Atherosclerosis

Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis manifests itself as vessel stenosis and a source of thromboembolic disease. The clinical manifestations depend on the specific vessels affected and include most notably coronary artery disease, carotid disease, and peripheral vascular disease. Atherosclerosis is the most common primary disease of the arterial vascular system and is responsible for coronary heart disease, the leading cause of death worldwide.

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Overview

Definition

Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls.

Epidemiology

  • Leading cause of cardiovascular disease and death worldwide
  • More common in men
  • Most common locations: abdominal aorta, coronary arteries, popliteal arteries, cerebral and carotid arteries
  • Often starts in childhood as fatty streaks that progress to atheromas in young adulthood
  • Data from intracoronary ultrasonography show that 1 in 6 teenagers in the United States will have abnormal intimal thickening (precursor to atherosclerosis).

Etiology

  • Physical stresses from turbulent blood flow: Lesions often form at vessel bifurcations/bends.
  • High blood lipid and cholesterol concentrations
  • Inflammation
  • Infections with some bacteria or viruses (Cytomegalovirus, Chlamydia pneumoniae, coxsackie B, Helicobacter pylori)
  • Genetic predisposition
  • Risk factors:
    • Family history
    • Hypercholesterolemia
    • Hyperlipidemia
    • Diabetes mellitus
    • Cigarette smoking
    • Hypertension
    • Dietary deficiencies of antioxidants
    • Advanced age
    • Male sex

Pathophysiology and Clinical Presentation

Pathogenesis

  • The pathogenesis of atherosclerosis is multifactorial.
  • Endothelial injury (often from turbulent blood flow) or dysfunction may be the 1st precipitating step.
  • Lipid and cholesterol abnormalities play the key roles in endothelial dysfunction.
  • Lipid retention with activation of the endothelial adhesion molecules happens early in the process.
  • High levels of LDL are particularly important.
  • Monocyte adhesion and migration into the intima follows lipid deposition.
  • Oxidative modification of LDL facilitates macrophage uptake → formation of foam cells with embedded lipid droplets → early atherosclerotic lesions, also known as fatty streaks
  • Release of inflammatory cytokines by macrophages/foam cells leads to smooth muscle recruitment.
  • Smooth muscle hyperplasia, extracellular matrix production, and recruitment of lymphocytes → fibrous plaque (atheroma) formation
  • Death of foam cells and formation of necrotic center

Pathologic effects of atherosclerosis

  • Can affect large, medium, or small vessels
  • Chronic inflammation contributes to progression of atherosclerotic lesions.
  • Chronic progression:
    • Leads to vessel narrowing, loss of elasticity, and reduced or obstructed blood flow
    • Contributes to development of hypertension, which causes more endothelial damage and eventually more plaque formation
  • Acute progression:
    • Plaque rupture or ulceration precipitates thrombus formation, which can cause vessel obstruction or embolization to distal vessels
    • More inflamed plaques are more prone to rupture.
    • Risk of end-organ damage such as heart attack (myocardial infarction), stroke (cerebrovascular accident), and CKD
Composition of the atherosclerotic plaque

Composition of the atherosclerotic plaque

Image: “Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis” by Subbotin, VM/ Encyclopeadia Britannica. License: CC BY 2.0
Atherosclerosis grade 1

Atherosclerosis grade 1:
This mild form of atherosclerosis is caused by connective tissue proliferation in the tunica intima, also known as intimal fibrosis.

Image: “Evaluation of the intraoperative specimens of the thoracic and abdominal aorta” by Juraszek A, Bayer G, Dziodzio T, Kral A, Laufer G, Ehrlich M. License: CC BY 2.0

Clinical presentation

  • Develops slowly and can be asymptomatic for many years
  • Symptoms arise as disease progresses to cause vessel narrowing (usually > 70%–80%), thrombosis or embolization.
  • The organs affected:
    • Heart: coronary artery disease (ischemia, myocardial infarction)
    • Brain: transient ischemic attack, cerebrovascular accident (stroke) due to carotid disease
    • Eyes: central retinal artery occlusion
    • Extremities: intermittent claudication, gangrene, or acute limb ischemia due to peripheral arterial disease
    • Kidneys: renal artery stenosis
    • Intestinal ischemia
Toe gangrene

Toe gangrene secondary to peripheral arterial disease of lower extremities

Image: “Education in wound care: Curricula for doctors and nurses, and experiences from the German wound healing society ICW” by Military Medical Research. License: CC BY 4.0, cropped by Lecturio.

Diagnosis and Management

Diagnosis

History:

  • Smoking
  • Hypertension
  • Hyperlipidemia/hypercholesterolemia
  • Family history

Physical exam:

  • Often normal
  • Carotid bruit (carotid stenosis)
  • Decreased peripheral pulses especially in lower extremities
  • Ankle brachial index: 
    • Ratio of systolic BP in the ankle to BP in the arm
    • An index of perfusion of lower extremities (ankle brachial index < 1 is associated with peripheral vascular disease)

Laboratory tests:

  • Lipid profile to assess for hyperlipidemia
  • Cholesterol (LDL and HDL) levels
  • Fasting glucose and hemoglobin A1c to assess for diabetes
  • Creatinine to assess kidney insufficiency

Electrocardiography (for findings of cardiac ischemia):

  • Left ventricular hypertrophy (usually associated with hypertension)
  • Heart block (conduction abnormalities)
  • ST-segment changes
  • T-wave inversions

Vessel imaging:

  • Noninvasive methods:
    • Ultrasonography: estimates degree of vessel stenosis based on blood velocity
    • CT angiography (CTA): provides anatomic images of the vessels being studied
    • MRA: indications and uses similar to those for CTA
  • Angiography (invasive): usually a gold standard for vessel imaging
Angiogram of internal carotid artery stenosis

Angiogram of internal carotid artery stenosis (arrow)

Image: “Review: Interventional radiology in peripheral vascular disease” by Imaging. License: CC BY 2.0, cropped by Lecturio.

Management

  • Treatment is focused on elimination of modifiable risk factors: 
    • Hypercholesterolemia
    • Diabetes
    • Hypertension
    • Obesity
    • Smoking
  • Nonpharmacologic treatment:
    • Healthy diet:
      • Low fat, low cholesterol
      • Omega-3 fatty acid supplements
    • Regular physical activity
    • Smoking cessation
    • Weight loss, if obese
  • Pharmacologic treatment: 
    • Increase HDL, decrease LDL (statins)
    • Decrease BP to goal (antihypertensive medications)
    • Manage diabetes, with the goal of A1c < 7.0

Clinical Relevance

The following diseases are consequences of atherosclerosis:

  • Coronary heart disease: ischemia of the myocardium secondary to atherosclerosis of coronary arteries: Coronary hearty disease can present in chronic (angina, ischemic cardiomyopathy) or acute (myocardial infarction) form and can present with intense chest pain, shortness of breath, new onset arrhythmias or heart failure. The disease can be managed medically or require revascularization procedures.
  • Cerebrovascular accident (stroke): a common complication of carotid artery stenosis usually secondary to embolization of carotid plaque/thrombus to cerebral vessels: Stroke presents with neurologic symptoms, such as paralysis, blindness, or speech impairment.
  • Peripheral arterial disease: acute or chronic ischemia usually affecting lower extremities secondary to atherosclerosis of peripheral arteries: Chronic disease can be asymptomatic or present with intermittent claudication. Acute ischemia can lead to gangrene and extremity amputation.
  • CKD: can develop secondary to atherosclerosis affecting renal arteries: This disease can also be associated with secondary hypertension.
  • Erectile dysfunction: can develop secondary to atherosclerosis affecting pelvic vessels
  • Blindness: due to central retinal artery occlusion
  • Intestinal mesenteric ischemia: can be acute or chronic and is usually secondary to atherosclerosis affecting the superior mesenteric artery or one of its branches: Acutely, intestinal mesenteric ischemia presents with intense abdominal pain and if left untreated leads to intestinal necrosis and can be fatal. Chronic ischemia is usually associated with intermittent postprandial abdominal pain.

References

  1. Carracedo M, Artiach G, Arnardottir H, Bäck M. (2019). The resolution of inflammation through omega-3-fatty acids in atherosclerosis, intimal hyperplasia, and vascular calcification. Semin Immunopathol 41:757–766. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881483/
  2. Ladich ER. (2019). Atherosclerosis pathology. Retrieved March 23, 2021, from https://reference.medscape.com/article/1612610-overview#a3
  3. Robbins and Cotran Pathologic Basis of Disease. (2015). 9th ed., pp. 491–501.
  4. Wilson P. (2020). Overview of established risk factors for cardiovascular disease. UpToDate. Retrieved March 19, 2021, from https://www.uptodate.com/contents/overview-of-established-risk-factors-for-cardiovascular-disease
  5. Zhao XQ. (2020). Pathogenesis of atherosclerosis. Retrieved March 23, 2021, from https://www.uptodate.com/contents/pathogenesis-of-atherosclerosis

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