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Atherosclerosis

Last updated: June 7, 2021

Summary

Atherosclerosis is the most common type of arteriosclerosis, or thickening and stiffening of the arterial wall. Major risk factors include smoking, diabetes mellitus, arterial hypertension, dyslipidemia, family history of early heart disease, and advanced age. The pathogenesis is a complicated process precipitated by endothelial damage, which leads to an invasion of inflammatory cells into the tunica intima and adhesion of platelets to the disrupted endothelium. Invading smooth muscle cells (SMCs) and macrophages take up cholesterol from oxidized low-density lipoprotein (LDL) in the vessel wall. They then become foam cells, which accumulate in early atherosclerotic lesions (fatty streaks), triggering the production of extracellular matrix (e.g., collagen). This leads to the formation of fibrous plaques (foam cells, extracellular matrix, free cholesterol, and cellular debris), which may rupture and lead to thrombosis. Common sites of atherosclerosis include the abdominal aorta, coronary arteries, popliteal arteries, and carotid arteries. Depending on the location, atherosclerosis may lead to a variety of conditions, collectively known as atherosclerotic cardiovascular disease (ASCVD), which include arterial aneurysms, dissection, coronary heart disease (CHD), peripheral artery disease (PAD), intestinal ischemia, subcortical vascular dementia (Binswanger disease), thrombosis (e.g., acute coronary syndrome and stroke), and renovascular hypertension. The risk of ASCVD should be estimated in all individuals aged 40–75 years using ASCVD risk calculators (e.g., the 2013 ACC/AHA pooled cohort equations) to guide timely primary prevention strategies for ASCVD, such as lifestyle modifications or prophylactic statin therapy. Secondary prevention strategies for ASCVD should be recommended for individuals diagnosed with clinical ASCVD to minimize the risk of future cardiovascular events.

Dyslipidemia 3 - Part 3: Atherosclerosis

Definition

Arteriosclerosis: arterial wall thickening (hardening) and elasticity loss with variable pathogenesis
- Atherosclerosis (most common type of arteriosclerosis)
  - Multifactorial inflammatory disease of the intima, manifesting at points of hemodynamic shear stress
  - Characterized by a build-up of cholesterol plaques in the intima
  - Affects elastic arteries and large/medium-sized muscular arteries
- Mönckeberg arteriosclerosis (less common)
  - Dystrophic calcification of the media and internal elastic lamina causes stiffening of the arteries (intima is not involved)
  - There is no blood flow obstruction.
  - Mainly affects medium-sized arteries
  - X-ray: pipestem appearance
- Arteriolosclerosis: hardening of the small arteries and arterioles
  - Hyaline arteriolosclerosis
    - Deposition of proteins below the endothelium due to leakage
    - H&E: pink amorphous deposits (hyaline) within the arteriolar walls
    - Causes: chronic essential hypertension, chronic diabetes, and normal aging
  - Hyperplastic arteriolosclerosis
    - Proliferation of subendothelial smooth muscle cells in response to very high blood pressure
    - H&E: "onion-skin" appearance of the arteriole
    - Cause: malignant hypertension

The terms “arteriosclerosis” and “atherosclerosis” are often used synonymously!

Hyaline arteriosclerosis Hyperplastic arteriosclerosis Monckeberg's arteriosclerosis
References:^[1]^[2]

Epidemiology

Leading cause of vascular disease worldwide
Sex: ♂ > ♀

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Modifiable risk factors
- Smoking
- Diabetes mellitus ^[3]
- Arterial hypertension
- Dyslipidemia ^[4]
- High homocysteine levels (homocystinuria)
- Obesity
- High fibrinogen levels
- Hyperphosphatemia
- Stress ^[5]
- Increased alcohol consumption ^[6]
Nonmodifiable risk factors
- Family history: cardiovascular events in first-degree relatives below the age of 55 (♂)/65 (♀)
- Age: males ≥ 45 years, females ≥ 55 years (postmenopause)

The term metabolic syndrome refers to the presence of at least 3 of the following risk factors: obesity, elevated triglycerides, low high-density lipoprotein (HDL), diabetes mellitus, and arterial hypertension. ^[4]

Pathophysiology

Pathogenesis of atherosclerosis

Chronic stress on the endothelium

Endothelial dysfunction, which leads to
- Invasion of inflammatory cells (mainly monocytes and lymphocytes) through the disrupted endothelial barrier
- Adhesion of platelets to the damaged vessel wall → platelets release inflammatory mediators (e.g., cytokines) and platelet-derived growth factor (PDGF)
- PDGF stimulates migration and proliferation of smooth muscle cells (SMC) in the tunica intima and mediates differentiation of fibroblasts into myofibroblasts

Inflammation of the vessel wall

Macrophages and SMCs ingest cholesterol from oxidized LDL and transform into foam cells.

Foam cells accumulate to form fatty streaks (early atherosclerotic lesions).

Lipid-laden macrophages and SMCs produce extracellular matrix (e.g., collagen) → development of a fibrous plaque (atheroma)

Inflammatory cells in the atheroma (e.g., macrophages) secrete matrix metalloproteinases → weakening of the fibrous cap of the plaque due to the breakdown of extracellular matrix → minor stress ruptures the fibrous cap

Calcification of the intima (the amount and pattern of calcification affect the risk of complications) ^[7]^[8]

Plaque rupture → exposure of thrombogenic material (e.g., collagen) → thrombus formation with vascular occlusion or spreading of thrombogenic material

Pathogenesis of atherosclerosis Severe atherosclerosis of the aorta Atherosclerosis of a coronary artery Foam cells Atheroma

Common sites (in order of increasing frequency)

To remember the order of vessels affected by atherosclerosis (in increasing order of frequency), think of the “Die hard” plot: Bruce Willis CAtches a Perceptive Criminal named HAns.

Atherosclerotic diseases

Weakening of vessel wall: arterial aneurysm or dissection
Demand-supply mismatch: coronary heart disease; (CHD), peripheral artery disease; (PAD), intestinal ischemia, and subcortical vascular dementia (Binswanger disease)
Thrombosis and thromboembolism: acute coronary syndrome, stroke
Renovascular hypertension: atherosclerosis of the renal artery → activation of the renin-angiotensin-aldosterone system

Arteriosclerotic plaque in the abdominal aorta Blue toe syndrome

References:^[1]^[9]^[10]^[11]^[12]

Atherosclerotic cardiovascular disease (ASCVD)

Definition ^[13]

ASCVD or clinical ASCVD is an umbrella term for a group of conditions that affect the cardiovascular system and are most likely due to atherosclerosis. Examples include:

Ischemic heart disease
- Acute coronary syndrome or myocardial infarction
- Stable coronary artery disease (e.g., stable angina)
- History of arterial revascularization
Stroke or TIA
Peripheral artery disease
Aortic aneurysm

ASCVD risk assessment

Risk factors for ASCVD

Traditional ASCVD risk factors: a set of ASCVD risk factors included in the 2013 ACC/AHA pooled cohort equations (PCE) and used to estimate the risk of future clinical ASCVD
ASCVD risk-enhancing factors: factors associated with ASCVD that are not part of the PCE; used to guide primary prevention strategies for ASCVD ^[14]

Traditional ASCVD risk factors ^[15]
Demographics	Patient history	Clinical information
Age Sex Race	Smoking status Diabetes mellitus Currently on antihypertensives	Systolic blood pressure Total cholesterol HDL cholesterol

2013 ACC/AHA pooled cohort equation (PCE) ^[15]^[16]^[17]

Overview
- Risk assessment calculators can be used to estimate the ASCVD risk in individuals with no history of ASCVD (see the table below for specific indications).
- PCE, which is based on traditional ASCVD risk factors, is appropriate in most instances. ^[18]^[19]
- ASCVD risk categories should be used to guide patient counseling and risk reduction management : See “ASCVD prevention.” ^[20]
Important considerations
- Individuals with LDL ≥ 190 mg/dL or familial hypercholesterolemia are at high risk of ASCVD; PCE should not be used to assess risk in this group of individuals.
Impact of treatment on ASCVD risk: not accounted for in the original 2013 ACC/AHA ASCVD risk calculator
- Included in the ASCVD Risk Estimator Plus (see “Tips and Links”) ^[16]^[17]^[21]^[22]
- Includes additional factors for risk estimation such as LDL cholesterol and current statin and/or aspirin therapy
- Can be used to assess ASCVD risk and to estimate the impact of therapeutic interventions during follow-up visits

ASCVD risk calculator (2013 ACC/AHA pooled cohort equations)

PCE should only be used in individuals with no history of ASCVD or familial hypercholesterolemia, who are not on statin therapy, and who have LDL cholesterol < 190 mg/dL. ^[16]

Indications for risk assessment and ASCVD risk categories

ASCVD risk assessment should be guided by clinical history, age-specific screening for traditional ASCVD risk factors, and identification of ASCVD risk-enhancing factors; see also screening for lipid disorders, screening for hypertension, and screening for diabetes mellitus.

ASCVD risk assessment
	Individuals with no history of ASCVD	Patients with a history of clinical ASCVD
Indications for risk assessment	All individuals aged 40–75 years (universal screening) PCE calculates the 10-year ASCVD risk in this age group. ^[15] Screening frequency should be individualized (not specifically defined). Consider risk assessment in individuals aged 21–39 years. ^[18]^[19] PCE calculates the lifetime ASCVD risk in this age group. Consider reassessment of ASCVD risk every 4–6 years.	All individuals with a history of clinical ASCVD
ASCVD risk categories ^[16]	Estimate the ACSVD risk using a risk-assessment calculator (e.g., PCE ). ^[18]^[19] 10-year ASCVD risk categories (in individuals aged 40–75 years) ^[16] Low risk: < 5% Borderline risk: 5% to < 7.5% Intermediate risk: 7.5% to < 20% High risk: ≥ 20%	Estimate the risk based on patient history of ASCVD and additional high-risk factors. Very high risk of future cardiovascular events if any of the following are present: ^[13] Multiple major ASCVD events; examples include > 1 of the following: ACS in the past 12 months Myocardial infarction Ischemic stroke Symptomatic peripheral arterial disease OR 1 major ASCVD event PLUS > 1 high-risk condition, including: Age ≥ 65 years Current smoking LDL cholesterol ≥ 100 mg/dL on maximally tolerated statin therapy and ezetimibe History of coronary revascularization not associated with the major ASCVD event(s) Heterozygous familial hypercholesterolemia Comorbidities: e.g., diabetes mellitus, hypertension, CKD, history of congestive heart failure
Further management	Primary prevention of ASCVD	Secondary prevention of ASCVD

ASVCD risk assessment is not recommended in individuals with familial hypercholesterolemia or LDL ≥ 190 mg/dL, as these individuals are considered high risk for ASCVD regardless of the risk assessment score. ^[16]

ASCVD prevention ^[16]^[20]

The aim of ASCVD prevention is to reduce the estimated ASCVD risk to the optimal ASCVD risk.

Primary prevention is aimed at individuals with no prior history of ASCVD.
Secondary prevention is aimed at patients with a previous history of ASCVD.
Common components of primary and secondary prevention include :
- Lifestyle modification (e.g., dietary modification, smoking cessation)
- Management of chronic medical conditions (e.g., treatment of hypertension, diabetes, and hyperlipidemia, and weight reduction in overweight and obesity)
- Antiplatelet therapy (if indicated)
Additionally, secondary prevention of ASCVD should include management of the underlying condition. See the following for further details:

Overview of primary prevention strategies according to ASCVD risk categories ^[16]
All ages and risk categories	Reinforce adherence to healthy lifestyle practices. Address any modifiable risk factors. See “Primary prevention of ASCVD” for details (only the main interventions are detailed in this table).
Age < 40 years	Consider statin therapy if any of the following are present: Family history of early ASCVD (i.e., ♂: < 55 years; ♀: < 65 years) LDL levels ≥ 190 mg/dL
Age 40–75 years with diabetes or LDL ≥ 190 mg/dL	Initiate statin therapy regardless of risk category.
Age 40–75 years, no diabetes, and LDL < 190 mg/dL	Low risk: < 5% Reinforce adherence to healthy lifestyle practices. Address any modifiable risk factors. Borderline risk: 5% to < 7.5% If ASCVD risk enhancing factors are present consider further preventive measures (e.g., statin therapy). Intermediate risk: 7.5% to < 20% Consider coronary artery calcium score if there are inconclusive indications to initiate preventive interventions. Consider antiplatelet therapy in individuals < 70 years of age with no risk of bleeding. High risk: ≥ 20% Initiate statin therapy. Consider antiplatelet therapy in individuals < 70 years of age with no risk of bleeding.
Age > 75 years	Discuss ASCVD preventive strategies based on life expectancy, comorbidities, and a risk-benefit assessment of preventive interventions.

Although ASCVD risk calculators are important tools for guiding primary prevention strategies in individuals with no history of ASCVD, results should always be considered in conjunction with other factors, e.g., ASCVD risk-enhancing factors, coronary artery calcium scoring, and patient preferences.

Strategies for primary and secondary prevention of ASCVD ^[16]^[20]^[21]^[22]
		Primary prevention of ASCVD	Secondary prevention of ASCVD
Lifestyle modifications		Dietary modification with a heart-healthy diet Replacement of saturated fat with monounsaturated and polyunsaturated fats Reduced dietary cholesterol Reduced dietary sodium intake (ideally < 1,500 mg/day) ^[16] Exercise (ideally, the equivalent of one of the following per week) : ≥ 150 minutes of moderate-intensity exercise ≥ 75 minutes of high-intensity aerobic exercise Smoking cessation (see “Counseling on smoking cessation”) Limit alcohol use to ≤ 2 drinks/day (♂) or ≤ 1 drink/day (♀)
Management of chronic medical conditions	Blood pressure control	The decision to start antihypertensives in patients with elevated BP should be guided by the 10-year ASCVD risk (see “Antihypertensive therapy”). A blood pressure target < 130/80 mm Hg is appropriate for most patients with hypertension.
	Cholesterol management	Age 40–75 years Initiate statin therapy in individuals with intermediate or high 10-year ASCVD risk and ≥ 1 traditional ASCVD risk factor(s) Consider statin therapy in individuals with ≥ 1 of the following: Diabetes mellitus (regardless of risk category) Borderline 10-year ASCVD risk and either: ASCVD risk-enhancing factors Elevated coronary artery calcium score LDL ≥190 mg/dL: Initiate statin therapy.	Consider high-intensity statin therapy for all patients. Consider combination therapy for patients at very high risk for ASCVD and with LDL ≥ 70 mg/dL on the maximally tolerated statin dose.
	Cholesterol management	See “Guidelines for lipid-lowering therapy in adults.”
	Diabetes mellitus	Glycemic control: lifestyle modifications and medications as needed (see “Treatment” in “Diabetes mellitus”)
	Overweight and obesity	Weight loss of ≥ 5% Consider pharmacotherapy (e.g., lipase inhibitors). See also “Bariatric surgery.”
Antiplatelet therapy		Consider low-dose aspirin for patients with all of the following : ^[16] Age 40–70 years High 10-year ASCVD risk Low risk of bleeding	First-line: aspirin ^[23]^[24]^[25] Second-line :clopidogrel monotherapy ^[26] In certain circumstances, dual antiplatelet therapy is indicated in patients with ACS (see “Antiplatelet therapy and anticoagulation in STEMI” and “Antiplatelet therapy and anticoagulation in NSTE-ACS”).

Remember the ABCDS of ASCVD primary and secondary prevention: Aspirin (if there are indications), Blood pressure control, Cholesterol management, Diabetes management, Smoking cessation. ^[20]

Smoking cessation is one of the most effective interventions to reduce all-cause mortality and prevent recurrent vascular events in patients with ASCVD! ^[27]

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