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.
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
- 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
- Proliferation of subendothelial smooth muscle cells in response to very high blood pressure
- H&E: "onion-skin" appearance of the arteriole
- Cause: malignant hypertension
- Hyaline arteriolosclerosis
- Atherosclerosis (most common type of arteriosclerosis)
The terms “arteriosclerosis” and “atherosclerosis” are often used synonymously!
Modifiable risk factors
- Diabetes mellitus 
- Arterial hypertension
- Dyslipidemia 
- High homocysteine levels (homocystinuria)
- High fibrinogen levels
- Stress 
- Increased alcohol consumption 
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. 
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) 
- Plaque rupture; → exposure of thrombogenic material; (e.g., collagen) → thrombus formation with vascular occlusion or spreading of thrombogenic material
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.
- 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
Atherosclerotic cardiovascular disease (ASCVD)
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 (including carotid artery stenosis)
- Aortic aneurysm
ASCVD risk assessment
Traditional ASCVD risk factors
Traditional ASCVD risk factors are 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.
|Traditional ASCVD risk factors |
|Demographics||Patient history||Clinical information|
| || || |
ASCVD risk-enhancing factors 
ASCVD risk-enhancing factors are factors associated with ASCVD that are not part of the PCE. They are used to guide primary prevention strategies for ASCVD. 
|ASCVD risk-enhancing factors|
|Medical history|| |
|Abnormal laboratory findings|| |
2013 ACC/AHA pooled cohort equation (PCE) 
- 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. 
PCE estimates the following risk categories:
- 10-year ASCVD risk in individuals 40–75 years of age
- Lifetime ASCVD risk in individuals 21–39 years of age 
- Optimal ASCVD risk
- ASCVD risk categories should be used to guide patient counseling and risk reduction management : See “ASCVD prevention.” 
- 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.
- PCE is currently only validated for African American and non-Hispanic white individuals aged 40–79 years.
- There is insufficient data to accurately estimate ASCVD risk in individuals from other races and ethnicities using PCE.
- PCE has not been validated for use in individuals older than 79 years of age.
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”) 
- 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
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. 
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|| || |
|ASCVD risk categories || || |
ASCVD 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. 
ASCVD prevention 
- 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 |
|All ages and risk categories|| |
|Age < 20–39 years|| |
|Age 40–75 years with diabetes|| |
|Age 40–75 years, no diabetes, and LDL 70–190 mg/dL|| |
|Age > 75 years|| |
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 |
|Primary prevention of ASCVD||Secondary prevention of ASCVD|
|Lifestyle modifications for ASCVD prevention|| |
|Management of chronic medical conditions||Management of hypertension|| |
|Management of diabetes mellitus|| |
|Management of obesity|| |
|Statin therapy (in adults aged 40–75 years) || || |
| || |
Remember the ABCDS of ASCVD primary and secondary prevention: Aspirin (if there are indications), Blood pressure control, Cholesterol management, Diabetes management, Smoking cessation. 
Smoking cessation is one of the most effective interventions to reduce all-cause mortality and prevent recurrent vascular events in patients with ASCVD! 
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