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 Coronary heart disease Coronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis. 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 Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries, popliteal arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries, cerebral and carotid arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. 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 Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure: Lesions often form at vessel bifurcations/bends.
  • High blood lipid and cholesterol concentrations
  • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Infections with some bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview or viruses ( Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus, Chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia pneumoniae, coxsackie B, Helicobacter Helicobacter Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation. Helicobacter pylori)
  • Genetic predisposition
  • Risk factors:
    • Family history
    • Hypercholesterolemia
    • Hyperlipidemia
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Cigarette smoking
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure) 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 Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. 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 Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure
    • 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 Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction), stroke ( cerebrovascular accident Cerebrovascular accident An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke), and CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
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 Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. 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 Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction)
    • Brain: transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA), cerebrovascular accident Cerebrovascular accident An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke (stroke) due to carotid disease
    • Eyes: central retinal artery occlusion
    • Extremities: intermittent claudication, gangrene, or acute limb ischemia Acute limb ischemia Acute limb ischemia (ALI) is a major vascular emergency because of the rapid decrease in limb perfusion that causes a potential threat to limb viability. The majority of cases are caused by arterial thrombosis due to plaque progression or embolism, but ALI can also be caused by blockage of the venous drainage. Acute Limb Ischemia due to peripheral arterial disease
    • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: renal artery stenosis Renal artery stenosis Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis
    • Intestinal ischemia Intestinal ischemia Intestinal ischemia occurs when perfusion fails to meet the demands of the intestines, resulting in ischemic tissue injury that can be life-threatening if bowel necrosis and/or perforation occurs. Symptoms can range from mild indigestion or diarrhea to severe abdominal pain. 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 Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing society ICW” by Military Medical Research. License: CC BY 4.0, cropped by Lecturio.

Diagnosis and Management

Diagnosis

History:

  • Smoking
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). 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 Electrocardiography Recording of the moment-to-moment electromotive forces of the heart as projected onto various sites on the body's surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow moving chart paper or by observing it on a cardioscope, which is a cathode ray tube display. Normal Electrocardiogram (ECG) (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 Carotid artery stenosis Carotid artery stenosis is a chronic atherosclerotic disease resulting in narrowing of the common and internal carotid arteries. Common risk factors include family history, advanced age, hyperlipidemia, smoking, and diabetes mellitus. Patients may present with or without symptoms of decreased cerebral perfusion. 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 Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. 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 Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Coronary hearty disease can present in chronic (angina, ischemic cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies) or acute ( myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction) form and can present with intense chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. 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 Carotid artery stenosis Carotid artery stenosis is a chronic atherosclerotic disease resulting in narrowing of the common and internal carotid arteries. Common risk factors include family history, advanced age, hyperlipidemia, smoking, and diabetes mellitus. Patients may present with or without symptoms of decreased cerebral perfusion. 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 Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Chronic disease can be asymptomatic or present with intermittent claudication. Acute ischemia can lead to gangrene and extremity amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation.
  • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease: can develop secondary to atherosclerosis affecting renal arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: This disease can also be associated with secondary hypertension.
  • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction: can develop secondary to atherosclerosis affecting pelvic vessels
  • Blindness: due to central retinal artery occlusion
  • Intestinal mesenteric ischemia Mesenteric Ischemia Mesenteric ischemia is a rare, life-threatening condition caused by inadequate blood flow through the mesenteric vessels, which results in ischemia and necrosis of the intestinal wall. Mesenteric ischemia can be either acute or chronic. 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 Mesenteric Ischemia Mesenteric ischemia is a rare, life-threatening condition caused by inadequate blood flow through the mesenteric vessels, which results in ischemia and necrosis of the intestinal wall. Mesenteric ischemia can be either acute or chronic. Mesenteric Ischemia presents with intense abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and if left untreated leads to intestinal necrosis and can be fatal. Chronic ischemia is usually associated with intermittent postprandial abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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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