Atherosclerosis Topic Review

BySteven Lome, MD

Atherosclerosis is a chronic, systemic, inflammatory and metabolic disease and pathologic process characterized by the accumulation of cholesterol and calcium plaque within the arterial wall. [Kobiyama K, et al. Circ Res. 2018;1a]

The term “athero” means porridge and “sclerosis” means scarring, which is how atherosclerosis was first described on autopsy.

A healthy artery (left) and progressively diseased arteries with atherosclerotic plaque.
Source: Adobe Stock

Atherosclerotic plaque within the coronary arteries is responsible for atherosclerotic cardiovascular disease (ASCVD). [Libby P, et al. Nat Rev Dis Primers. 2019;1a] The specific manifestation of ASCVD depends on the anatomic location (vascular bed) affected; the most prevalent and burdensome forms include coronary artery disease (CAD; also known as ischemic heart disease), cerebrovascular disease (CBVD) and peripheral artery disease (PAD). [Libby P, et al. Nat Rev Dis Primers. 2019;8a] Regardless of the vascular bed affected, atherosclerotic plaque may cause chronic ischemia by limiting blood flow to the affected tissue or acute ischemia by thrombus formation following plaque rupture or erosion; the latter scenario causes the most serious forms of ASCVD, including acute coronary syndromes (ACS; unstable angina, non-ST-elevation myocardial infarction [non-STEMI], and ST-elevation myocardial infarction [STEMI]) and stroke. [Libby P, et al. Nat Rev Dis Primers. 2019;7a-b]

Epidemiology

The worldwide burden of ASCVD is immense, with heart disease (including CAD) and stroke (including ischemic stroke due to ASCVD) being the leading causes of death worldwide and the first and fifth cause of death, respectively, in the United States. [Libby P, et al. Nat Rev Dis Primers. 2019;2a] An estimated 197 million people in the world were living with CAD in 2019 [Roth GA, et al. J Am Coll Cardiol. 2020;7a] (20.1 million in the United States) [Tsao CW, et al. Circulation. 2022;376a] while 101 million were stroke survivors [Roth GA, et al. J Am Coll Cardiol. 2020;7b] (7.6 million in the United States). [Tsao CW, et al. Circulation. 2022;;239a] While PAD-associated mortality is comparably low (0.4% of all cardiovascular-related deaths), it still represents a significant burden, with 113 million cases worldwide [Roth GA, et al. J Am Coll Cardiol. 2020;23a] and 8.5 million cases in the United States. [Aday AW, et al. Circ Res. 2021;3a]

Pathogenesis and Pathophysiology

The pathophysiologic process by which atherosclerosis occurs is complex and somewhat controversial. Atherosclerotic plaques form in the inner layer of the arterial wall (the intima) which is separated from the lumen by a monolayer of endothelial cells. [Libby P, et al. Nat Rev Dis Primers. 2019;3a] Low density lipoprotein (LDL) particles are a type of cholesterol carrier in the blood and are the most important contributor to atherosclerosis; [Libby P, et al. Nat Rev Dis Primers. 2019;2b,3a] LDL cholesterol (LDL-C) can pass through the endothelial layer and accumulate in the intima, initiating the development of atherosclerotic plaque. [Libby P, et al. Nat Rev Dis Primers. 2019;3a] Common ASCVD risk factors, including an unhealthy diet, smoking, hypertension and hyperlipidemia, may increase inflammation and contribute to endothelial dysfunction, allowing more LDL-C to enter the intima. [Libby P, et al. Nat Rev Dis Primers. 2019;2b;4a-b] Once in the arterial wall, LDL-C is chemically modified into pro-inflammatory and immunogenic molecules, which attract monocytes from the lumen. [Libby P, et al. Nat Rev Dis Primers. 2019;3a] In the intima, monocytes mature into macrophages, which in turn become overloaded with cholesteryl ester, turning into “foam cells”. [Libby P, et al. Nat Rev Dis Primers. 2019;3a-b] Attracted by signals from foam cells, smooth muscle cells (SMCs) from the media (the middle layer of the arterial wall) also enter the intima, as do populations of T lymphocytes, some of which promote atherogenesis while others mitigate it. [Libby P, et al. Nat Rev Dis Primers. 2019;3a,4a]

The sequence of LDL-C infiltration followed by immune cell and SMC migration into the intima initiates the development of atherosclerotic plaque. The initial plaque grows and progresses into an atheroma — an atherosclerotic plaque characterized by a lipid-rich core composed of SMCs and foam cells, which continue to migrate into the intima and can transform into one another by a process called metaplasia. [Libby P, et al. Nat Rev Dis Primers. 2019;5a] Because dead macrophages, foam cells, and SMCs are not efficiently cleared from the lipid core, it is also known as the “necrotic core”. [Libby P, et al. Nat Rev Dis Primers. 2019;5a] This necrotic core is separated from the lumen not only by the endothelial monolayer but by a “fibrous cap” composed of extracellular matrix proteins secreted by the SMCs, including collagen, elastin, proteoglycans and glycosaminoglycans. [Libby P, et al. Nat Rev Dis Primers. 2019;5a] Atheromata may be classified by the relative abundance of core and cap material into “stable” plaques, which contain a large fibrous cap and a comparatively small necrotic core, and “vulnerable” plaques, which contain a large necrotic core and a thin fibrous cap. [Libby P, et al. Nat Rev Dis Primers. 2019;7a] At least two known processed contribute to cap thinning: reduced collagen synthesis by the SMCs (mediated by interferon gamma from T cells) and increased collagen breakdown (mediated by matrix metalloproteases secreted from macrophages). [Libby P, et al. Nat Rev Dis Primers. 2019;5a] Although stable plaques may cause chronic ischemia by occluding the affected artery, vulnerable plaques are prone to rupture, an event which may trigger thrombogenesis and cause acute ischemic events such as stroke or MI — the most severe manifestations of ASCVD. [Libby P, et al. Nat Rev Dis Primers. 2019;1a,7a]

Stages of endothelial dysfunction development, which can start early in life.
Source: Adobe Stock

The pathogenesis of atherosclerosis is outlined above in only the broadest terms. Several different views about the stages of plaque progression have been proposed; this area is subject to ongoing research and no consensus has emerged thus far. One working theory proposes the following stages:

Early fatty streak. Beginning in childhood, this is the initial stage of the process of atherosclerotic plaque formation. Fatty streaks are characterized by deposition of LDL-C particles in arterial locations prone to atherosclerosis, such as areas of high oscillatory shear, including arterial bifurcation points and inner walls of curvatures. [Pahwa R, et al. StatPearls. 2022;2a,3a; Hurst’s The Heart, 14th edition;871a] Early fatty streak areas are also characterized by high expression of key inflammatory markers, such as NF-κB (nuclear factor kappa B). Because the endothelium is constantly exposed to the circulation, the initial endothelial dysfunction caused by local inflammation and LDL-C infiltration is augmented by toxins present in the circulation, as occurs during tobacco use, diabetes and dyslipidemia. Hypertension contributes to endothelial dysfunction by increasing the physical force exerted in atherosclerosis-prone areas. [Pahwa R, et al. StatPearls. 2022;2a,3a] Monocytes also begin their migration into the plaque at this stage, turning into macrophages and, after being loaded with chemically modified lipids, becoming foam cells. [Pahwa R, et al. StatPearls. 2022;3a]

Atheroma/fibro-atheroma. This is the progressive stage of plaque formation, characterized by the migration of SMCs into the intima, attracted by signals from the foam cells. LDL-C particles and macrophages progressively accumulate into a lipid core, while SMCs produce extracellular matrix proteins that comprise the fibrous cap. [Pahwa R, et al. StatPearls. 2022;3a; Hurst’s The Heart, 14th edition;914a]

Advancing atheroma. The final stage of atheroma progression is characterized by a large necrotic core and low SMC density, with a correspondingly thin fibrous cap — a vulnerable plaque prone to rupture and thrombosis. Atherosclerotic plaques typically progress to the advancing atheroma stage at age 55 years to 65 years. [Pahwa R, et al. StatPearls. 2022;3a]

A proposed sequence of atherosclerotic plaque progression.
*Source: Wikimedia Commons. Distributed in accordance with license. The only changes made to the source material were to typefaces*

Disruption of vulnerable plaques by rupture or erosion is the most serious clinical outcome of atheromata, as it can result in thrombus formation and acute ischemia in downstream tissues. [Libby P, et al. Nat Rev Dis Primers. 2019;1a,7a] Rupture occurs when the fibrous cap covering the atheroma becomes thin and bursts, exposing the contents of the necrotic core to the bloodstream. This event brings thrombogenic material from the core, most notably tissue factor, with other clotting cascade molecules in the bloodstream, leading to thrombin-mediated fibrin generation, platelet aggregation and the formation of clot. [Libby P, et al. Nat Rev Dis Primers. 2019;7a-b-J] Another mechanism of atheroma-related thrombogenesis is plaque erosion. Although not completely understood, plaque erosion affects atheromata which are less inflamed and lipid-rich, and have a more resilient fibrous cap. Innate immune receptors and neutrophil extracellular traps (NETs; complexes of DNA and enzymes derived from dead neutrophils) which contain fibrin are believed to promote thrombogenesis at eroding plaques. [Libby P, et al. Nat Rev Dis Primers. 2019;7a-b]

The dysfunctional endothelium that characterizes atherosclerotic lesions also contributes to thrombogenesis, as it both lacks the anti-thrombotic properties of a healthy endothelium and produces the pro-thrombotic tissue factor. [Libby P, et al. Nat Rev Dis Primers. 2019;7b] Occasionally a thrombus created by plaque rupture will not completely occlude a vessel and will be resorbed; this promotes SMC migration and production of more extracellular material, burying the old fibrous cap and healing the lesion. However, plaques with buried caps tend to be larger and more occlusive. It is unknown if the same process can occur with thrombi generated by plaque erosion. [Libby P, et al. Nat Rev Dis Primers. 2019;6a]

Presentations

The presentation of ASCVD depends on two factors: whether the symptomatic atheroma is causing chronic blood flow obstruction or acute occlusion (often thrombotic), and on its anatomic location. [Libby P, et al. Nat Rev Dis Primers. 2019;8a]

The chronic manifestation of CAD (ASCVD in the coronary arteries) is stable angina (also known as stable ischemic heart disease) — chest pain or discomfort upon exertion that is alleviated by rest. [Libby P, et al. Nat Rev Dis Primers. 2019;8a; Gillen C, et al. StatPearls. 2022;1a] Acute manifestations of CAD (ACS) include, in order of severity, unstable angina (acute ischemic episode not alleviated by rest but without myocardial injury) and the two types of myocardial infarction (non-STEMI and STEMI). [Libby P, et al. Nat Rev Dis Primers. 2019;8a; Shahjehan RD, et al. StatPearls. 2023;1a; Thygesen K, et al. Circulation. 2018;5b,6b]

In CBVD (ASCVD in the carotid or cerebral arteries), the acute presentations are transient ischemic attack (TIA; an ischemic episode without brain tissue loss) and stroke (an ischemic episode with brain tissue loss). [Libby P, et al. Nat Rev Dis Primers. 2019;8a; Amarenco P. N Engl J Med. 2020;1a] Recurrent strokes may give rise to vascular dementia, a chronic manifestation of CBVD. [Libby P, et al. Nat Rev Dis Primers. 2019;8a; Bir SC, et al. J Stroke Cerebrovasc Dis. 2021;2a]

The chronic manifestations of PAD (ASCVD in the aortoiliac, common or superficial femoral, popliteal, tibial or peroneal arteries) include intermittent claudication (calf pain during walking and relieved by rest) and critical limb ischemia or chronic limb-threatening ischemia (CLI or CLTI; ischemic limb pain at rest, sometimes accompanied by ulceration or gangrene). [Libby P, et al. Nat Rev Dis Primers. 2019;8a; Golledge J. Nat Rev Cardiol. 2022;2a] Its acute manifestation is acute limb ischemia (ALI), a sudden ischemic episode that threatens the viability of a limb. It should be noted that ALI may also occur due to thromboembolism, ie, from a thrombus which formed elsewhere in the body and traveled to the limb. [Libby P, et al. Nat Rev Dis Primers. 2019;8a; Olinic DM, et al. J Clin Med. 2019;1a,2a]

Less common manifestations of ASCVD affect the thoracic or abdominal aorta, the renal arteries or the mesenteric arteries. [Libby P, et al. Nat Rev Dis Primers. 2019;8a]

Management

Optimal management of atherosclerosis would ideally target every known and modifiable risk factor that contributes to atheroma development. Lifestyle management, including adopting a healthy diet, moderate exercise and tobacco abstinence, should begin as early as possible. [Libby P, et al. Nat Rev Dis Primers. 2019;11b,12a] The 2018 multisociety guideline on cholesterol management includes as the first of its 10 take-home messages an emphasis on a heart-healthy lifestyle in all individuals throughout the entire life course. [Grundy SM, et al. Circulation. 2018;2b]

Because of the central role of LDL-C in the pathogenesis of atherosclerosis, LDL-C-lowering pharmacotherapy is the cornerstone of medical management of ASCVD. [Libby P, et al. Nat Rev Dis Primers. 2019;12a] Statins — inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a key enzyme in cholesterol synthesis — are the most widely used type of lipid-lowering medication. For each mmol/L reduction in LDL-C levels, statins provide a 22% reduction in the log-linear risk of adverse ASCVD events. In patients who require statins, the doses should be maximized to achieve the guideline-directed LDL-C reduction goal for each individual patient. [Libby P, et al. Nat Rev Dis Primers. 2019;12b]

The 2018 cholesterol guideline recommends high-intensity or maximally tolerated statin therapy for the secondary prevention of ASCVD in all patients with very high risk ASCVD (defined as a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions, such as diabetes, hypertension, tobacco use, etc) and in patients 75 years of age and younger with non-very high risk ASCVD. [Grundy SM, et al. Circulation. 2018;12a] Statins are also recommended for the primary prevention of ASCVD in all patients with primary severe hypercholesterolemia (LDL-C ≥ 190 mg/dL [4.9 mmol/L]; high-intensity statin), those 40 to 75 years of age with diabetes (moderate intensity statin, or high intensity statin if needed), those 40 to 75 years of age with a 10-year ASCVD risk of 20% or higher (high-intensity statin). Following a risk discussion, statins may also be used in primary prevention of ASCVD in younger patients or those with a lower 10-year ASCVD risk, if risk enhancers favor their use. [Grundy SM, et al. Circulation. 2018;13a] See the Topic Review on statins for a more detailed discussion of the guideline recommendations.

If a patient cannot tolerate the required statin dose, a number of nonstatin agents are now available for further LDL-C reduction. [Libby P, et al. Nat Rev Dis Primers. 2019;12b] These include ezetimibe, an enterocyte cholesterol absorption inhibitor (15% to 20% additional LDL-C reduction); [Libby P, et al. Nat Rev Dis Primers. 2019;13a] bile acid sequestrants (15% to 30% additional LDL-C reduction); inhibitors of PCSK9 (proprotein convertase kexin/subtilisin type 9; a key effector of LDL receptor degradation in hepatocytes, whose activity increases LDL-C levels in the bloodstream), including the monoclonal antibodies evolocumab and alirocumab and the small interfering RNA inclisiran (43% to 64% additional LDL-C reduction); [Coppinger C, et al. J Cardiovasc Pharmacol Ther. 2022;1a,4a-b,5a; Grundy SM, et al. Circulation. 2018;10b] and bempedoic acid, an inhibitor of adenosine triphosphate-citrate lyase (ACL), an enzyme that acts in the cholesterol synthesis pathway upstream of statins (13% to 22% additional LDL-C reduction). [Marrs JC, et al. Drugs Context. 2020;2a,3a-b,4a-b]

The 2018 cholesterol management guideline provides recommendations for the addition of nonstatins — ezetimibe, PCSK9 inhibitors, and bile acid sequestrants — to maximally tolerated statin therapy under certain conditions. [Grundy SM, et al. Circulation. 2018;10b] For specific recommendations, see the dedicated Topic Reviews for these drugs. Note that the guideline does not contain recommendations for bempedoic acid, as its use was not approved by the FDA until several years after the guideline was released.

Finally, antithrombotic therapy (antiplatelet agents and anticoagulants) is also useful in the secondary prevention of ASCVD, since thrombosis plays a key role in the most severe ASCVD outcomes. Aspirin, an antiplatelet agent, is a cornerstone of antithrombotic therapy in patients with ASCVD; P2Y12 inhibitors (which like aspirin are also antiplatelet agents) may be added to aspirin (a regimen called “dual antiplatelet therapy”) in the context of an ACS event or a percutaneous coronary intervention. [Libby P, et al. Nat Rev Dis Primers. 2019;13b] The anticoagulant rivaroxaban (Xarelto, Janssen/Bayer) in combination with aspirin (a regimen called “dual pathway inhibition” [DPI] because it combines an antiplatelet and an anticoagulant) has also demonstrated a benefit in reducing major adverse cardiovascular and limb events in patients with CAD and PAD. [Libby P, et al. Nat Rev Dis Primers. 2019;13b; Golledge J. Nat Rev Cardiol. 2022;14a] Because antithrombotic therapy increases bleeding risk, it is not employed in the primary prevention of ASCVD. [Libby P, et al. Nat Rev Dis Primers. 2019;13b]

Topic Reviews A-Z

Atherosclerosis Topic Review

Epidemiology

Pathogenesis and Pathophysiology

Presentations

Management

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