Atherosclerosis

All stages of atherosclerosis—from initiation and growth to complication of the plaque (eg, myocardial infarction, stroke) —are considered an inflammatory response to injury mediated by specific cytokines. Endothelial injury is thought to have a primary initiating or inciting role.

Nonlaminar or turbulent blood flow (eg, at branch points in the arterial tree) leads to endothelial dysfunction and inhibits endothelial production of nitric oxide, a potent vasodilator and anti-inflammatory molecule. Such blood flow also stimulates endothelial cells to produce adhesion molecules, which recruit and bind inflammatory cells.

Risk factors for atherosclerosis (eg, dyslipidemia, diabetes, cigarette smoking, hypertension

Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. Degraded erythrocyte membranes that result from rupture of vasa vasorum and intraplaque hemorrhage may be an important additional source of lipids within plaques.

Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. Various factors promote smooth muscle cell replication and increase production of dense extracellular matrix. The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. A process similar to bone formation causes calcification within the plaque.

A link between infection and atherosclerosis has been observed, specifically an association between serologic evidence of certain infections (eg, Chlamydia pneumoniae, cytomegalovirus) and coronary artery disease (CAD). Putative mechanisms include indirect effects of chronic inflammation in the bloodstream, cross-reactive antibodies, and inflammatory effects of infectious pathogens on the arterial wall. However, evidence in favor of such a link is conflicting, and infection likely plays a minor role in atherosclerosis.

Atherosclerotic plaques may be stable or unstable.

Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion.

Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. Most clinical events result from unstable plaques, which are often not hemodynamically significant on angiography; thus, plaque stabilization may be a way to reduce morbidity and mortality.

The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. T cells in the plaque contribute by secreting cytokines. Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.

• The resultant thrombus may organize and be incorporated into the plaque, changing the plaque’s shape and causing its rapid growth.

• The thrombus may rapidly occlude the vascular lumen and precipitate an acute ischemic event.

• The thrombus may embolize.

• The plaque may fill with blood, balloon out, and immediately occlude the artery.

• Plaque contents (rather than thrombus) may embolize, occluding vessels downstream.

Plaque stability depends on multiple factors, including plaque composition (relative proportion of lipids, inflammatory cells, smooth muscle cells, connective tissue, and thrombus), wall stress (cap fatigue), size and location of the core, and configuration of the plaque in relation to blood flow. By contributing to rapid growth and lipid deposition, intraplaque hemorrhage may play an important role in transforming stable into unstable plaques.

In general, unstable coronary artery plaques have a high macrophage content, a thick lipid core, and a thin fibrous cap; they narrow the vessel lumen by < 50% and tend to rupture unpredictably. Unstable carotid artery plaques have the same composition but typically cause problems through severe stenosis and occlusion or deposition of platelet thrombi, which embolize rather than rupture. Low-risk plaques have a thicker cap and contain fewer lipids; they often narrow the vessel lumen by > 50% and may produce predictable exercise-induced stable angina.

Clinical consequences of plaque rupture in coronary arteries depend not only on that anatomical location of the plaque anatomy but also on relative balance of procoagulant and anticoagulant activity in the blood and on the vulnerability of the myocardium to arrhythmias.

The presence of atherosclerotic disease in one vascular territory increases the likelihood of disease in other vascular territories. Patients with noncoronary atherosclerotic vascular disease have cardiac event rates comparable to those of patients with known CAD, and they are now considered to have a CAD risk equivalent and should be treated as aggressively.

1. 1. Yusuf S, Hawken S, Ounpuu S, et al: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364: 937–952, 2004.

2. 2. White J, Swedlow DI, Preiss D, et al: Association of lipid fractions with risks for coronary artery disease and diabetes. JAMA Cardiol 1: 692–699, 2016.

3. 3. Emerging risk factors collaboration, Eroquo S, Kaptoge S, Perry PL, et al: Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302: 412–423, 2009.

4. 4. Thanassoulis, G, Campbell CY, Owens DS, et al for the CHARGE Extracoronary Calcium Working Group: Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 368: 503–512, 2013.

5. 5. Nordestgaard BG, Chapman MJ, Ray K, et al and the European Atherosclerosis Society Consensus Panel: Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 31: 2844–2853, 2010.

Patients with symptoms and signs of ischemia are evaluated for the amount and location of vascular occlusion by various invasive and noninvasive tests, depending on the organ involved (see elsewhere in THE MANUAL). Such patients also should be evaluated for atherosclerosis risk factors by using

• History and physical examination

• Fasting lipid profile

• Plasma glucose and glycosylated hemoglobin (HbA1C) levels

Patients with documented disease at one site (eg, peripheral arteries) should be evaluated for disease at other sites (eg, coronary and carotid arteries).

Noninvasive imaging techniques that can assess plaque morphology and characteristics include

• Three-dimensional vascular ultrasonography, which can be used to assess plaque in the carotid and other arteries

• Computed tomography (CT) angiography, which is used clinically to identify significant lesions in the coronary arteries

• Magnetic resonance (MR) angiography, which is used sometimes to image large arteries (eg, aorta)

Invasive catheter-based tests are also used. These include

• Intravascular ultrasonography, which uses an ultrasound transducer on the tip of a catheter to produce images of the arterial lumen and wall

• Angioscopy, which uses special fiberoptic catheters that can directly visualize the arterial surface

• Plaque thermography, which is used to detect the increased temperature in plaques with active inflammation

• Optical coherence tomography, which uses infrared laser light for imaging

• Elastography, which is used to identify soft, lipid-rich plaques

Immunoscintigraphy is a noninvasive alternative that uses radioactive tracers that localize in vulnerable plaque. Positron emission tomography (PET) imaging of the vasculature is another emerging approach to assess vulnerable plaque.

Because not all atherosclerotic plaques have similar risk, various imaging technologies (eg, positron emission tomography) are being studied as a way to identify plaques especially vulnerable to rupture; however, these techniques are not yet used clinically.

Atherosclerotic Plaque in Descending Aorta

Image

© Springer Science+Business Media

In addition to the fasting lipid profile and plasma glucose and hemoglobin A1C measurements, some clinicians measure serum markers of inflammation. High-sensitivity C-reactive protein levels ≥ 3.1 mg/L (≥ 29.5 nmol/L) are highly predictive of cardiovascular events.

In patients with risk factors for atherosclerosis but no symptoms or signs of ischemia, the role of additional testing beyond the lipid profile is unclear. Although imaging studies such as carotid ultrasonography to measure intimal medial thickness and other studies that can detect atherosclerotic plaque are being studied, they do not reliably improve prediction of ischemic events over assessment of risk factors or established prediction tools and are not recommended. An exception is CT imaging for coronary artery calcium (ie, to obtain a calcium score), for which there is more robust evidence for risk reclassification; it may be useful for refining risk estimates and for deciding on statin therapy in select patients (eg, those with intermediate risk, family history of premature cardiovascular disease).

Most guidelines recommend lipid profile screening in patients with any of the following characteristics:

• Men ≥ 40 years

• Women ≥ 40 years and post-menopausal women

• Family history of familial hypercholesterolemia or premature cardiovascular disease (ie, age of onset < 55 years in male 1st degree relative, or < 65 years in female 1st degree relative)

• Type 2 diabetes

• Hypertension

• Metabolic syndrome

• Chronic kidney disease (estimated glomerular filtration rate [eGFR] ≤ 60 mL/minute/1.73 m²

• Current cigarette smoking

• Chronic inflammatory conditions

• HIV infection

• History of hypertensive disorder of pregnancy (preeclampsia or eclampsia)

Currently, the American Heart Association (AHA) recommends using the pooled cohort risk assessment equations (see Downloadable AHA Risk Calculator) to estimate lifetime and 10-year risk of atherosclerotic cardiovascular disease. This calculator has replaced previous risk calculation tools (eg, Framingham score). The new risk calculator is based on sex, age, race, total and HDL cholesterol levels, systolic blood pressure (and whether blood pressure is being treated), diabetes, and smoking status (1). The European Cardiovascular Society (ESC) and the European Atherosclerosis Society (EAS) 2016 guideline suggests using the Systemic Coronary Risk Estimation (SCORE), which calculates risk based on age, gender, smoking, systolic blood pressure, and total cholesterol, to estimate the 10-year risk of the first fatal atherosclerotic event (2). For patients deemed at intermediate risk, lipoprotein(a) measurement has been suggested to help refine classification (3, 4).

Clinical Calculators

Cardiovascular Risk Assessment (10-year, Revised Pooled Cohort Equations 2018)

Urinary albuminuria (>

1. 1. Arnett DK, Blumenthal RS, Albert MA, et al: 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 74:1376–1414, 2019.

2. 2. Catapano AL, Graham I, De Backe G, et al: 2016 ESC/EAS guidelines for the management of dyslipidaemias: The task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Association for Cardiovascular Prevention and Rehabilitation (EACPR). Eur Heart J 37: 2999–3058, 2016. doi:10.1093/eurheartj/ehw272

3. 3. Pearson GJ, Thanassoulis G, Anderson TJ, et al: 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol 37:1129–1150, 2021.

4. 4. Willeit P, Kiechl S, Kronenberg F, et al: Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 64: 851–860, 2014. doi: 10.1016/j.jacc.2014.03.061

  Several changes are beneficial:

• Less saturated fat

• No trans fats

• Fewer refined carbohydrates

• More fruits and vegetables

• More fiber

• Moderate (if any) alcohol

Substantial decreases in saturated fat and refined and processed carbohydrates and increases in carbohydrates with fiber (eg, fruits, vegetables) are recommended. These dietary changes are a prerequisite for lipid control and weight reduction and are essential for all patients. Calorie intake should be limited to keep weight within the normal range.

Small decreases in fat intake do not appear to lessen or stabilize atherosclerosis. Effective change requires limiting fat intake to 20 g a day, consisting of 6 to 10 g of polyunsaturated fat with omega-6 (linoleic acid) and omega-3 (eicosapentaenoic acid, docosahexaenoic acid) fatty acids in equal proportion, ≤ 2 g of saturated fat, and the rest as monounsaturated fat. Trans fats, which are highly atherogenic, should be avoided.

Increasing carbohydrates to compensate for decreasing saturated fats in the diet increases plasma triglyceride levels and reduces HDL levels. Thus, any caloric deficiency should be made up with proteins and unsaturated fats rather than simple carbohydrates. Excessive fat and refined sugar intake should be avoided, especially in people at risk of diabetes, although sugar intake has not been directly related to cardiovascular risk. Instead, consumption of complex carbohydrates (eg, vegetables, whole grains) is encouraged.

Fruits and vegetables (5 daily servings) seem to decrease risk of coronary atherosclerosis, but whether this effect is due to phytochemicals or to a proportional decrease in saturated fat intake and increase in fiber and vitamin intake is unclear. Phytochemicals called flavonoids (in red and purple grapes, red wine, black teas, and dark beers) appear especially protective; high concentrations in red wine may help explain why incidence of coronary atherosclerosis in the French is relatively low, even though they use more tobacco and consume more fat than Americans do. But no clinical data indicate that eating flavonoid-rich foods or using supplements instead of foods prevents atherosclerosis.

Increased fiber intake decreases total cholesterol and may have a beneficial effect on glucose and insulin

Alcohol increases HDL and has poorly defined antithrombotic, antioxidant, and anti-inflammatory properties. These effects appear to be the same for wine, beer, and hard liquor, and occur at moderate levels of consumption; about 30 mL of ethanol (1 oz, contained in about 2 average servings of typical alcoholic beverages) 5 to 6 times a week protects against coronary atherosclerosis. However, at higher doses, alcohol can cause significant health problems. Thus, the relationship between alcohol and total mortality rate is J-shaped; mortality rate is lowest for men who consume < 14 drinks a week and women who consume < 9 drinks a week. People who consume greater amounts of alcohol should cut back. However, clinicians are hesitant to recommend that nondrinkers begin consuming alcohol based on any apparent protective effect.

There is little evidence that dietary supplementation with vitamins, phytochemicals, and trace minerals reduces risk of atherosclerosis. The one exception is . Although alternative medicines and health foods are becoming more popular, and some may have minor effects on blood pressure or cholesterol, these treatments are not always proven safe or effective and may have negative interactions with proven drugs. Levels of coenzyme Q10, which is necessary for the basic functioning of cells, tend to decrease with age and may be low in patients with certain heart and other chronic diseases; thus, coenzyme Q10 supplementation has been used or recommended, but its therapeutic benefit remains controversial.

Regular physical activity (eg, 30 to 45 minutes of walking, running, swimming, or cycling 3 to 5 times a week) reduces incidence of some risk factors (hypertension, dyslipidemia, diabetes), coronary artery disease (eg, myocardial infarction), and death attributable to atherosclerosis in patients with and without previous ischemic events. Whether the association is causal or merely indicates that healthier people are more likely to exercise regularly is unclear.

Optimal intensity, duration, frequency, and type of exercise have not been established, but most evidence suggests an inverse linear relationship between aerobic physical activity and risk. Walking regularly increases the distance patients with peripheral vascular disease can walk without pain.

An exercise program that involves aerobic exercise has a clear role in preventing atherosclerosis and promoting weight loss. Before starting a new exercise program, older people and people who have risk factors for atherosclerosis or who have had recent ischemic events should be evaluated by a physician. Evaluation includes history, physical examination, and assessment of risk factor control.

Oral antiplatelet drugs are essential because most complications result from plaque fissure or rupture, leading to platelet activation and thrombosis. The following are used:

≥ 20% risk of cardiac events within 10 years in whom bleeding risk is not prohibitive, and patients at intermediate risk who have a 10 to 20% risk of cardiac events within 10 years and have low risk of bleeding). Recent evidence suggests that the net-benefit of aspirin

aspirin is used in combination with other antithrombotic drugs. In about 10 to 20% of patients taking aspirin for secondary prevention, ischemic events recur. The reason may be aspirin resistance; assays to detect lack of thromboxane suppression (indicated by elevated urinary 11-dehydrothromboxane B2) are being studied for clinical use.

aspirin’s antithrombotic effect, so other nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended for patients taking aspirin for prevention. However, all NSAIDs, some more than others, including cyclooxygenase 2 (COX-2) selective inhibitors, appear to increase cardiovascular risks.

aspirin when ischemic events recur in patients taking aspirin and in patients intolerant of aspirin. Clopidogrel in combination with aspirin is effective in treating acute ST-segment and non-ST-segment elevation myocardial infarction; the combination is also given for 12 months after percutaneous intervention (PCI) to reduce risk of recurrent ischemic events. Resistance to clopidogrelclopidogrel for coronary disease prevention in select patient groups.

Ticlopidine is no longer widely used because it causes severe neutropenia in 1% of users and has severe GI adverse effects.

Statins primarily lower LDL cholesterol. Other potential beneficial effects include enhanced endothelial nitric oxide production, stabilization of atherosclerotic plaques, reduced lipid accumulation in the arterial wall, and regression of plaques. Statins are recommended as preventive therapy in 4 groups of patients (1), comprised of those with any of the following:

• Clinical atherosclerotic cardiovascular disease

• LDL cholesterol ≥ 190 mg/dL (≥ 4.92 mmol/L)

• Age 40 to 75 years, with diabetes and LDL cholesterol 70 to 189 mg/dL (1.81 to 4.90 mmol/L)

• Age 40 to 75 years, with LDL cholesterol 70 to 189 mg/dL, and estimated 10-year risk of arteriosclerotic cardiovascular disease ≥ 7.5%

There is also support for the use of statins in patients with other risk factors, including family history of premature arteriosclerotic cardiovascular disease (ie, age of onset < 55 in male 1st degree relative, or < 65 in female 1st degree relative), high-sensitivity C-reactive protein ≥ 2 mg/L (19.05 nmol/L), coronary artery calcium score ≥ 300 Agatston units (or ≥ 75th percentile for the patient's demographic), ankle-brachial blood pressure index < 0.9, or chronic kidney disease not treated with dialysis or kidney transplantation.

Statin treatment is classified as high, moderate, or low intensity and is given based on treatment group and age (see table Statins for ASCVD Prevention). Specific LDL cholesterol targets are no longer recommended to guide lipid-lowering therapy. Instead, response to therapy is determined by whether LDL cholesterol levels decrease as expected based on therapy intensity (ie, patients receiving high-intensity therapy should have a ≥ 50% decrease in LDL cholesterol).

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin IIfactor Xa

ACE inhibitors and angiotensin II receptor blockers inhibit the contributions of angiotensin to endothelial dysfunction and inflammation.

Ezetimibe, added to standard statin therapy, has been shown to reduce cardiovascular events in patients with prior cardiovascular event and LDL cholesterol > 70 mg/dL (1.8 mmol/L).

PCSK9 inhibitors are monoclonal antibodies that keep PCSK9 from attaching to LDL receptors, leading to increased recycling of these receptors to the plasma membrane leading to further clearance of plasma LDL cholesterol to the liver. LDL cholesterol is lowered by 40 to 70%. Long-term clinical trials have shown reduction in atherosclerosis and cardiovascular events. These drugs are most useful in patients with familial hypercholesterolemia, patients with prior cardiovascular events whose LDL is not at goal despite maximal medical therapy with statins, and patients who require lipid lowering but have documented objective evidence of statin intolerance.

The factor Xarivaroxaban and aspirin2).

Thiazolidinediones may control expression of proinflammatory genes, although studies suggest that they increase the risk of coronary events.

Macrolide and other antibiotics given to treat chronic occult C. pneumoniae infections (and thereby suppress inflammation and theoretically alter the course and manifestations of atherosclerosis) have not been shown useful.

1. 1. Grundy SM, Stone NJ, Bailey AL, et al: 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 139(25):e1082–e143, 2019.

2. 2. Eikelboom JW, Connolly SJ, Bosch J, et al: Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 377:1319–1330, 2017. doi: 10.1056/NEJMoa1709118