Atherosclerosis is a chronic disease where fatty deposits build up inside artery walls, and it is the leading cause of heart attacks, strokes, and peripheral artery disease worldwide. This comprehensive primer explains that LDL cholesterol particles are the primary trigger for the disease, while inflammation, high blood pressure, smoking, and diabetes all contribute to its development and complications. The article reviews how plaques form and progress, the latest diagnostic techniques, and the expanding arsenal of treatments that have dramatically improved survival rates for patients who reach medical care. Despite major advances, the authors emphasize that too many people still die from acute complications outside hospitals, and significant challenges remain in ensuring equitable access to treatments and addressing the global epidemic of cardiovascular disease.
Atherosclerosis is the buildup of fatty and fibrous material in the innermost layer of arteries, called the intima. The term comes from the Greek word for "gruel" or "porridge," which describes the appearance of the fatty material found in the core of a typical atherosclerotic plaque (also called an atheroma). Over time, these plaques can become more fibrous and accumulate calcium deposits, hardening the arteries.
Advanced plaques can narrow the artery and restrict blood flow, causing tissue ischemia (insufficient oxygen supply). Some plaques that don't block blood flow can still be dangerous—they can rupture and trigger the formation of a blood clot (thrombus) that suddenly blocks the artery. This second route to ischemia is often more acute and more deadly.
When atherosclerosis affects the heart's own blood vessels, it can cause acute coronary syndromes including myocardial infarction (heart attack) or chronic conditions like stable angina pectoris (chest pain or discomfort caused by insufficient blood flow to the heart muscle). The disease also causes many ischemic strokes and transient cerebral ischemic attacks (sometimes called "mini-strokes"). It can lead to the formation of aneurysms, including those in the abdominal aorta, and when it affects the peripheral arteries, it can cause intermittent claudication (leg pain with walking), ulceration, and even gangrene that threatens limb survival.
Despite the serious nature of this disease, there is good news. The authors note that if a patient reaches the healthcare system with an acute manifestation of atherosclerosis, they overwhelmingly survive with current interventions and management strategies. This progress represents a sterling example of how scientific discoveries applied in clinical practice can yield enormous benefits for patients.
Cardiovascular diseases (CVDs)—which include coronary heart disease, hypertension, and stroke—collectively comprise the number one cause of death globally. Heart disease (most commonly due to atherosclerosis of the coronary arteries) and stroke are the two leading causes of death worldwide. In the USA, heart disease is the first cause of death and stroke is the fifth.
The numbers are staggering. Over 17 million people died from CVD in 2015, representing 31% of all global deaths. Of these, an estimated 7.4 million deaths were due to coronary heart disease and 6.7 million to stroke. In the USA, among individuals over 20 years of age, 37.4% of men and 35.9% of women have some form of CVD, with men representing 50.6% of deaths from CVD.
The disease does not affect all populations equally. Among men with CVD in the USA, 37.7% are non-Hispanic white, 46.0% are black, and 31.3% are Hispanic. In women, these figures are 35.1%, 47.7%, and 33.3%, respectively.
Globally, more than 75% of deaths from CVD occur in low-income and middle-income countries. In these countries, individuals with CVD often have limited access to effective and equitable healthcare services, which can delay detection until late in the disease course and increase premature mortality. CVD leads to 18% of disability-adjusted life years lost in high-income countries and 10% in low-income and middle-income countries, placing a heavy burden on developing economies.
There is some encouraging news in the data. Since the 1950s, advances in cardiovascular health have led to striking declines in mortality from heart disease and stroke in both men and women. For example, in the UK, CVD mortality in men aged 35–69 years decreased from 22% in 1950 to 6% in 2010. However, the Global Burden of Disease 2010 study estimated that this decrease has not occurred consistently in low-income and middle-income countries. While stroke mortality has declined, deaths from heart disease have dropped less consistently, with some countries—especially in Eastern Europe and Asia—reporting increases in mortality.
Data from the US National Health and Nutrition Examination Survey showed that the overall population prevalence of high LDL cholesterol did not change substantially from 1999–2002 (34.5%) to 2005–2008 (33.5%). However, treatment of high LDL-C increased significantly, from 28.4% in 1999–2002 to 48.1% in 2005–2008. The prevalence of individuals achieving a significant degree of LDL lowering more than doubled during the study period, from 14.6% to 33.2%.
In 2016, the WHO and the US Centers for Disease Control and Prevention launched Global Hearts, a new initiative to reduce the global threat of CVD by 2025, especially in developing countries. This program promotes population-level interventions to reduce risk factors, including reducing tobacco use and dietary salt intake, and strengthening CVD management in primary health care.
LDL particles are the primary cause of atherosclerosis. These spheroidal packets of cholesterol-rich lipids are enveloped in a phospholipid coating with apolipoprotein B snaking through their equatorial region. They transport water-insoluble cholesterol through the blood.
Atherosclerosis probably would not occur in the absence of LDL cholesterol concentrations in excess of physiological needs (on the order of 10–20 mg/dL). Phylogenetic, comparative population studies, and pharmacological intervention investigations suggest that LDL-C concentrations in the 20–30 mg/dL range (about 0.5–0.8 mmol/L) are sufficient for good health. Despite recent trends toward lowering cholesterol levels, the concentrations of blood cholesterol prevalent in most contemporary human societies far exceed the biological needs of the organism, permitting the development of atherosclerosis.
The cumulative exposure of an artery to LDL-C over years remains a principal determinant of disease initiation and progression. This explains why patients with familial hypercholesterolemia—a genetic condition causing very high cholesterol from birth—develop premature atherosclerotic CVD. They reach the cumulative LDL-C burden threshold at an early age.
Conversely, individuals with proprotein convertase subtilisin/kexin type 9 (PCSK9) loss-of-function mutations have lifelong low LDL-C concentrations due to reduced catabolism of LDL receptors. These individuals show a greater reduction in coronary events than that afforded by statin treatment alone, providing powerful genetic evidence that LDL causes atherosclerosis.
Many decades of research have supported the concept that oxidized LDL particles can promote atherogenesis. When LDL particles accumulate in the intima, they are protected from plasma antioxidants and can undergo oxidative and other modifications that make them pro-inflammatory and immunogenic. Pathways that can lead to modification of LDL particles include the formation of reactive oxygen species in the intima due to metal ion catalysis (the Fenton reaction), among other sources.
Here's what happens step by step:
The expression of high-capacity scavenger receptors for LDL particles does not drop when cellular cholesterol content rises, as does the expression of the high-affinity LDL receptor. Thus, these scavenger receptors permit overloading of macrophages with cholesteryl ester, generating foam cells—a hallmark of the early atherosclerotic lesion.
However, the authors are careful to note that despite the wealth of experimental data supporting this sequence, we still lack rigorous proof that oxidized LDL particles initiate human atherosclerosis. No antioxidant vitamin has forestalled atherosclerotic events in a suitably powered clinical trial. A lipid-soluble antioxidant that effectively blocks LDL particle oxidation, succinobucol, did not reduce cardiovascular events in a large-scale clinical study. Moreover, laboratory studies suggest that native rather than oxidized LDL particles stimulate T cell responses thought to participate in atherogenesis.
Despite these uncertainties about the exact mechanism, strong human genetic evidence, results of observational epidemiological studies, and pharmacological interventions establish LDL-C as an indubitable causal factor and therapeutic target in atherosclerosis.
High-density lipoprotein cholesterol (HDL-C) concentrations consistently associate inversely with the risk of atherosclerotic events in observational epidemiological studies. However, current human genetic evidence does not support a protective role for HDL-C against atherosclerosis. Moreover, numerous therapies that raise HDL-C have failed to improve cardiovascular outcomes. The disparity with the observational data may be because HDL-C tracks inversely with triglyceride concentrations.
Substantial human genetic evidence now supports a causal role for triglyceride-rich lipoproteins in atherosclerosis. In contrast to HDL, convincing human genetic evidence supports the strong observational relationship between lipoprotein(a) (Lp(a)) and atherosclerotic risk.
Other risk factors implicated causally in atherogenesis include hypertension, tobacco use, and the components of the metabolic syndrome cluster, which include elevated blood pressure, visceral adiposity (belly fat), insulin resistance, and high blood concentrations of triglyceride-rich lipoproteins—factors that ultimately can lead to full-blown diabetes mellitus.
Many if not all of these risk factors participate in the activation of inflammatory pathways. Inflammation can alter the function of the cells of the artery wall in a manner that drives atherosclerosis. For example:
These extravascular sites of inflammation can affect distant artery walls, as they release soluble inflammatory mediators such as cytokines that can activate cells in the intima. Biomarkers of inflammation, notably C-reactive protein (CRP; measured with a highly sensitive assay, hsCRP), prospectively predict cardiovascular risk and rise in tandem with many established cardiovascular risk factors.
A rich experimental basis has established a role for adaptive immunity in atherogenesis as well. Human atherosclerotic lesions contain T lymphocytes and display markers of adaptive immune activation. Some T cell subtypes (for example, type 1 T helper (TH1) cells) promote experimental atherosclerosis, whereas others (for example, regulatory T (Treg) cells) seem to mitigate atherogenesis.
The endothelium—the monolayer of cells that provides the interface between blood and the arterial intima—is the site where atheroma initiation occurs. Exposure to atherogenic risk factors interferes with the production of endogenous vasodilators, such as nitric oxide, by endothelial cells. Consumption of a cholesterol-containing diet can activate the expression of adhesion molecules, such as vascular cell adhesion protein 1, that bind blood leukocytes to the endothelial surface, and of chemoattractants that promote entry of the bound leukocytes into the intima.
The local hemodynamic environment also affects endothelial functions. Changes to blood flow are sensed by flow-dependent ion channels or surface structures, such as members of the integrin family of transmembrane proteins. Downstream transcriptional mechanisms that transduce the effects of flow into altered gene expression include Krüppel-like factor 2.
Abnormal flow patterns disturb the physiological homeostatic atheroprotective functions of the endothelium, reversing tonic vasodilatation, anti-thrombotic and anti-inflammatory properties, and mechanisms that resist thrombus formation and persistence. This explains why atherosclerotic plaques tend to form at sites of flow disturbance (where arteries branch or curve), whereas sites in the arterial tree where laminar shear stress predominates generally resist atheroma formation.
Once established, atherosclerotic plaques progress by continued accumulation of lipid and lipid-engorged cells. For many years, most researchers considered macrophages derived from blood monocytes as the precursors of lipid-laden foam cells in atheromata. Recent experimental data suggest that metaplasia of smooth muscle cells may also give rise to foam cells resembling macrophages.
The human intima contains resident smooth muscle cells, particularly at sites where atheromata tend to develop. Migration of smooth muscle cells from the media into the intima can contribute to the accumulation of smooth muscle cells in the growing plaque. These cells can proliferate over the years and elaborate extracellular matrix macromolecules that comprise much of the bulk of an established atherosclerotic plaque.
The extracellular matrix of atherosclerotic plaques contains interstitial collagen, elastin, proteoglycans, and glycosaminoglycans. Many of these extracellular matrix macromolecules can entrap lipoproteins and promote lipid accumulation within the intima. Inflammatory leukocytes not only arrive in the intima by infiltration but can also proliferate within the lesion. Various retention factors such as semaphorins can retard the egress of these leukocytes and contribute to their accumulation.
The most dangerous plaques are those with thin fibrous caps. Several processes contribute to fibrous cap thinning:
These processes can destabilize the plaque, making it prone to rupture and cause blood clots that block arteries, leading to heart attacks and strokes.
This research has several direct implications for patients. First, the evidence that LDL cholesterol causes atherosclerosis is now beyond doubt. This means that lowering LDL cholesterol—whether through lifestyle changes, statins, or newer medications like PCSK9 inhibitors—is a proven strategy to reduce cardiovascular risk.
Second, the recognition that inflammation plays a key role in atherosclerosis opens new avenues for treatment. Patients with elevated inflammatory markers like hsCRP may be at higher risk even when their cholesterol is well controlled.
Third, the finding that triglyceride-rich lipoproteins are causally linked to atherosclerosis means that patients with high triglycerides should take this seriously, not dismiss it as a "less important" lipid abnormality.
Fourth, the observation that HDL cholesterol may not actually be protective challenges the old notion that "good cholesterol" is always beneficial. Raising HDL with drugs has not improved outcomes, so patients should focus on proven therapies rather than unproven HDL-raising approaches.
Finally, the dramatic improvements in survival for patients who reach the hospital with acute cardiovascular events should give patients hope. The authors note that with current interventions and management strategies, patients who present with acute manifestations of atherosclerosis overwhelmingly survive.
The authors are candid about the limitations of current knowledge. Despite decades of research, we still lack rigorous proof that oxidized LDL particles initiate human atherosclerosis. The "oxidized LDL particle hypothesis" rests on solid experimental evidence, but its relevance to human atherosclerosis remains conjectural, and from a clinical perspective, it has not yielded an actionable therapy.
Similarly, the mechanisms that link many risk factors (hypertension, smoking, diabetes) to atherogenesis remain incompletely elucidated. While inflammation appears to be a common pathway, the details are still being worked out.
The authors also note that although most patients survive acute coronary syndromes, they can be left with impaired cardiac function that sets the stage for heart failure—a growing epidemic. Much remains to be done in applying what we already know more effectively and equitably in practice, and in confronting the remaining unacceptable burden of residual risk.
Based on this comprehensive review, here are actionable recommendations for patients:
The authors emphasize that exposure to risk factors has a cumulative effect throughout life. It's never too early—or too late—to address cardiovascular risk factors. Even in countries where mortality has declined dramatically since the 1950s, continued efforts are needed to ensure these improvements apply evenly across all populations.
Atherosclerosis is a chronic disease where fatty and fibrous material builds up in the inner layer of arteries. These plaques can narrow arteries, restricting blood flow, or rupture and trigger blood clots that suddenly block arteries. This can cause heart attacks, strokes, and peripheral artery disease.
LDL cholesterol particles are the primary cause of atherosclerosis. LDL particles accumulate in the artery wall, become oxidized, and trigger an inflammatory response. Other risk factors include high blood pressure, smoking, diabetes, and high triglycerides. These factors activate inflammatory pathways that drive the disease.
LDL particles enter the inner layer of the artery wall, become oxidized, and attract white blood cells called monocytes. These monocytes mature into macrophages, which take up the LDL and become foam cells. This process leads to the formation of fatty streaks and plaques, a hallmark of early atherosclerosis.
Plaques with thin fibrous caps are the most dangerous. Thinning occurs due to increased collagen breakdown, decreased collagen synthesis, smooth muscle cell death, and defective clearance of dead cells. These processes can destabilize the plaque, making it prone to rupture and cause blood clots that block arteries, leading to heart attacks and strokes.
Know your LDL cholesterol level and work with your doctor to achieve your target. Take cholesterol-lowering medications as prescribed, don't smoke, control blood pressure, manage diabetes, pay attention to triglycerides, maintain a healthy weight, and seek care promptly for symptoms like chest pain or shortness of breath.
Inflammation plays a key role in atherosclerosis. Many risk factors, such as high blood pressure, smoking, and diabetes, activate inflammatory pathways. Biomarkers like C-reactive protein (hsCRP) predict cardiovascular risk. Patients with elevated hsCRP may be at higher risk even when cholesterol is well controlled.
Original Article: "Atherosclerosis" by Peter Libby, Julie E. Buring, Lina Badimon, Göran K. Hansson, John Deanfield, Márcio Sommer Bittencourt, Lale Tokgözoğlu, and Eldrin F. Lewis
Publication: Nature Reviews Disease Primers, 2019, Volume 5, Article citation ID: (2019) 5:56
DOI: https://doi.org/10.1038/s41572-019-0106-z
Author Affiliations: Department of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA; Centre d'Investigació Cardiovascular CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Center for Molecular Medicine, Karolinska Universitetssjukhuset, Stockholm, Sweden; Institute of Cardiovascular Sciences, University College London, London, UK; Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil; Faculdade Israelita de Ciencias da Saude Albert Einstein, São Paulo, Brazil; DASA, São Paulo, Brazil; Hacettepe University, Ankara, Turkey.
This patient-friendly article is based on peer-reviewed research published in Nature Reviews Disease Primers. It has been written to make the scientific content accessible to a general audience while preserving all key data, findings, and conclusions from the original publication.
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