems including metabolic disorders, cardiovascular disease, and cardiovascular and all-cause mortality.²⁸²

It is important to emphasize that a largely conclusive body of evidence supports a link between overweight/obesity and increased risks of coronary artery and other cardiometabolic diseases.^283-285 Weight loss has been shown to reduce cardiovascular risk and is an important objective in obese patients.^286,287 Because even modest weight loss improves risk factors for atherosclerosis in those with overweight or obesity, an initial goal of 5‒10% loss of body weight is appropriate.²⁸⁸

Maintain Healthy Sleep

Seven to nine hours of sleep per night is generally recommended as optimal for adults.^289-291 Shorter sleep duration and poorer sleep quality, including sleep fragmentation, have been linked to greater atherosclerotic plaque burden as well as worse cardiovascular and metabolic health.⁹⁴ Furthermore, irregular sleep schedules that result in variable sleep duration and timing can disrupt circadian rhythms and have been associated with increased cardiovascular risk.^94,292,293

Obstructive sleep apnea is a major cause of sleep fragmentation and is increasingly recognized as an important contributor to coronary artery disease.⁶³ Treating sleep apnea with continuous positive airway pressure (CPAP) has been shown to reduce carotid artery thickening, especially in patients with severe sleep apnea.²⁹⁴ While adherence to CPAP is challenging for many sleep apnea patients, it is critical to heart disease prevention.^295,296 In a systematic review and meta-analysis that included findings from 10 randomized controlled trials and three observational studies, the risk of major adverse cardiovascular events and cardiovascular mortality was reduced in a subgroup of sleep apnea patients who used CPAP four or more hours per night, although no effect was found when analyzing data from all CPAP users.²⁹⁷

Sleep hygiene is an umbrella term for healthy sleep habits that encourage proper and restful sleep. Habits such as avoiding caffeine, alcohol, and light exposure late in the day, having a consistent bedtime routine, and maintaining a regular sleep/wake schedule can help improve sleep duration and quality and reduce sleep fragmentation.²⁸⁹ Although there have not been controlled sleep hygiene intervention trials in people with cardiovascular diseases, sleep and lifestyle habits that encourage restful, restorative sleep are important for everyone.

Build Psycho-Social Health and Well-Being

Mental health and cardiovascular health are fundamentally connected, such that depression, anxiety, and chronic stress are closely associated with coronary artery disease and its risk factors.^57,298,299 A positive outlook may also be important for heart health: pessimism has been associated with a 30% increase in coronary artery disease mortality, 41% increase in cardiovascular mortality, and 42% increase in stroke risk.³⁰⁰

Observational studies have linked loneliness and poor social health to increased risk of coronary artery disease and stroke, more health care visits and hospitalizations, and worse outcomes from cardiovascular events.³⁰¹ Even in adolescents and young adults, loneliness has been associated with hypertension and other health problems.³⁰² On the other hand, strong social relationships have been associated with a 50% decrease in mortality rate.³⁰¹

Although the mechanisms linking loneliness to heart disease and mortality are not completely understood, it appears to involve increased stress signaling, leading to increased inflammation and oxidative stress, impaired lipid and glucose metabolism, and atherosclerosis.^303-305 In addition, loneliness can contribute to poor self-care (eg, smoking, drinking alcohol, lack of exercise, unhealthy eating, and irregular sleep habits).³⁰³

While interventions to treat mental health disorders are well described, less is known about how to combat social isolation and loneliness. Building mental resilience through self-awareness, relaxation, and stress management practices, working to increase positive interactions with other people and pets, and engaging in self-care as much as possible may help reduce the impact of loneliness and social isolation on cardiovascular and overall health. Community programs and policy initiatives that support healthy connections may further contribute to better health outcomes.³⁰⁵

Stop Smoking and Avoid Second-Hand Smoke Exposure

Tobacco smoke exposure is a well-known risk factor for atherosclerosis. It is known to damage the heart and blood vessels, elevate cholesterol levels and blood pressure, and prevent oxygen from adequately reaching all of the body’s organs and tissues. Research suggests smoking, passive exposure to smoke, vaping, and waterpipe use can all cause oxidative stress, vascular dysfunction and inflammation, platelet coagulation, and dyslipidemia.^97,98,306

Quitting smoking, though difficult, can lead to reversal of some of its cardiovascular harms, reducing the risk of developing and dying from heart disease.³⁰⁷ Successful quitting is tailored to the individual and may involve individual or group counseling and/or nicotine replacement.³⁰⁸ Avoiding places where people are smoking and asking others not to smoke in your house or car may help reduce exposure to second-hand smoke.³⁰⁷

Limit Alcohol Intake

The relationship between alcohol and cardiovascular disease is complex and controversial. Among other harms, alcohol abuse increases the risks of stroke, hypertension, arrhythmias, and heart failure.³⁰⁹ Furthermore, drinking more than one to two drinks per day or binge drinking can increase arterial stiffness and impair endothelial function.^310,311 While some research indicates a possible cardiovascular benefit from low-to-moderate alcohol consumption, other findings suggest it may increase all-cause mortality.³¹² In the absence of conclusive evidence of benefit, the U.S. 2020–2025 Dietary Guidelines recommend avoiding or reducing alcohol intake as a health measure.^309,313

Consider an Anti-Platelet Drug

Aspirin has long been used as a preventive measure against heart attacks. This approach is based on meta-analyses showing a clear benefit in patients who had already experienced a heart attack, ischemic stroke, or a coronary intervention.³¹⁴ This type of usage, referred to as “secondary prevention,” continues as part of current medical practice.³¹⁵ Even low doses of aspirin can reduce platelet aggregation, which is the immediate cause of thrombosis leading to heart attack and ischemic stroke.³¹⁶

In 2022, the U.S. Preventive Services Task Force updated its recommendations to advise that daily low-dose aspirin not be initiated as “primary prevention” (ie, to prevent heart disease in those with no cardiovascular event history) in individuals aged 60 years and older. The task force found aspirin-related harms from serious bleeding events outweighed cardiovascular benefits in this population.³¹⁷ Aspirin should also be avoided by anyone with an increased risk of bleeding due to health conditions or medications.^318,319 Thus, low-dose aspirin is only recommended for primary prevention in 40–59-year-olds with a 10% or higher 10-year risk of a cardiovascular event.³¹⁷ Consult your health care provider before initiating daily low-dose aspirin, as the risks and benefits vary between individuals.

Another class of antiplatelet drugs, known as P2Y12 inhibitors, has emerged as a safer and more effective approach to cardiovascular risk reduction. This family of drugs includes clopidogrel (Plavix), ticlopidine (Ticlid), ticagrelor (Brilinta), and prasugrel (Effient). One meta-analysis found P2Y12-treated coronary artery disease patients had a 12% lower risk of cardiovascular events, with a 23% lower risk of heart attack in particular, than those treated with aspirin. Despite causing a similar number of major bleeding events, P2Y12 inhibitors caused fewer adverse side effects overall than aspirin.³²⁰

The American Heart Association provides atherosclerosis treatment guidelines to health care providers and their patients.¹⁸⁸ These guidelines are intended to lower the risk of cardiovascular disease, events, and mortality. The cornerstone of therapy for atherosclerosis is managing the underlying conditions that lead to its progression. This section summarizes several key conditions that should be targeted.

Managing Blood Lipids

Cholesterol-lowering Therapy

Intrusion of LDL-cholesterol (specifically ApoB) into the arterial wall is an essential step in initiating atherosclerosis.^36,321 Therefore, lowering LDL-cholesterol levels is frontline prevention and therapy. Lifestyle interventions, including quitting smoking, adopting a healthy diet, being physically active, achieving a healthy weight, and getting healthy sleep, are universally beneficial, but are especially important for those with dyslipidemia (a plaque-promoting lipid profile).^188,321

When lipid-lowering through diet, lifestyle, and nutrient supplements does not achieve target levels, prescription medication is recommended. Atorvastatin (Lipitor) and rosuvastatin (Crestor), both high-potency statins and the most widely prescribed drugs for preventing cardiovascular disease, are recommended by the American Heart Association as first-line treatment for cholesterol lowering.¹⁸⁸ Statins inhibit the activity of HMG-CoA reductase, a key enzyme in cholesterol synthesis, and may also reduce coronary heart disease risk by other mechanisms, such as reducing inflammation. Ezetimibe, which inhibits cholesterol absorption, is often used in combination with statins to meet cholesterol-lowering goals.³²² Other cholesterol-lowering drugs include bempedoic acid, bile acid sequestrants, and PCSK9 inhibitors.³²³

As risk of a heart attack or stroke increases, target LDL-cholesterol levels decrease. For individuals at high cardiovascular risk, Life Extension recommends LDL-cholesterol levels be kept below 70 mg/dL. Targets for fasting blood triglyceride levels are <80 mg/dL for individuals with any cardiovascular risk factors and <60 mg/dL for those with a history of cardiovascular disease. Life Extension further recommends targeting non-fasting triglyceride levels (which may be even more indicative of atherosclerosis risk) of <116 mg/dL.

Refer to Life Extension’s Cholesterol Management Protocol for more information.

Triglyceride-lowering Therapy

High triglyceride levels (hypertriglyceridemia) are associated with atherosclerotic cardiovascular disease, and tend to co-occur with other known risk factors, including various other lipid and cholesterol abnormalities, and with diabetes. Standard diet and lifestyle management of cardiometabolic risk factors applies to triglycerides as well; managing hypertension and diabetes, stopping smoking, being physically active, appropriate weight loss, and healthy diet are all indicated.³²⁴

In most people with hypertriglyceridemia, there are both genetic and acquired causes. Acquired causes can include the side effects of medications, other medical conditions, and inappropriate diet and alcohol consumption.^324,325

Medical-grade omega-3 fatty acids have been tested for their ability to improve cardiovascular outcomes in patients with hypertriglyceridemia. In particular, a prescription-only, purified, ethyl ester of EPA called icosapent ethyl (Vascepa) has been shown to improve cardiovascular outcomes and is FDA approved to reduce the risk of atherosclerotic cardiovascular disease in patients with residual hypertriglyceridemia while on statin therapy.^326,327 Interestingly, the cardiovascular benefits of icosapent ethyl are not adequately explained by a triglyceride-lowering effect alone. Other actions of EPA include favorable effects on other lipids, inflammation, oxidative stress, inflammatory signaling, platelet activation, and arterial stiffness, as well as increasing vasodilation, NO availability, and plaque stability. EPA also reduces gene expression related to cardiovascular disease.^324,328

In the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention (REDUCE-IT) trial, 4 grams per day of icosapent ethyl reduced the risk of cardiovascular events compared with a mineral oil placebo in statin-treated patients with cardiovascular disease or diabetes plus at least one other risk factor, and with high triglyceride levels. The trial, which involved 8,179 participants, found treatment resulted in a 25% reduction in risk of a composite outcome that included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, and a 31% reduction in heart attacks during a median of 4.9 years.³²⁹

An earlier trial, known as JELIS, was a randomized open-label trial that included 18,645 Japanese participants with total cholesterol of ≥250 mg/dL and LDL-cholesterol of ≥170 mg/dL, but without serious heart or other diseases. After 4–8 weeks of abstaining from all lipid-lowering medication, participants were randomized to receive either a low-dose statin drug or that drug plus 1.8 grams of highly purified EPA per day, and followed for an average of 4.6 years. Those who received treatment with EPA and statins had a 19% reduction in major coronary events compared with statin therapy alone. However the addition of EPA did not offer significant protection against any type of coronary fatality.³³⁰ A follow-up sub-analysis of the JELIS data found that in those with low HDL-cholesterol and high triglycerides, the addition of EPA resulted in a 53% lower rate of major coronary events compared with statins alone.³³¹

In a third trial that enrolled 2,506 coronary artery disease patients with low ratios of EPA-to-arachidonic acid (an omega-6 fatty acid), the rate of a composite of major adverse cardiovascular events that included cardiovascular death, nonfatal heart attack, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization was 9.1% in those who received 1,800 mg icosapent ethyl per day and 12.6% in those who did not. This result did not reach statistical significance; however, a reduction in strictly coronary events in the icosapent ethyl group was statistically significant.³³²

A trial called EVAPORATE that included 80 statin-treated subjects with coronary artery disease and high triglyceride levels showed icosapent ethyl may slow coronary artery disease progression. Participants were given 4 grams of icosapent ethyl or a mineral oil placebo daily for 18 months. In those treated with icosapent ethyl, unstable plaque volume was reduced by 17%, while in the placebo group, unstable plaque volumes more than doubled.³³³

On the other hand, a high-potency prescription combination of EPA plus DHA did not show cardiovascular benefits in a randomized controlled trial. The STRENGTH trial compared the effects of 4 grams per day of the carboxylic acid forms of EPA plus DHA to a corn oil placebo in 13,078 patients with high cardiovascular risk treated with statins, who also had high triglyceride and low HDL-cholesterol levels. After a maximum of five years of treatment, no difference in the rate of major cardiovascular events was found between the treatment and placebo groups.³³⁴

It is important to note that treatment with icosapent ethyl, despite its positive effects on cardiovascular events, including death, has been associated with an increased risk of developing atrial fibrillation.³²⁷

Managing Blood Pressure

Blood pressure control is essential in those who have atherosclerosis. Lifestyle strategies, including weight management, physical activity, restricted alcohol intake, and a healthy low-sodium/high-potassium diet, are the foundation of hypertension management; however, medication is often needed to optimally lower blood pressure.³³⁵

The American Heart Association defines normal blood pressure as <120/80 mm Hg and stage 1 hypertension as a blood pressure of ≥130/80 mm Hg.³³⁵ Based on evidence showing strict blood pressure management can substantially lower the risk of cardiovascular events and deaths, the American Heart Association currently recommends drug treatment for adults with hypertension plus a 10-year cardiovascular risk estimate of ≥10% or type 2 diabetes. In individuals with stage 2 hypertension (≥140/90 mm Hg) and/or CKD, the recommended target blood pressure is <130/80 mm Hg.^188,336 Life Extension recommends an optimal target of 115/75 mm Hg for cardiovascular disease prevention in healthy individuals.

The most widely used drugs for first-line treatment of hypertension are thiazide diuretics (eg, hydrochlorothiazide [HCTZ, Microzide], chlorthalidone [Thalitone], and others), calcium channel blockers (eg, nifedipine [Procardia] and amlodipine [Norvasc]), angiotensin converting enzyme (ACE) inhibitors (eg, lisinopril [Zestril], captopril [Capoten], and others), and angiotensin II receptor blockers (ARBs) (eg, losartan [Cozaar], telmisartan [Micardis], and others). A large literature review concluded these classes of drugs were associated with similar cardiovascular benefits.³³⁵ Certain medications are preferred for patients with certain conditions, and sometimes combinations of two different classes of antihypertensives are needed to reach blood pressure goals.

Refer to Life Extension’s High Blood Pressure (Hypertension) Protocol for more information.

Managing Type 2 Diabetes

Appropriate management of type 2 diabetes is a fundamental part of atherosclerosis treatment. Glucose control and insulin signaling can be improved through adhering to healthy eating patterns such as the Mediterranean diet, increasing soluble fiber in the diet, increasing physical activity, taking targeted supplements, and the use of glucose-lowering medication.^337,338

Hemoglobin A1c (HbA1c) is the main biomarker of long-term blood glucose control. An HbA1c below 5.7% is considered normal while ≥6.5% usually indicates type 2 diabetes. Intensive blood sugar control in diabetics, to a target HbA1c of below 7.0%, has been associated in some trials with better cardiovascular outcomes, but individualization of therapy to each patient is recommended by the American Diabetes Association, taking into account risk of hypoglycemic events, disease duration, life expectancy, and other factors.^338,339

Metformin (Glucophage) is the most widely used oral anti-diabetes medication in the world. It not only lowers blood glucose levels, but also improves dyslipidemia.³⁴⁰ Multiple meta-analyses have concluded that metformin treatment reduces cardiovascular events, cardiovascular deaths, and all-cause mortality in type 2 diabetics with coronary artery disease.^341-343

Refer to Life Extension’s Diabetes and Glucose Control Protocol for more information.

Targeting Residual Inflammation

Colchicine

In 2023, the FDA granted approval to low-dose colchicine (0.5–0.6 mg per day) to reduce cardiovascular risk in adults with established cardiovascular disease or with multiple risk factors. This approval represented a new approach to cardiovascular disease treatment and prevention—targeting inflammation as a driver of atherosclerosis.³⁵³

Colchicine, an anti-inflammatory compound originally derived from the autumn crocus (Colchicum autumnale) plant, is used to treat gout and for Mediterranean fever.^354,355 It is also used off-label to treat pericarditis, a condition in which tissue encasing the heart becomes inflamed.³⁵⁶ Colchicine has demonstrated anti-atherogenic effects such as improving endothelial function, reducing clot formation, and reducing plaque progression in preclinical studies.^357,358

In a meta-analysis of six randomized controlled trials involving a total of 13,165 subjects with coronary artery disease, those who received low-dose colchicine had lower risks of stroke, heart attack, and revascularization (surgery to restore coronary blood flow), as well as major cardiovascular events as a combined outcome, compared with those who received placebo; however, cardiovascular death and all-cause mortality risks were not significantly different, and colchicine increased the risk of gastrointestinal side effects. The analysis further showed colchicine had cardiovascular benefits only in subjects aged 65 years and younger.³⁵⁹ Another meta-analysis found low-dose colchicine reduced the risk of major cardiovascular events, without affecting mortality, in patients with acute coronary syndrome (sudden loss of coronary blood flow [ie, heart attack or unstable angina]) and when used perioperatively in patients who underwent percutaneous coronary intervention (PCI, a surgical procedure that opens coronary arteries).^360,361

Other Therapeutic Strategies

Enhanced External Counterpulsation (EECP)

Enhanced external counterpulsation (EECP) is a procedure that involves sequential inflating and deflating of pressure cuffs on the calves, thighs, and buttocks in counter-synchrony with the heartbeat, in effect doubling the rate of blood pressure cycles. This increases lower extremity circulation and strengthens cardiac output in a way that is similar to exercise.^362,363 EECP has been shown to increase NO production, improve endothelial function, and mitigate inflammatory signaling.³⁶² Research also shows EECP stimulates the formation and growth of new coronary blood vessels, leading to better heart muscle oxygenation and function in patients with coronary artery disease.^364,365 EECP has been reported to benefit patients with vascular diseases including angina, peripheral artery disease, heart failure, cerebrovascular disease, diabetes, and erectile dysfunction.^362,363 EECP is typically administered in one-hour treatment sessions five days per week for seven weeks.³⁶⁶

EECP is currently FDA approved for the treatment of stable angina that has not responded to other treatments.³⁶⁶ In addition, research suggests it may be beneficial in patients with known coronary artery disease, class II–III heart failure, and peripheral artery disease, as well as those who have experienced a heart attack or ischemic stroke.^363,367-370

It is important to note that, while EECP is non-invasive and safe for most people, it is contraindicated in a number of conditions, including uncontrolled hypertension, uncontrolled arrhythmias, clotting disorders, unstable angina, and severe heart failure, among others.³⁶⁶

Surgical Procedures and Interventions

Invasive procedures including surgical or catheter-based interventions are generally reserved for patients with severe coronary atherosclerosis. These techniques are used to restore coronary artery blood flow in acute or emergency circumstances, or when more conservative measures have not adequately relieved symptoms or improved quality of life.

Coronary artery bypass grafting (CABG) surgery, often referred to as heart bypass, involves using a section of heathy blood vessel taken from elsewhere in the body and attaching it to a coronary vessel above and below an area obstructed by plaque, creating an alternate pathway for blood flow to the heart muscle. As with any complicated, invasive, potentially life-saving surgical procedure, CABG carries considerable risks and potential complications.^371,372

Percutaneous coronary intervention (PCI, also known as angioplasty) is a catheter-based intervention in which the heart is accessed through a puncture in a wrist or groin artery and a catheter is delivered to a coronary artery blocked with plaque. The inserted end of the catheter is equipped with a balloon, which is inflated, disrupting the atherosclerotic plaque and opening the narrowed artery, allowing greater blood flow. In many cases, a metallic stent is then permanently implanted at the site of the angioplasty to prop open the artery and maintain blood flow. Specialized drug-eluting stents are coated with slow-release drugs and sometimes used to prevent the artery from becoming blocked again.^373,374

Atherectomy is a minimally invasive method of removing plaque from the insides of affected arteries to restore blood flow. It involves the use of a catheter equipped with a cutting tool, such as specialized blades or a laser.³⁷⁵ Atherectomy can be used to treat severe peripheral artery disease.³⁷⁶ It may help prevent ischemic tissue death and reduce the need for amputation; however, its benefits on outcomes, including mortality, are uncertain.^377,378 Atherectomy is also an option for removing highly calcified plaque in coronary or carotid arteries.^379,380 It has demonstrated comparable benefits to angioplasty in patients with total occlusion of a coronary artery, and may be used to prepare the artery for balloon dilatation or stent placement.^381,382

In patients with stable coronary artery disease, invasive strategies are not necessarily superior to conservative medical management.³⁸³ The decision to opt for invasive therapies depends on patient preference, disease extent and complexity, and whether the procedure has a proven survival benefit in similar patients.³⁸⁴

Treatments Targeting Symptom Relief

Unstable angina, characterized by unpredictable, sudden onset chest pain that does not subside with rest, is a form of acute coronary syndrome and an emergency. Conversely, stable angina, which is predictable and episodic (typically aggravated by or occurring with exertion or stress), is a manageable condition.^391-393 Several classes of medications are used to prevent or relieve stable angina.

Beta Blockers

Beta blockers (metoprolol [Lopressor, Toprol], atenolol [Tenormin], and others) reduce heart rate and strength of contraction, as well as blood pressure, and along with certain calcium channel blockers and nitrates are first-line therapy for relieving and preventing angina and increasing exercise tolerance in most cases. When a single one of these classes of medication does not provide adequate relief, another from among the three is often added.¹⁸⁸ Beta blockers have the additional benefit of improving survival in those who have experienced a heart attack.³⁹⁴

Calcium Channel Blockers

Calcium channel blockers, such as diltiazem [Cardizem] and verapamil [Isoptin], are indicated for angina and can be used as an alternative to, or in combination with, beta blockers. Calcium channel blockers are used in patients intolerant of beta blockers due to severe obstructive airway disease or vasospastic disorders.¹⁸⁸ Other calcium channel blockers used in the treatment of coronary artery disease and hypertension include amlodipine (Norvasc), felodipine (Plendil), and nifedipine (Procardia). Nifedipine is only used in combination with beta blockers. Combined therapy with beta blockers plus calcium channel blockers carries a risk of low blood pressure and slow heartrate.

Nitrates

Nitrates relax coronary and other blood vessel walls by relaxing smooth muscle, thereby reducing demand on the heart muscle.³⁹⁵ A long-acting nitrate (isosorbide mononitrate [Imdur]) may be used as an alternative to, or in combination with, beta blockers and/or calcium channel blockers to prevent angina, while short-acting nitrates (sublingual formulations of nitroglycerine [GoNitro, Nitrolingual, and others] and isosorbide dinitrate [Dilatrate or Isordil]) are used to provide immediate symptom relief or as short-term angina prevention, such as before exercise.^44,188 Nitrates commonly cause side effects such as headache, low blood pressure, flushing, dizziness, and rapid heartbeat. In addition, some people develop nitrate tolerance, in which the medication becomes less effective with ongoing use.³⁹⁵

Ranolazine

Ranolazine (Ranexa) is a newer medication that may be used in combination with standard anti-angina medications to improve symptom relief. This medication relaxes the heart muscle without lowering blood pressure or heart rate.³⁹⁶ It is recommended as an add-on to treatment in those who continue to have angina symptoms despite therapy with tolerable doses of beta blockers, calcium channel blockers, and nitrates.^44,188

There are many nutritional preparations and supplements that have been studied in the context of cardiovascular disease. Here, we summarize the evidence for many of these supplements. We have grouped these nutrients and supplements into the following categories:

• Amino Acids & Cofactors and Other Nutrients
• Carotenoids
• Fatty Acids & Fatty Acid Derivatives
• Gut-Health Support
• Herbal Extracts & Preparations
• Phytonutrients & Polyphenols
• Vitamins & Minerals

The order in which the categories are listed in this Protocol is alphabetical. However, the lists of nutrients within each category are generally organized with those nutrients or supplements with the best evidence at the top of each list.

Amino Acids & Cofactors and Other Nutrients

Coenzyme Q10

Coenzyme Q10 (CoQ10) is a naturally occurring lipid-soluble antioxidant that plays an important role in cellular energy metabolism. Because statin therapy significantly lowers blood CoQ10 levels, many health care providers recommend CoQ10 supplementation for those taking statins.³⁹⁷

CoQ10 may prevent atherosclerosis through several mechanisms, including reducing oxidative stress, inflammation, and cholesterol synthesis, as well as enhancing mitochondrial and cellular function.^398-400 In a randomized placebo-controlled trial in 51 patients with untreated high LDL-cholesterol levels and moderate endothelial dysfunction, CoQ10, at 100 mg and 200 mg daily for eight weeks, improved endothelial function and increased NO production; in addition, LDL oxidation was reduced in those receiving 200 mg CoQ10 daily.¹¹ A crossover trial in 11 subjects with peripheral artery disease found 80 mg per day of a highly bioavailable form of CoQ10 called MitoQ improved endothelial function, raised levels of an antioxidant enzyme, and increased walking capacity better than placebo after two weeks.⁴⁰¹

A meta-analysis that included eight randomized controlled trials involving 526 coronary artery disease patients found 100–300 mg CoQ10 daily for 4–48 weeks decreased total cholesterol and increased HDL-cholesterol levels, but did not affect LDL-cholesterol levels.¹⁰ CoQ10 has also been found to improve exercise capacity and endothelial function and reduce mortality in randomized controlled trials in heart failure patients.^402,403

A randomized placebo-controlled trial with 443 healthy, elderly, Swedish participants found 200 mg CoQ10 plus 200 mcg selenium daily for five years reduced cardiovascular mortality.¹² The effect persisted at a 12-year follow-up, at which time 38.7% of those in the placebo group and 28.1% of those in the supplement group had died from cardiovascular causes. Analyses of the data showed patients with hypertension, diabetes, heart disease, and impaired functional capacity all benefited from CoQ10 plus selenium therapy.⁴⁰⁴ Several secondary studies based on data from this trial suggest mechanisms such as reduced oxidative stress, inflammation, and glycation^405-407; improved cellular metabolism; and improvement in markers of aging^408,409 may be partly responsible.

L-arginine

L-arginine, a conditionally essential amino acid found in protein-rich foods, has attracted attention for its ability to improve endothelial function and dilate blood vessels. L-arginine serves as a precursor for NO in the endothelium.⁴¹⁰ It also enhances mitochondrial function, lowers oxidative stress, and reduces oxidized LDL levels.^411,412 Multiple clinical trials have indicated L-arginine supplementation may have beneficial effects on blood pressure, endothelial and microvascular function, glucose metabolism, insulin sensitivity, lipid profiles, and body weight and composition.^410,413 However, findings have been inconsistent.^411,412 In a meta-analysis of 22 randomized controlled trials involving a total of more than 1,100 subjects, L-arginine supplementation, at doses of 4 grams per day or higher for at least 24 weeks, was found to reduce systolic and diastolic blood pressures, with no additional benefit from doses higher than 9 grams per day. The effect was consistently seen in men and women, healthy and unhealthy individuals, and those with and without high blood pressure.⁴¹⁴ On the other hand, a meta-analysis that included 13 randomized controlled trials was unable to show L-arginine could improve measures of endothelial function,⁴¹² while another meta-analysis of two randomized controlled trials found a statistically non-significant 7% reduction in mortality in heart attack patients treated with L-arginine versus placebo.⁴¹⁵ Findings from a pilot crossover trial suggest a sustained-release formulation of L-arginine may be more effective than standard immediate-release formulations for raising NO synthesis.⁴¹⁶

Lipoic Acid

Lipoic acid, a naturally occurring antioxidant, serves as a coenzyme in metabolism of fats, carbohydrates, and proteins. It can restore radical-scavenging capacity to other antioxidants like 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. By decreasing oxidative stress and improving glucose and lipid metabolism, lipoic acid may promote cardiovascular health.⁴¹⁷

A large systematic review of 11 clinical trials concluded alpha-lipoic acid improved endothelial function by reducing oxidative stress and inflammation and increasing endothelial NO synthesis.¹⁵ In addition, a meta-analysis of findings from five randomized controlled trials found lipoic acid improved flow-mediated dilation, a measure of endothelial function.⁴¹⁸

Lipoic acid may be beneficial in individuals with conditions that increase cardiovascular risk. Multiple controlled trials have reported lipoic acid improved markers of blood glucose control and inflammation.⁴¹⁹ Lipoic acid supplementation, at a dose of 600 mg daily for 12 weeks, was also found to reduce total cholesterol and triglyceride levels in a placebo-controlled trial in 46 patients with metabolic syndrome⁴²⁰ and reduce blood pressure in a small placebo-controlled trial conducted in 67 stroke patients.⁴²¹

Propionyl-L-carnitine

Propionyl-L-carnitine is a naturally produced derivative of L-carnitine that rapidly passes into cells to supply free L-carnitine, a much-needed factor for mitochondrial energy production. L-carnitine and its derivatives are also free radical scavengers.⁴²² Preclinical research suggests propionyl-L-carnitine may have a role in slowing atherosclerosis progression and improving glucose and lipid metabolism.^423,424

Clinical trials indicate propionyl-L-carnitine may relieve symptoms in individuals with peripheral artery disease. A large review examined findings from 12 randomized controlled trials with a combined total of 1,423 participants. The accumulated evidence showed propionyl-L-carnitine, at doses of 1–2 grams per day, increased maximum and pain-free walking distances by 26% and 31%, respectively, in those with intermittent claudication (pain while walking due to atherosclerosis in the legs) relative to placebo. Propionyl-L-carnitine also improved endothelial function and quality of life.⁴²⁵

Glucosamine and Chondroitin

Known best as supplements for combating osteoarthritis and joint pain, glucosamine and chondroitin may have benefits beyond these indications. In one clinical trial, 3,000 mg glucosamine for four weeks improved vascular endothelial function in 20 healthy volunteers compared with 19 untreated individuals who served as controls.⁴²⁶

A growing body of observational evidence suggests glucosamine and chondroitin may have cardio-protective effects. Findings from a study that included data collected over a median of 8.9 years from 495,077 participants in the United Kingdom’s health resource databank (UK Biobank) suggested people taking glucosamine supplements for arthritis had a lower risk of death from cardiovascular disease, atherosclerosis, and heart attack and stroke.⁴²⁷ A previous study using the same database found glucosamine users were less likely to develop coronary artery disease or have a major cardiovascular event or stroke during seven years of monitoring.⁴²⁸ Chondroitin use was found in another study to be associated with 52% lower odds of heart attack during a 13-year period in people at high cardiovascular risk.⁴²⁹ Another observational study that used data from 38,021 adults in the United States who were followed for 15 years found that the use of glucosamine and chondroitin supplements was associated with a trend towards decreased cardiovascular mortality, but it did not reach statistical significance.⁴³⁰ Further rigorous investigations are necessary to elucidate the effects of glucosamine and chondroitin on cardiovascular health.

Carotenoids

Lycopene

Lycopene is an antioxidant carotenoid obtained mainly from cooked tomatoes and present in smaller amounts in watermelon, pink grapefruit, papaya, apricots, and guava.^16,431 Lycopene not only reduces inflammation and oxidative stress, but has also demonstrated anti-atherogenic effects such as decreasing cholesterol levels, lowering blood pressure, inhibiting LDL oxidation, decreasing blood clot and foam cell formation, enhancing NO production and healthy endothelial function, and inhibiting smooth muscle proliferation.¹⁶

Observational studies have linked higher lycopene levels with lower atherosclerotic plaque burden in people with type 2 diabetes⁴³² and decreased carotid arterial wall thickness, particularly in men.^433-435 A meta-analysis of findings from 25 observational studies indicated individuals with the highest lycopene intake or blood levels had a 14% lower likelihood of cardiovascular disease, 26% lower likelihood of stroke, and 37% lower likelihood of death compared with individuals with the lowest lycopene intake or blood levels.⁴³⁶

A meta-analysis of data from 17 randomized controlled trials investigating the effects of tomato or lycopene interventions on cardiovascular risk factors showed supplementing with tomato lowered LDL-cholesterol levels and improved endothelial function (measured as flow-mediated dilation), and lycopene supplementation reduced systolic blood pressure.⁴³⁷ For example, in a randomized placebo-controlled trial involving 36 patients with stable cardiovascular disease, adding 7 mg per day of lycopene to statin therapy for two months led to improved endothelial function.⁴³⁸ In another randomized controlled trial, 144 middle-aged participants were assigned to receive 20 mg lutein (another carotenoid), 20 mg lutein plus 20 mg lycopene, or placebo daily for eight weeks. Carotid artery thickness was reduced in both treatment groups relative to the placebo group, but the combination of lutein and lycopene had a greater effect than lutein alone.⁴³⁹ In a randomized crossover trial in 28 volunteers with high cardiovascular risk, daily tomato juice consumption for four weeks reduced expression of adhesion molecules involved in the atherosclerotic process compared with water consumption, and the effect was correlated with a rise in lycopene levels.⁴⁴⁰

Lutein

Lutein, which belongs to the class of carotenoids known as xanthophylls, is found in high concentrations in many types of fruits and vegetables, and possesses strong anti-inflammatory and oxidative stress-reducing properties.^441,442 Lutein, along with zeaxanthin (another xanthophyll), are best known for their impact on eye health; however, they may also affect cardiometabolic health.⁴⁴¹ Lutein has demonstrated anti-atherosclerotic potential by improving endothelial function, arterial thickness, blood pressure, and lipid profiles in preclinical studies.⁴⁴³

In a randomized placebo-controlled trial in 65 individuals with early atherosclerosis, 20 mg lutein daily for three months resulted in decreased levels of the inflammatory cytokine interleukin (IL)-6, as well as LDL and triglyceride levels; it also decreased expression of an inflammatory protein.⁴⁴⁴ In another trial that included 117 healthy subjects, taking 10 or 20 mg of lutein per day for 12 weeks increased total antioxidant capacity compared with placebo; in addition, those receiving the 20 mg per day dose had reduced levels of CRP and malondialdehyde (a marker of oxidative stress).⁴⁴⁵

In observational studies, higher intake or blood levels of lutein, or lutein plus zeaxanthin, were associated with lower concentrations of IL-6, lower risk of coronary artery disease and stroke, and better cardiometabolic health.^446-448 Lower lutein levels have also been correlated with increased carotid artery wall thickening.⁴⁴⁹

Fatty Acids & Fatty Acid Derivatives

Fish Oil

Fish oil is rich in omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These omega-3 PUFAs work in part by suppressing inflammation, the main driver of atherosclerosis.²⁴³ One way they do this is through the action of derivatives known as specialized pro-resolving mediators, or SPMs. SPMs mediate the resolution of inflammation, limiting tissue damage, clearing dead cells, and promoting repair without impairing immune defenses.^450,451

A number of controlled trials and meta-analyses have examined the potential role of omega-3 PUFA supplementation in cardiovascular disease prevention. Although findings have been mixed, the overall evidence suggests omega-3 supplements, at doses of 2–4 grams per day, are most likely to reduce the risk of major adverse cardiovascular events in those who have already had one, individuals with very high triglyceride levels, and heart failure patients.^452,453 One meta-analysis that included data from 19 randomized controlled trials with a total of more than 97,000 participants found supplementing with 2 grams of omega-3 fatty acids per day lowered the risk of cardiovascular mortality by 45%, but had no significant effects on other outcomes.⁴⁵⁴ Another meta-analysis of 28 randomized controlled trials with a total of 136,965 participants found omega-3 supplementation lowered the risk of cardiovascular events and deaths, but no other adverse outcomes.⁴⁵⁵ In a meta-analysis that examined findings from 17 randomized controlled trials, EPA supplementation was found to reduce cardiovascular events relative to a mineral oil placebo, but this benefit was not present when olive oil or corn oil was used as the placebo; importantly, the analysis also found that treatment with EPA plus DHA lowered the risk of cardiovascular disease-related death compared with no treatment (including no placebo).⁴⁵⁶

A comprehensive review of findings from 17 randomized controlled trials concluded that supplementing with 1.8–3.4 grams of omega-3 fatty acids per day for three to six months, or 4.4 grams per day for as little as one month, could effectively raise blood levels into a range that may help counteract some pathways that contribute to atherosclerosis.⁴⁵⁷

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 artery disease, although the agency described the evidence available at the time as “inconclusive.”⁴⁵⁸

Although the use of fish oil has been associated with an increased risk of atrial fibrillation, there are important caveats and nuances regarding this concern, and the prodigious cardiovascular and other benefits of marine omega-3s overshadow this potential risk.

One of the strongest findings for an association with atrial fibrillation came from the REDUCE-IT trial that used 4 grams per day of a prescription-only, purified, ethyl ester of EPA called icosapent ethyl (Vascepa).³²⁹ Another trial, STRENGTH, used 4 grams of a prescription combination of EPA and DHA in a carboxylic acid form, and also found an increased risk.³³⁴ Most data linking atrial fibrillation and marine omega-3 fatty acids find that the risk is considerably greater in those with a previous history of atrial fibrillation, and with very high doses of omega-3s.

However, it is important to note that much remains to be learned about this association, and there is not any conclusive mechanistic explanation to suggest a causative role of omega-3s in atrial fibrillation. In fact, omega-3s have anti-arrhythmic activity.⁴⁵⁹ Furthermore, observational studies of circulating and adipose omega-3 levels have shown that higher levels were associated with a lower risk of atrial fibrillation.⁴⁶⁰ And an observational study in the large UK Biobank Cohort found that in those with existing atrial fibrillation, fish oil use was associated with a lower risk of major adverse cardiovascular events and heart attack.⁴⁶¹

Cumulative evidence suggests individuals with existing atrial fibrillation should consider working with a health care practitioner regarding omega-3 supplementation, and doses below 4 grams per day may be advisable.

Specialized Pro-resolving Mediators (SPMs)

Polyunsaturated fatty acids stored in cell membranes can be metabolized into byproducts called eicosanoids that help regulate local inflammation. For example, prostaglandins made from the omega-3 PUFAs EPA and DHA downregulate inflammatory signaling, while those made from arachidonic acid, an omega-6 PUFA from animal fat, upregulate inflammation.⁴⁶² A more recently discovered family of eicosanoids, called specialized pro-resolving mediators (SPMs), participate in actively terminating the inflammatory response through “stop” signals.^462,463 Unlike anti-inflammatory therapies that suppress immune function, SPMs shape immune activity to promote tissue healing and limit pain.⁴⁶³ Inadequate resolution of inflammation is now recognized as an underlying feature of many chronic inflammatory conditions, including atherosclerosis.^451,464

SPMs have been shown to promote anti-inflammatory activities of macrophages and reduce accumulation of necrotic macrophages and foam cells within atherosclerotic lesions.⁴⁶⁵ In one study, just five days of supplementing with 15 mL, 30 mL, or 60 mL of an SPM-enriched fish oil increased the expression of anti-inflammatory features in macrophages from subjects with peripheral artery disease and healthy volunteers, and this effect was strongest at the maximum dose.⁴⁶⁶ A study that used blood samples from subjects with atherosclerosis found SPM treatment reduced free radical production and reversed pro-thrombotic activity in neutrophils (a type of immune cell).⁴⁶⁷

Tissue and blood SPM concentrations are currently being investigated as possible biomarkers of cardiovascular risk. In addition, by addressing unresolved inflammation in atherosclerotic vessels, SPMs may have a therapeutic role in cardioprotection.^463,468

Gut-Health Support

Supplemental Fiber

A meta-analysis of observational and clinical trials reported that increasing dietary fiber intake through food or supplements can reduce all-cause mortality and lower blood pressure, and may improve lipid profiles and glucose metabolism.⁴⁶⁹ One meta-analysis of findings from 28 randomized controlled trials found a median dose of 10.2 grams (about 2 teaspoons) of psyllium can reduce LDL-cholesterol, non‒HDL-cholesterol, and ApoB levels.⁴⁷⁰ A meta-analysis of data from 12 randomized controlled trials with 370 participants found supplementing with about 3 grams of glucomannan, a soluble fiber from konjac root, daily for three weeks or longer lowered LDL-cholesterol and non‒HDL-cholesterol levels, but did not affect ApoB levels.⁴⁷¹ Other meta-analyses have shown supplementing with beta-glucan (a soluble fiber from oats and barley) can improve cardiovascular risk factors such as lipid levels, glucose control, and waist circumference.^472-474

Probiotics

An imbalance in the composition of the gut microbiome can promote progression of atherosclerosis by up-regulating inflammation through decreased short-chain fatty acid production and increased inflammatory cytokine release. It may also lead to dysregulated cholesterol and bile acid metabolism.⁴⁷⁵ Probiotic supplements can be help counter these mechanisms, and have been found to shrink atherosclerotic plaques in animal research.⁴⁷⁶

A growing body of clinical research indicates probiotic supplements may improve atherosclerosis risk factors. For example, Lactobacillus plantarum 299v, at a dose of 50 million colony forming units (CFUs) daily for six weeks, decreased levels of fibrinogen and leptin (an inflammatory cytokine from fat cells), lowered blood pressure, reduced markers of oxidative stress and inflammation, and decreased monocyte activation in a randomized placebo-controlled trial with 36 healthy participants.⁴⁷⁷

Another probiotic of interest is L. reuteri NCIMB 30242. A randomized placebo-controlled trial with 127 participants found supplementing with 50 billion CFUs L. reuteri NCIMB 30242 twice daily for six weeks reduced levels of LDL-cholesterol by 11.6%, total cholesterol by 9.1%, non–HDL-cholesterol by 11.3%, and ApoB by 8.4% relative to placebo. In addition, ratios of LDL- to HDL-cholesterol and ApoB to ApoA were reduced by 13.4% and 9%, respectively, and hs-CRP and fibrinogen levels were reduced by 1.05 mg/L and 14.3%, respectively, compared with placebo.⁴⁷⁸

A randomized placebo-controlled trial in 128 non-diabetic individuals with high triglyceride levels found 2 grams of a probiotic supplement containing L. curvatus HY7601 and L. plantarum KY1032 (CFUs not specified) daily for 12 weeks reduced triglyceride levels and increased LDL size.⁴⁷⁹ (Larger and less dense LDL particles are less harmful than small dense LDL particles).⁴⁸⁰

Herbal Extracts & Preparations

Garlic

Garlic is a well-studied herbal medicine and food that has demonstrated antioxidant, anti-inflammatory, endothelial-protecting, lipid-lowering, blood pressure-lowering, blood clot-inhibiting, blood glucose-lowering, and anti-atherosclerotic effects in preclinical and clinical research.^481,482 Its ability to decrease elevated CRP levels, reduce high blood pressure, lower high LDL-cholesterol levels, and improve poor blood glucose regulation has been demonstrated in multiple meta-analyses of randomized controlled trials.^483-485 Together, these effects may result in improved cardiovascular health.

Garlic is rich in sulfur compounds that are believed to be largely responsible for its therapeutic actions, as well as its characteristic odor. Aging is a method of processing garlic that changes and stabilizes its sulfur compounds and increases its polyphenol content, possibly enhancing its therapeutic effects.^486,487

A review of 10 randomized controlled trials concluded that, despite some inconsistent findings, garlic may improve vascular function, especially in people with high cardiovascular risk.⁴⁸⁸ Aged garlic extract, at a dose of 2,400 mg per day for one year, was found to increase measures of microcirculation and tissue blood flow in a randomized placebo-controlled trial in 93 patients with confirmed coronary artery atherosclerosis⁴⁸⁹ and a similar trial in 122 individuals with high cardiovascular risk scores.⁴⁹⁰ In another trial by the same research group that involved 104 subjects with coronary artery disease, 2,400 mg aged garlic extract daily for one year not only slowed progression of coronary artery calcification, but also reduced blood glucose levels and blood pressure.⁴⁹¹ A randomized controlled trial in 55 participants with metabolic syndrome found 2,400 mg aged garlic extract per day reduced the volume of low-density plaque (the most unstable type of plaque) in the coronary arteries compared with placebo after one year.⁴⁹² In a similar trial in 80 participants with type 2 diabetes, volume of a type of coronary artery plaque susceptible to rupture and triggering of a heart attack decreased by 29% in those taking 2,400 mg aged garlic extract daily versus a 57% increase in those taking placebo after one year.⁴⁹³

In a randomized controlled trial conducted in India, 56 healthy subjects received either a placebo or an aged black garlic extract called Garlzac for 12 weeks. The aged black garlic extract was standardized to contain at least 0.5% S-allyl-L-cysteine (SAC), and participants took 500 mg of the extract (providing 2.5 mg of SAC) or the placebo daily. Compared with those who took the placebo, study subjects who took the black garlic extract had significant reductions in triglycerides, LDL and total cholesterol, blood pressure, and fasting blood glucose, as well as an improvement in HDL cholesterol levels. Systolic blood pressure dropped by about 6.7 mm Hg in the garlic group compared with no significant change in the placebo group. A similarly meaningful difference was observed for total cholesterol, with a 24 mg/dL drop in the black garlic group and no significant change in the placebo group. LDL cholesterol fell by about 20 mg/dL in the black garlic group compared with just 5 mg/dL in the placebo group.⁴⁹⁴ This study provided intriguing preliminary evidence that aged black garlic extract improved several biomarkers relevant to cardiovascular health.

In a 12-week controlled clinical trial of aged black garlic consumption, improvement in markers of endothelial dysfunction was observed in 62 individuals with and without hypercholesterolemia. Subjects consumed four cloves of black garlic per day (12 g/day), after which there were significant reductions in endothelial adhesion molecules including monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), suggesting benefits to endothelial function.⁴⁹⁵ Another 12-week trial using 6 g/day of aged black garlic supplementation in 60 participants led to a rise in HLD-cholesterol, reduction in ApoB, and reduced ApoB-to-LDL cholesterol ratio, without significant effects on triglycerides, LDL-cholesterol, or total cholesterol.⁴⁹⁶

Hawthorn

Hawthorn (Crataegus) species are flowering shrubs in the rose family that have traditionally been used to treat high blood pressure and heart disease.⁴⁹⁷ Extracts from hawthorn berries, leaves, and flowers are high in flavonoids and phenolic compounds with anti-inflammatory and free radical-scavenging effects, and have been found in preclinical research to lower blood pressure, improve lipid and glucose levels, and protect the heart muscle from injury due to oxidative stress and ischemia.^497-499 Hawthorn may also inhibit foam cell formation, promote healthy endothelial function, and reduce atherosclerotic plaque growth.⁴⁹⁸ In an uncontrolled trial in 37 subjects with type 2 diabetes, hypertension, and overweight being medically managed to lower their cardiovascular risk, taking 20 mL of vinegar made from hawthorn berries after meals for four weeks resulted in reduced body weight and BMI, blood pressure, blood glucose levels, and HbA1c, and improved lipid profiles.⁵⁰⁰ Although several randomized controlled trials have suggested hawthorn extracts may have mild blood pressure-lowering effects,^501-503 little is known about their possible benefits in patients with atherosclerosis or on long-term cardiovascular outcomes.

Ginkgo Biloba

Ginkgo (Ginkgo biloba) has been used for thousands of years to treat a wide range of conditions and promote healthy circulation, relax the airways, and support brain function.^504,505 More recent evidence shows ginkgo may help dilate blood vessels, regulate blood glucose and lipid levels, protect endothelial cells, promote endothelial NO synthesis, reduce oxidized LDL levels, and slow the effects of aging on vascular function.^505-507 Ginkgo has been found to increase coronary blood flow, as well as blood flow to the eyes, ears, skin, and brain in healthy people.⁵⁰⁶

In a randomized placebo-controlled trial in 40 patients with metabolic syndrome being treated with metformin, adding 120 mg ginkgo daily for 90 days decreased markers of insulin resistance, waist circumference and abdominal fat, and inflammatory marker levels, thereby lowering cardiovascular risk.⁵⁰⁸ A preliminary trial in 11 metabolic syndrome patients found ginkgo extract, taken for two months, decreased levels of hs-CRP, IL-6, and other markers of inflammation and oxidative stress, as well as early atherosclerotic plaque development.⁵⁰⁹ The same researchers found ginkgo extract, at 120 mg twice daily, reduced early atherosclerotic plaque formation in eight patients who had recently undergone coronary artery bypass surgery. Furthermore, ginkgo increased levels of endogenous antioxidant enzymes and reduced oxidized LDL levels.⁵¹⁰ While older studies have also found ginkgo reduced claudication (pain while walking) in individuals with peripheral artery disease, more recent meta-analyses have not confirmed a benefit.^511-513

Arjuna

The bark from the arjuna (Terminalia arjuna) tree has been used in traditional Ayurvedic medicine to treat angina, hypertension, heart failure, and dyslipidemia for centuries. Preclinical research indicates it reduces oxidative stress and inflammation and can improve lipid levels, inhibit platelet aggregation, increase coronary blood flow, and strengthen heart muscle contraction.^514,515 Small uncontrolled clinical trials have reported that treatment with arjuna reduced angina frequency and improved cardiac function in patients with stable angina.^514,516 In a randomized, placebo-controlled, crossover trial involving 58 men with stable angina, 500 mg arjuna bark extract three times daily for one week reduced angina episodes, reducing the need for acute isosorbide dinitrate therapy compared with placebo (18.22 mg of the drug used per week for the placebo group vs. 5.69 mg per week with arjuna extract), and improved treadmill performance. Furthermore, these effects were similar to those of daily isosorbide mononitrate therapy.⁵¹⁷ A placebo-controlled trial in 116 subjects receiving standard care for stable coronary artery disease found 500 mg arjuna twice daily for six months reduced markers of inflammation.⁵¹⁸ In a randomized placebo-controlled trial that included 100 heart failure patients, 750 mg arjuna twice daily for 12 weeks did not improve cardiac function, but did improve functional capacity, antioxidant status, and symptom-related quality of life in some participants.⁵¹⁹ In other clinical studies, arjuna improved cardiac function in heart failure patients,⁵²⁰ lipid profiles in coronary artery disease patients,⁵²¹ and endothelial function in smokers, and inhibited platelet aggregation in subjects with type 2 diabetes.⁵¹⁴

Chili Pepper and Capsaicin

Chili peppers (Capsicum species) are a common culinary spice, estimated to be enjoyed daily by 25% of people around the world. Large observational studies and multiple meta-analyses have indicated regular chili-eaters live longer and healthier lives than non–chili-eaters.^522-525 According to one meta-analysis of four studies that included nearly 565,000 people, those who consumed chili pepper ever or more than once a week had a 13% lower chance of dying from any cause and an 11% lower risk of dying from cardiovascular disease than those who rarely or never used chili pepper.⁵²⁶

Clinical trials further support the cardio-protective effects of chili peppers and their main active ingredients, capsaicin and related capsaicinoids. For example, multiple controlled trials have shown capsaicinoid supplements can reduce total and LDL-cholesterol levels, an effect that may contribute to cardiovascular protection.⁵²⁷ In a placebo-controlled crossover trial in 12 men with coronary artery disease, applying a capsaicin patch prior to an exercise stress test enhanced blood NO levels, increased coronary blood flow during exercise, and increased exercise tolerance as assessed by ECG.⁵²⁸ Clinical research has also shown capsaicin can support weight loss by increasing heat production and energy expenditure, and preclinical research suggests capsaicin reduces atherosclerotic plaque formation and oxidative stress, while increasing NO production and promoting vasodilation and blood flow.⁵²²

Gotu Kola

Gotu kola (Centella asiatica) is a plant used in traditional Ayurvedic and Chinese medicine for thousands of years. The most important bioactive components in gotu kola are triterpenes, which may have plaque-stabilizing abilities.⁵²⁹ Gotu kola extracts have demonstrated anti-inflammatory, oxidative stress-reducing, anti-hypertensive, and lipid-lowering actions, and improved endothelial function in preclinical studies.^529,530

A single team of researchers has conducted multiple clinical studies using gotu kola extract, alone or combined with pycnogenol, in subjects with known coronary artery disease. In two placebo-controlled trials in atherosclerosis patients, 60 mg gotu kola extract three times daily for 12 months stabilized atherosclerotic plaques in femoral and carotid arteries.^531,532 In an observational study in 391 people with asymptomatic atherosclerosis receiving standard management (education, exercise, diet, and lifestyle interventions), supplementing with gotu kola extract plus pycnogenol, at 100 mg per day each, was associated with greater reductions in plaque progression and oxidative stress after four years than pycnogenol alone or no supplements.⁵³³

An observational study monitored outcomes in 184 subjects with asymptomatic atherosclerosis receiving standard management, standard management plus 100 mg aspirin/day, or standard management, aspirin, and 450 mg gotu kola extract/day plus 150 mg pycnogenol/day. After three years, a substantially reduced rate of cardiovascular events was seen in participants who received gotu kola plus pycnogenol; the rate of cardiovascular events requiring hospitalization was <4% in the supplement group and >12% in those who received standard care, with or without aspirin.⁵³⁴ A similar study that involved 90 men with coronary artery calcifications found the same pycnogenol plus gotu kola combination improved patterns of calcification after one year.⁵³⁵ Other studies by the same research team consistently found that combinations of pycnogenol plus gotu kola extract increased plaque stability and/or reduced the number and size of plaques, as assessed by ultrasound, in atherosclerosis patients.^536-540

Phytonutrients & Polyphenols

Curcumin

Curcumin is found in turmeric and has been shown to strongly inhibit inflammatory signaling.⁵⁴¹ Clinical trials have shown curcumin can promote metabolic health, support weight loss, improve lipid levels, and lower high blood pressure, oxidative stress, and inflammation.¹⁴ According to a meta-analysis of findings from 11 randomized controlled trials, curcumin use for 12 weeks or longer may lower high systolic blood pressure.⁵⁴² Other meta-analyses have indicated curcumin can improve lipid profiles,⁵⁴³ decrease hs-CRP levels,⁵⁴⁴ and improve flow-mediated dilation, a measure of endothelial function.^545,546 Curcumin has also been found to reduce cardiovascular risk markers in patients with chronic kidney disease,⁵⁴⁷ non-alcoholic fatty liver disease,^548,549 and type 2 diabetes,^95,550 particularly when used long-term at doses of up to 1,500 mg per day.

In a randomized controlled trial in 64 subjects with type 2 diabetes and mild-to-moderate coronary artery disease, taking 80 mg nano-curcumin (a highly bioavailable form of curcumin) daily for three months reduced hs-CRP and lipoprotein (a) levels.⁵⁵¹ In another trial, 90 patients undergoing coronary angioplasty (ie, percutaneous coronary intervention [PCI]) were assigned to receive 500 mg standard curcumin, 80 mg nano-curcumin, or placebo daily for eight weeks. Both forms of curcumin improved levels of lipids (total cholesterol, LDL-cholesterol, and triglycerides), markers of oxidative stress (total antioxidant capacity, superoxide dismutase, glutathione, and malondialdehyde), inflammatory markers (hs-CRP, interleukin-1-beta [IL-1β], and tumor necrosis factor-alpha [TNF-α]) relative to placebo, but nano-curcumin was more effective than standard curcumin at changing some of these parameters (total cholesterol, triglycerides, superoxide dismutase, malondialdehyde, and TNF-α).⁵⁵² Taking 2,000 mg curcumin daily for 12 weeks was found to increase NO availability and reduce arterial stiffness in a placebo-controlled trial in 39 healthy middle-aged and older adults; in addition, flow-mediated dilation increased by 36%, indicating enhanced endothelial function, in those receiving curcumin.⁵⁵³

Tea Polyphenols

Tea is rich in flavanols called catechins. Green tea in particular contains the well-studied catechin epigallocatechin gallate (EGCG), which has been shown to prevent lipid peroxidation and lower oxidative stress, reduce inflammation, and improve glucose metabolism.^554,555 In large observational studies, regular habitual tea-drinking has been associated with lower risks of coronary artery disease, peripheral artery disease, and all-cause mortality.^556-559

Clinical evidence shows green tea polyphenols improve endothelial function and become incorporated into LDL particles where they protect against oxidation.^560,561 In a randomized placebo-controlled trial in 20 subjects with type 2 diabetes, 400 mg green tea extract daily for 12 weeks reduced arterial stiffness.⁵⁶² Another randomized controlled trial in 30 male smokers found 580 mg per day of green tea catechins for two weeks led to increased NO synthesis, improved forearm blood flow, and decreased levels of markers of inflammation and oxidative stress.⁵⁶³ Eight weeks of treatment with 250 mg green tea extract daily was found to improve lipid profiles compared with placebo in 33 patients with dyslipidemia participating in a randomized crossover trial.⁵⁶⁴ Other small placebo-controlled trials have shown green tea lowers platelet activation, CRP levels, and oxidized LDL levels in healthy adults.^565,566

Resveratrol

Resveratrol is a polyphenol found in red grapes and red wine, berries, and peanuts. Preclinical studies have suggested resveratrol can slow aging and may have a positive effect on atherosclerosis by improving glucose and lipid metabolism and supporting healthy endothelial cell and vascular smooth muscle cell function.^567-569

A randomized placebo-controlled trial in 50 patients with type 2 diabetes found 100 mg resveratrol daily for 12 weeks not only improved blood pressure and body weight, but also improved measures of arterial stiffness and oxidative stress.⁵⁷⁰ In another randomized controlled trial with 75 participants, 350 mg of resveratrol-enriched grape extract daily for six months lowered LDL-cholesterol, oxidized LDL, and ApoB levels.⁵⁷¹ A randomized controlled trial in people with type 2 diabetes found resveratrol improved glucose control and insulin sensitivity, and combatted oxidative stress and inflammation—benefits that could also aid in prevention of atherosclerosis.⁵⁷²

Meta-analyses of findings from randomized controlled trials have shown resveratrol can improve flow-mediated dilation (a test of vascular function) and other markers of endothelial function.^573,574 For example, in a randomized, placebo-controlled, crossover trial, 28 patients with obesity received 75 mg of trans-resveratrol per day for six weeks and placebo for six weeks, in random order; flow-mediated dilation improved by 23% after resveratrol compared with placebo.⁵⁷⁵ In another crossover trial, 24 participants with hypertension and endothelial dysfunction received a single dose of 300 mg trans-resveratrol and placebo on separate occasions in random order; flow-mediated dilation was found to improve in women after resveratrol treatment, especially in those with high LDL-cholesterol levels.⁵⁷⁶

In a trial in 85 patients with coronary artery disease, those who received 100 mg resveratrol daily in addition to standard therapies for two months had better cardiac function compared with those who received standard therapies alone.⁵⁷⁷ Another placebo-controlled trial in 40 subjects who had experienced a heart attack found 10 mg resveratrol daily for three months improved endothelial function, lowered LDL-cholesterol levels, and improved markers of blood clot susceptibility.⁵⁷⁸

Cocoa Flavanols

Flavanols are a type of polyphenol found in cocoa, as well as fruits, vegetables, and tea. Cocoa flavanols may support cardiovascular health by reducing lipid oxidation, inhibiting platelet aggregation, modulating inflammation, reducing blood pressure, and improving insulin sensitivity.^19,579 Furthermore, a number of clinical trials in people with varying health statuses have indicated cocoa flavanols can enhance endothelial function.⁵⁸⁰ In a small trial involving patients with heart failure, eating flavanol-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.⁵⁸¹ In a placebo-controlled crossover trial in 11 type 2 diabetics and 11 healthy individuals, a single dose of 1,350 mg cocoa flavanols led to improvement on tests of vascular function in all participants.⁵⁸² Two weeks of supplementing with 450 mg cocoa flavanols twice daily improved markers of endothelial function in 39 healthy young and elderly adults in another trial.⁵⁸³ In a controlled crossover trial in 30 middle-aged overweight men and women, 814 mg cocoa flavanols per day (in the form of dark chocolate and a sugar-free cocoa beverage) for four weeks improved vascular endothelial function. The women in the study also had improvement in arterial stiffness while receiving cocoa flavanols.⁵⁸⁴

In a large, randomized, controlled trial, 21,442 U.S. adults received either 500 mg cocoa flavanols (including 80 mg epicatechin) daily or placebo, along with a multivitamin supplement or another placebo. During a median follow-up of 3.6 years, cocoa flavanols were found to have reduced cardiovascular deaths by 27% but did not significantly affect other adverse cardiovascular outcomes or all-cause mortality.⁵⁸⁵

Green Coffee Bean Extract

Green coffee beans are higher in polyphenols called chlorogenic acids compared with roasted coffee beans, which are typically used to make coffee beverages. A meta-analysis of data from 14 randomized controlled trials with a combined total of 821 participants found green coffee bean extract, at doses of 180–376 mg daily, improved cardiometabolic health by reducing triglyceride levels, lowering systolic and diastolic blood pressures, and increasing HDL-cholesterol levels.⁵⁸⁶ Another meta-analysis that included 15 randomized controlled trials with a total of 637 participants found green coffee extract also lowered total cholesterol and fasting blood glucose levels.⁵⁸⁷ Other meta-analyses have also reported green coffee extract’s positive effects on lipid levels, glucose metabolism, and blood pressure.^588-590 A placebo-controlled crossover trial in 21 healthy middle-aged volunteers found a single dose of 302 mg decaffeinated green coffee extract (but not higher doses) improved blood vessel function up to 24 hours post-dose.²⁵⁹ Another placebo-controlled trial in 16 healthy men found blood vessel function and a measure of arterial stiffness improved after two weeks of supplementing with a green coffee bean beverage.⁵⁹¹

Oligomeric Proanthocyanidins

Oligomeric proanthocyanidins (OPCs) are polyphenols found in the flowers, pulp, seeds, and bark of many fruits, grains, and vegetables. Good sources of OPCs include grape seeds and skins, blueberries, and coffee.⁵⁹² Preclinical research indicates OPCs may lower LDL-cholesterol and triglyceride levels, oxidative stress, and levels of markers of inflammatory immune activity, while increasing NO production and improving metabolic and cardiovascular risk factors.⁵⁹³ The health benefits of OPCs are related to their powerful free radical-scavenging properties.^592,594

In a controlled trial involving 287 patients with known carotid artery thickening and/or plaque, diet and lifestyle counseling plus 100 mg grape seed OPCs twice daily for two years decreased carotid artery thickness by 5.8% and reduced plaque scores by 33.1%; these measures were stable or increased with diet and lifestyle counseling alone. Furthermore, those who received grape seed extract had lower rates of TIAs, coronary artery surgeries, and hospitalizations for unstable angina.⁵⁹⁵ In a randomized controlled trial that included 30 middle-aged adults with pre-hypertension, those who received 400 mg grape seed proanthocyanidins daily (but not 200 mg daily) for 12 weeks had greater reductions in systolic blood pressure than those receiving placebo; in addition, among non-smoking participants, 400 mg grape seed extract improved measures of vascular function.⁵⁹⁶

Aronia Melanocarpa

Aronia melanocarpa, also called black chokeberry, is a member of the rose family. It produces small berries rich in a wide variety of polyphenols.⁵⁹⁷ Aronia extract has been found to reduce lipid oxidation, improve blood lipid levels, and increase total blood antioxidant capacity in studies in humans.⁵⁹⁸ In an open-label trial in 143 adults with metabolic syndrome, treatment with a standardized aronia extract for 28 days led to improvements in body weight, cholesterol levels, blood pressure, and blood glucose levels.⁵⁹⁹ In a randomized placebo-controlled trial in 102 middle-aged participants with pre-hypertension, taking 106 mg of aronia polyphenols daily for 12 weeks resulted in improved endothelial function, as well as changes to the gut microbiome with a shift toward increased presence of beneficial bacteria.⁶⁰⁰ Similarly, in a controlled clinical trial in which 66 healthy male adults received an aronia extract containing 116 mg of polyphenols, a whole fruit powder, or a placebo daily for 12 weeks, those receiving aronia had improvement in a measure of vascular function and potentially beneficial modifications of the gut microbiota.⁶⁰¹

A meta-analysis of findings from controlled trials indicated daily aronia use for six to eight weeks can reduce systolic blood pressure and total cholesterol levels, with stronger effects in individuals over 50 years of age.⁶⁰² However, not all findings agree. In a randomized controlled trial that included 109 healthy men with mildly elevated cholesterol levels, 150 mg of aronia polyphenols daily for 90 days reduced total and LDL-cholesterol levels in men under 40 years of age, but not those 40 years and older, and had no effects on measures of glucose metabolism, blood pressure, oxidative stress, or inflammation.⁶⁰³ Another randomized controlled trial with 84 participants found neither a high-polyphenol nor low-polyphenol aronia juice, taken daily for four weeks, affected cholesterol levels or blood pressure compared with placebo.⁶⁰⁴

Hydroxytyrosol

Olive polyphenols, including hydroxytyrosol, have demonstrated anti-inflammatory, antioxidant, anti-hypertensive, anti-diabetic, anti-thrombotic, HDL-cholesterol-raising, and anti-atherosclerotic effects in preclinical research.^605,606 Studies further indicate hydroxytyrosol, which is highly concentrated in extra virgin olive oil, may counteract endothelial dysfunction not only by reducing oxidative stress and inflammation, but also vascular aging and stiffness.⁶⁰⁷

Several clinical trials have found hydroxytyrosol can reduce levels of inflammatory markers, improve lipid profiles, enhance endothelial function, lower blood pressure, and reduce oxidative stress.⁶⁰⁸ For example, in a crossover trial, 30 patients with coronary artery disease took olive oil capsules providing 10 mg of hydroxytyrosol daily for one month and placebo for one month, in random order. Measures of coronary artery and cardiac function, as well as markers of oxidative stress and inflammation, were improved during treatment with hydroxytyrosol-rich olive oil.⁶⁰⁹ A randomized controlled crossover trial in 60 men with stage 1 hypertension found 6 mg hydroxytyrosol plus 136 mg oleuropein (another olive polyphenol) daily for six weeks significantly reduced blood pressure and total cholesterol, LDL-cholesterol, and triglyceride levels compared with a polyphenol-free supplement.⁶¹⁰

Hesperidin

Hesperidin is a polyphenol that occurs in citrus fruits, especially their peels. Digestion of hesperidin by intestinal bacteria produces a compound called hesperetin, along with other metabolites. Hesperidin and hesperetin are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity in animal studies.^611,612

Several controlled clinical trials have examined the effects of hesperidin on markers of cardiovascular risk. In one randomized controlled trial, 159 participants with pre- or stage 1 hypertension received either 500 mL of hesperidin-enriched orange juice (providing 600 mg hesperidin), standard orange juice (providing 345 mg hesperidin), or a control drink (providing no hesperidin) daily for 12 weeks. Hesperidin-enriched orange juice was found to have greater immediate and sustained blood pressure-lowering effects than the other drinks.⁶¹³ A randomized controlled trial that had 68 participants with overweight or obesity found 450 mg hesperidin daily for six weeks did not improve vascular function overall; however, in a subgroup of 48 participants with baseline flow-mediated dilation of 3% or greater (healthy flow-mediated dilation is around 7%),⁶¹⁴ hesperidin mitigated the negative effect of a high-fat meal on endothelial function.⁶¹⁵ Another trial in 24 overweight men found 292 mg of hesperidin, taken daily in an orange juice or control drink, improved after-meal endothelial function as well as diastolic blood pressure after four weeks.⁶¹⁶ In a crossover trial, 24 adults with metabolic syndrome were treated with 500 mg hesperidin per day or placebo for three weeks. Hesperidin improved endothelial function, reduced CRP levels by 32%, and decreased levels of total cholesterol, ApoB, and markers of vascular inflammation, relative to placebo.⁶¹⁷

Pine Bark Extract (Pycnogenol)

Pycnogenol is obtained from the French maritime pine tree (Pinus pinaster) and contains several types of polyphenols, including catechins and epicatechins, proanthocyanidins, and cinnamic acids.⁶¹⁸ Pycnogenol may benefit cardiovascular health through a variety of mechanisms, such as inhibiting inflammation and clotting, reducing oxidative stress, and improving endothelial function.⁶¹⁹

In a randomized, placebo-controlled, crossover trial, 23 individuals with coronary artery disease received 200 mg pycnogenol daily for eight weeks followed by placebo for eight weeks, or vice versa. Treatment with pycnogenol resulted in a significant reduction in oxidative stress and a 32% increase in a measure of endothelial function.⁶²⁰ A small trial in 16 healthy young men found 180 mg pycnogenol daily for two weeks increased NO synthesis, vasodilation, and forearm blood flow, indicating improved endothelial function.⁶²¹

Quercetin

Quercetin is a polyphenol found in virtually all plants and plant foods. Good sources of quercetin include apples, onions, cherries, berries, red grapes, red wine, and tea. Quercetin has well-established anti-inflammatory and antioxidant properties, and has been found to have beneficial effects on diabetes, obesity, dyslipidemia, high blood pressure, and atherosclerosis.⁶²² Although quercetin is poorly absorbed in the intestines, it is digested by gut microbes, producing other compounds that may contribute to its cardio-protective effects; in addition, quercetin appears to support cardiovascular health by modulating gut microbiome composition.⁶²³

Although there have been mixed findings from clinical trials investigating the use of quercetin for cardiovascular prevention and treatment, some studies have found benefits.⁶²⁴ In a randomized, placebo-controlled, crossover trial that included 37 participants with pre-hypertension, 160 mg quercetin daily for four weeks led to reduced inflammatory marker levels and improved a marker of endothelial function.⁵⁶⁰ In another randomized, controlled, crossover trial that included 70 subjects with pre-hypertension and obesity or overweight, 162 mg quercetin daily for six weeks was found to reduce ambulatory blood pressure (an average calculated from 24 hours of monitoring), but did not affect markers of oxidation, inflammation, lipid or glucose metabolism, or endothelial function.⁶²⁵ Taking 150 mg quercetin daily for six weeks was also found to lower high blood pressure and levels of oxidized LDL in another crossover trial in 93 overweight or obese subjects with other components of metabolic syndrome.⁶²⁶

Vitamins & Minerals

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). B vitamins are found in many foods including fish, leafy greens, whole grains, legumes, meat, eggs, dairy products, and nutritional yeast. As coenzymes for enzymatic reactions that support every aspect of cellular function, B vitamins are essential for cardiovascular health.⁶²⁷ In a large observational study with 115,664 participants who were followed for 8‒12 years, higher folate intake in particular was associated with lower risks of stroke, heart attack, and cardiovascular mortality.⁶²⁸ Another study examined data from 55,569 participants in the ongoing National Health and Nutrition Examination Survey and found higher intakes of folate and B6 were associated with lower rates of all-cause, cardiovascular, and cancer deaths in men and all-cause and cardiovascular deaths in women.⁶²⁹

A randomized controlled trial in 60 individuals with pre-hypertension found supplementing with B vitamins (providing 10 mg B1, 10 mg B2, 100 mg B3, 50 mg B5, 3 mg B6, 1.5 mg B9, and 15 mcg B12) plus vitamin C (150 mg) daily for four months lowered levels of homocysteine and hs-CRP and reduced insulin resistance compared with placebo.⁶³⁰ In another trial involving 81 people with mild-to-moderate high blood pressure who were not on blood pressure medication, a supplement providing 2.4 grams L-arginine, 3 mg B6, 0.4 mg folic acid, and 2 mcg B12 per day for six months mitigated the negative effects of a high-fat meal on vascular function and lowered blood pressure and homocysteine levels compared with placebo.⁶³¹

Vitamin E

Vitamin E is a family of fat-soluble antioxidant compounds comprising four tocopherols and four tocotrienols (each type has alpha, beta, gamma, and delta forms), with the highest concentrations found in oils, nuts, whole grains, and green leafy vegetables.⁶³²

Although findings from clinical trials have been mixed, multiple meta-analyses have found that supplementing with vitamin E, alone or in combination with other nutrients, reduced adverse cardiovascular outcomes including heart attacks and cardiovascular mortality.^632-634 For example, a meta-analysis that included 10 randomized controlled trials found vitamin E supplementation reduced cardiovascular mortality by 12%.⁶³⁴ Another meta-analysis that included 27 trials found supplementing with 300–1,800 IU (201–1,206 mg d-alpha tocopherol equivalent) vitamin E per day improved endothelial function in those with low baseline serum vitamin E.⁶³⁵

Human bodies primarily use the alpha-tocopherol form of vitamin E, and alpha-tocopherol is necessary to treat vitamin E deficiency. However, preclinical evidence suggests gamma-tocopherol has stronger antioxidant, anti-inflammatory, and cardioprotective effects than alpha-tocopherol. Multiple clinical trials have found benefits of gamma-tocopherol supplementation for lowering oxidative stress, inhibiting platelet aggregation, and improving endothelial function.⁶³⁶ Further clinical research into the various forms of vitamin E is necessarily to more fully establish their effects on atherosclerosis and cardiovascular outcomes.

Vitamin K

Vitamin K is a fat-soluble vitamin with two naturally occurring forms: phylloquinone (K1) from plant sources and menaquinones (K2) from animal and bacterial sources. Much of the vitamin K1 in the diet is converted to K2 in the body. K1 is recognized for its involvement in blood clotting, while K2 plays an important role in healthy calcium metabolism in tissues throughout the body.⁶³⁷ Anticoagulant drugs that work by blocking the activity of vitamin K, including warfarin (Coumadin), are associated with increased vascular calcification.^638-641 Also, kidney transplant recipients, in whom vitamin K deficiency is common, tend to experience increased vascular calcification and stiffness.⁶⁴²

An open-label randomized trial compared the effect of supplementing with 2 mg per day vitamin K1 with placebo in 72 patients with mild or moderate aortic valve calcification and thickening. After 12 months, the aortic valve calcification volume score increased by 22% in the placebo group compared with just 10% in the vitamin K group.⁶⁴³ In an earlier clinical trial, 388 healthy older men and women (aged 60–80 years) received either a daily multivitamin with 500 mcg vitamin K1 or a multivitamin alone for three years. In an analysis limited to participants who were at least 85% adherent to the supplement regimen, those receiving vitamin K had significantly less progression of coronary artery disease. In those with pre-existing CAC, there was 6% less progression in the vitamin K group.⁶⁴⁴

A meta-analysis of observational data from 21 studies with 222,592 participants found increased dietary intake of K1 and K2 were each associated with decreased risk of coronary artery disease, and vitamin K deficiency was linked to increased mortality from any cause.⁶⁴⁵ Similarly, another meta-analysis of data from three large U.S. cohorts, comprising a total of 3,891 participants, found the risk of all-cause mortality was 19% higher in those with the lowest circulating K1 levels compared to those with the highest levels. However, this study found no association between cardiovascular disease risk and K1 levels.⁶⁴⁶ An observational study in over 55,500 adults aged 50–64 years, followed for 21.5 years, found those in the highest 20% of dietary vitamin K1 intake—based on an initial diet survey—had a 23% lower risk of aortic stenosis and a 27% lower risk of aortic stenosis with complications.⁶⁴⁷

Analyses of controlled clinical trials have revealed some beneficial effects of vitamin K supplementation on vascular calcification. One systematic review and meta-analysis that included data from 13 controlled trials (2,162 subjects) and 14 longitudinal observational studies (10,726 subjects) concluded that vitamin K supplementation was associated with significant reductions in vascular calcification, undercarboxylated matrix Gla protein, and undercarboxylated osteocalcin.⁶⁴⁸ Another analysis concluded that although the benefit was not consistent across all studies, those with greater calcification at study entry had the greatest likelihood of benefit.⁶⁴⁸ A randomized controlled trial in 365 men with aortic valve calcification administered 720 mcg MK-7 (a form of vitamin K2) plus 1,000 IU (25 mcg) vitamin D daily for two years; this treatment had no significant effect on aortic or CAC scores or rates of heart valve surgeries, cardiovascular events, or all-cause deaths.⁶⁴⁹ A subsequent analysis of 304 subjects from this same trial found treatment slowed the progression of CAC in those with greater baseline CAC scores, but not in the overall set of participants, after two years. Additionally, a prespecified safety endpoint of the combined number of patients with heart attack, coronary revascularization, and all-cause mortality was reached in 10 placebo recipients but only three patients receiving the combined vitamin treatment.⁶⁵⁰

Vitamin C

Vitamin C (ascorbic acid) is a water-soluble vitamin with important free radical-scavenging effects. It is an essential cofactor in numerous enzymatic processes, including those related to wound healing, collagen synthesis, and control of gene expression. Observational studies have found that better vitamin C status is linked to protection against coronary artery disease, stroke, and high blood pressure. Controlled trials of vitamin C supplementation have demonstrated improvements in endothelial function, including in individuals with elevated cardiovascular risk.^635,651,652 Nevertheless, randomized controlled trials using 120–1,000 mg vitamin C daily for eight weeks to nine years have so far not shown a benefit in terms of cardiovascular events or mortality.^13,653

Vitamin D

Vitamin D is needed for immune regulation and cardiovascular health, and deficiency has been linked with atherosclerosis and cardiovascular disease.^161,162 In a randomized controlled trial published in 2023, a total of 21,302 people aged 60–84 years received either 60,000 IU (15,000 mcg) vitamin D3 or placebo monthly for up to five years; those receiving vitamin D had a 19% lower risk of heart attack compared with placebo. Those in the vitamin D group also had a lower rate of major cardiovascular events in general, but this difference was not statistically significant.¹⁶²

It is important to note that several randomized controlled trials have failed to show vitamin D supplementation improved cardiovascular outcomes.^654-657 However, many of these trials used relatively low doses (eg, the equivalent of about 2,000 IU [50 mcg] per day or less) and/or high intermittent doses rather than regular daily doses. Furthermore, because these trials often have not assessed vitamin D status, it is still unclear whether supplementation would have demonstrated cardiovascular benefits in individuals with vitamin D deficiency. More trials that assess participants’ baseline vitamin D status and target optimal blood levels of 25-hydroxyvitamin D with appropriate daily doses are needed to establish vitamin D’s potential role in improving cardiovascular outcomes.

Magnesium

Magnesium deficiency, which is more common with aging, can contribute to atherosclerosis by promoting high blood pressure, lipid accumulation, disturbed calcium metabolism, heart rhythm abnormalities, impaired insulin sensitivity, and vascular stiffness.^658,659 An observational study that monitored 14,446 participants for 27 years found lower blood magnesium levels were associated with a higher risk of developing coronary artery disease.⁶⁶⁰ In 13,826 individuals who were followed for about 24 years, low magnesium status was correlated with an increased risk of peripheral artery disease.⁶⁶¹ Multiple studies have linked low magnesium intake and blood levels with higher risk of cardiovascular disease and events.⁶⁶² Other observational evidence suggests healthy magnesium levels may help mitigate the effect of dyslipidemia on atherosclerosis risk.⁶⁶³

In a randomized placebo-controlled trial in 64 coronary artery disease patients, 300 mg magnesium sulfate (providing 30 mg of elemental magnesium) daily for six months improved markers of atherosclerotic risk, including levels of oxidized LDL, inflammatory markers, homocysteine, electrolytes, and thyroid hormone, as well as HbA1c.^664,665 In another randomized placebo-controlled trial in 60 people with coronary artery disease, 300 mg magnesium sulfate for three months lowered gene expression and blood levels of two out of five inflammatory cytokines measured.⁶⁶⁶ A meta-analysis that included seven randomized controlled trials with a total of 306 participants found magnesium supplementation improved endothelial function but did not change carotid artery wall thickness.⁶⁶⁷ In addition, a randomized placebo-controlled trial in 124 subjects with overweight or mild obesity found 150 mg elemental magnesium three times daily for 24 weeks had no effect on arterial stiffness or blood pressure, regardless of whether it was in the form of magnesium citrate, oxide, or sulfate.⁶⁶⁸