Atherosclerosis, also known as coronary artery disease (CAD), is the most common type of cardiovascular disease (CVD), with the main component being lipid accumulation and inflammation of the large arteries, which can eventually lead to clinical complications such as myocardial infarction (MI) and stroke. Clinically significant atherosclerosis is a slow-progressing disease that mostly affects the elderly and, despite a decline in prevalence in certain countries, remains the leading cause of death globally.

Atherosclerotic lesions are distinguished by the accumulation and transformation of lipids, inflammatory cells, smooth muscle cells, and necrotic cell debris in the intimal space underneath a monolayer of endothelial cells (ECs) that line the internal artery wall during a lifetime. Typically, lesion growth reduces blood flow in the lumen by more than 50%, which can cause angina, especially during exercise or stress. Lesions can become unstable and burst, especially if they are fatty and inflammatory. If this happens in the coronary arteries, it might form a local clot, which can fully impede blood flow and induce a MI. Alternatively, the clot may exit the heart and migrate to the brain, causing a stroke.

Lesion initiation and growth

The wall vessel is made up of a monolayer of endothelial cells (EC) that surrounds the luminal blood flow. The “intima” is a mostly acellular layer composed of glycosaminoglycans and collagen that lies underneath this. The “media” layers of smooth muscle cells (SMC) are accompanied by a fibrous layer termed as the “adventitia”. The buildup of certain plasma lipoproteins, particularly low-density lipoproteins (LDLs) and remnants of triglyceride-rich lipoproteins, in the intimal area of the artery is a major cause of atherosclerosis. This causes the overlying EC to be activated via a mechanism that is still unknown, but is likely to involve the generation of proinflammatory oxidized lipids. Blood monocytes then adhere to endothelial adhesion molecules, penetrate the intima, and develop into macrophages. This, in turn, can absorb lipoproteins, resulting in cholesterol ester-engorged “foam cells.”

Fig: The formation of fatty stripe lesions Lipoproteins enters the intima at shear stress points. The lipoproteins subsequently agglomerate and get oxidized and otherwise changed, causing the overlaying EC to produce adhesion and chemotactic molecules for monocytes. Monocytes penetrate the intima, develop into macrophages, and take up modified lipoproteins, giving rise to foam cells. The size of the intima is exaggerated.

Advanced atherosclerotic lesions

Following the initial accumulation of lipids and foam cells, additional leukocytes, mainly T lymphocytes, enter the lesion and act with macrophages. The foam cells die over time, resulting in necrotic cores composed of cell debris and cholesterol. In addition, SMC change from a contractile to a proliferative state and move to the region underneath the EC to create a “fibrous cap” that shields the lesion from rupture. SMC can also develop into macrophage-like cells, which produce foam cells, and bone-like cells, which deposit calcium phosphate mineral. Although lesions can get large enough to obstruct blood flow, the most clinically relevant event is a MI caused by the development of a clot caused by lesion rupture or endothelial degradation.

Fig: Development of atherosclerosis lesions
Fig: Advanced atherosclerotic lesions

Aging and atherosclerosis

The majority of MIs and strokes occur in those above the age of 55, indicating that atherosclerosis is primarily a progressive disease. However, there are certain early-onset variants, such as familial hypercholesterolemia (FH), as well as extremely uncommon illnesses, such as Hutchinson-Gilford progeria. Three discovered aging mechanisms that relate to atherosclerosis have been identified.

Clonal hematopoiesis, which is rather frequent in the elderly, is significantly linked to atherosclerosis. One possible reason for the link is enhanced hematopoiesis, which will proportionally increase the risk of generating mutations affecting HSC proliferation, because mutations tend to emerge during replication. Another possibility is that the clones, notably monocytes and neutrophils, are more proinflammatory, increasing lesion formation.

Cellular senescence of EC and SMC, as well as macrophages, has been linked to lesion development, inflammation, and stability. Senescence can be induced by oxidative stress, damage to DNA, and replicative stress. Although it prevents against cancer and facilitates tissue repair, senescent cells in aged tissues have been related to degeneration and malfunction. Senescent cells affect the surrounding cells by secreting a range of inflammatory cytokines, immune modulators, and proteases, which is known as the senescence-associated secretory phenotype (SASP). Senescent cells in atherosclerosis contribute to the degradation of the fibrous cap, which is critical in preventing plaque rupture, whereas senolytic clearance restored SMC numbers and cap thickness.

Chronic, low-grade inflammation usually occurs with advanced age in the absence of infection and contributes to age-related diseases such as atherosclerosis. It can have a significant impact on systemic systems such as cholesterol and glucose metabolism. Aging is characterized by increasing macrophage numbers and altered polarization.

Genetics of atherosclerosis

GWAS investigations of CVD have revealed around 200 loci including candidate genes that fall into multiple risk categories, while a vast number of genes do not yet match into any recognized category. GWAS loci for CVD risk variables such as plasma lipid levels, hypertension, and diabetes have each discovered hundreds of additional, mostly non-overlapping loci.

Fig: Genetic factors contributing to atherosclerosis susceptibility

Traditional risk factors

Lipoprotein metabolism: Triglyceride-rich lipoprotein levels are related with atherosclerosis, although the link was previously assumed to be indirect, presumably from interactions with HDL metabolism. This was reinforced by the fact that several conditions with substantially increased plasma triglyceride levels, such as lipoprotein lipase deficiency, reveal only minor increases in atherosclerosis. Recent genetic research, on the other hand, reveal that particular triglyceride-rich lipoproteins do, in fact, directly induce atherosclerosis.

Hypertension: Elevated blood pressure is a key risk factor for coronary artery disease and stroke, with various environmental and genetic factors contributing. Despite being a well-known independent risk factor for atherosclerosis, the mechanism by which hypertension promotes CAD remains unknown.

Diabetes: Type 2 diabetes is characterized by an interaction of genetic and environmental factors. It has become quite prevalent as a result of the increase in obesity and is closely linked to CAD, despite the fact that the underlying processes remain unclear. Diabetics frequently have metabolic syndrome, a collection of features that includes insulin resistance, obesity, hypertension, and increased LDL levels, all of which contribute to atherosclerosis in their own right.

Environmental risk factors

The fact that changes in lifestyle choices and cultural practices may significantly affect CAD risk despite the same genetic background suggests that the environment appears to have a significant role in atherosclerosis.

Nutrition and obesity:  Unhealthy diets lead to several classic risk factors, such as LDL cholesterol, triglyceride levels, diabetes mellitus, and hypertension. CAD risk is altered by food composition irrespective of energy amount.

Exercise and physical activity: Physical exercise has been linked to a lower risk of CAD. Improved glucose tolerance, lower plasma lipids, higher anti-inflammatory pathways, and decreased adiposity are all potential mediators. Exercise, in contrast to stress, appears to decrease hematopoiesis and lower circulating monocytes and neutrophils.

Sleep and stress: Long-term sleep deprivation has been associated with numerous of disorders. Chronic stress, such lack of sleep, induces monocytosis and neutrophilia in mice and humans. The limbic-hypothalamic-pituitary-adrenal axis also increases glucocorticoid release from the adrenal glands. This may hasten atherosclerosis, as long-term corticosteroid medication has been linked to CAD.

Smoking: Although smoking raises the risk of cancer and respiratory disorders, CAD accounts for about half of the premature mortality linked with smoking. Smokers have a 2-fold increased risk of CAD, and even light smokers have a 2-fold increased risk of MI. E-cigarette usage is increasing, which had intermediate effects on lipid peroxidation and antioxidant defenses when compared to tobacco smoke, suggesting that they induce inflammation and provide a risk for CAD.

Pollution: The majority of air pollution is composed of aerosols that comprise both particulates and gas. It is estimated that it causes around 7 million premature deaths every year. Air pollution has been linked to dyslipidemia, endothelial dysfunction, platelet activation, atherosclerosis, and lesion stability.

Intestinal microbiota: Bacteria in particular aid in digestion, activate the immune system, and produces special metabolites that enter the host’s blood. Microbial metabolites have emerged as important atherosclerosis mediators. Trimethylamine N-oxide (TMAO) is the most important metabolite found thus far, formed by hepatic oxidation of trimethylamine, a molecule obtained through bacterial choline and carnitine metabolism. TMAO levels are higher in those who eat a lot of choline or carnitine, or who have renal illness. TMAO tends to increase platelet reactivity and vascular inflammation, which appears to cause atherosclerosis.

Infections: Bacterial and viral infections have long been linked to atherosclerosis. Recent large epidemiological investigations of SARS-CoV-2 infected individuals have showed significant postinfection increases in the occurrence of a multitude of CVD.

Clinical Diagnosis:

Clinical evaluation of atherosclerosis risk is mostly dependent on “traditional” risk factors and imaging technologies. Nontraditional risk factors such as TMAO levels, IgE levels, or plasma proteome analysis are growing for assessing the risk of atherosclerosis.

With the discovery of hundreds of genetic loci that contribute to illness, polygenic genetic risk scores based on high-density genotyping have the ability to predict the risk of CAD or the development of very high LDL-cholesterol early in life.

Management of Atherosclerosis:

Atherosclerotic lesions grow throughout a lifetime and are typically permanent, while recent research suggests that lipid-rich lesions may be reversible. The most essential clinical objectives are preventive and early identification. Advances in disease awareness, as well as technological advancements, have generated several potential for the creation of innovative medical applications.

  • Considering plasma LDL, Lp(a), and triglyceride-rich lipoproteins are key contributors to atherosclerosis, several efforts have been made to reduce their levels. Statins hinder the rate-limiting enzyme in cholesterol production, HMG-CoA reductase, and hence boost LDL receptor levels in the liver. They are commonly used and effective for decreasing LDL cholesterol levels. Statins, on the other hand, can have serious side effects such muscular weakness and can contribute to type 2 diabetes.
  • Ezetimibe, an inhibitor of the NPC1L1 transporter responsible for cholesterol absorption in the small intestine, is another option.
  • Another option is to use neutralizing antibodies against the secreted protease PCSK9, which inhibits LDL receptor recycling and so downregulates it.
  • Although probiotics and prebiotics are widely used, it is uncertain if they have a direct impact on the overall microbial composition of persons. Dietary changes can obviously impact the amounts of circulating microbial metabolites; for example, plant-based diets lower TMAO levels while increasing short-chain fatty acid levels.


  • Bj√∂rkegren JLM, Lusis AJ. Atherosclerosis: Recent developments. Cell. 2022 Apr 27:S0092-8674(22)00400-7. doi: 10.1016/j.cell.2022.04.004. Epub ahead of print. PMID: 35504280.
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