Week 11: Atherosclerosis Flashcards
Define Arteriosclerosis and explain its relationship with endothelial cell injury
Arteriosclerosis is a condition characterized by thickening and hardening of the vessel wall. Atherosclerosis is a form of arteriosclerosis that is caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called a plaque. Atherosclerosis is a pathologic process that can affect vascular systems throughout the body and is the leading cause of peripheral artery disease, CAD, and cerebrovascular disease.
Atherosclerosis is an inflammatory disease that begins with injury to the endothelial cells that line artery walls. Pathologically, the lesions progress from (1) endothelial injury and dysfunction to (2) fatty streak to (3) fibrotic plaque to (4) complicated lesion. Possible causes of endothelial injury include the common risk factors for atherosclerosis, such as smoking, hypertension, diabetes, increased levels of low-density lipoprotein (LDL), decreased levels of high-density lipoprotein (HDL), and autoimmunity. Other “nontraditional” risk factors include increased serum markers for inflammation and thrombosis (e.g., high-sensitivity C-reactive protein [hs-CRP]), troponin I, adipokines, infection, and air pollution.
(1) Injured endothelial cells become INFLAMED. Inflamed endothelial cells cannot make normal amounts of antithrombic and vasodilating cytokines and express adhesion molecules that bind macrophages and other inflammatory and immune cells, they are DYSFUNCTIONAL. Macrophages release numerous inflammatory CYTOKINES (e.g., tumor necrosis factor-alpha [TNF-α], interferons, interleukins, C-reactive protein) and enzymes that further injure the vessel wall. Toxic oxygen free radicals generated by the inflammatory process cause OXIDATION (i.e., addition of oxygen) of LDL that has accumulated in the vessel intima. Oxidized LDL causes additional adhesion molecule expression with the recruitment of monocytes that differentiate into macrophages. (2) These macrophages penetrate into the intima, where they engulf oxidized LDL, and are then called FOAM CELLS. When they accumulate in significant amounts, they form a lesion called a FATTY STREAK. Once formed, fatty streaks produce more toxic oxygen free radicals, and secrete additional inflammatory mediators resulting in progressive damage to the vessel wall. In addition, oxidized LDL and foam cells serve as damage-associated molecular patterns (DAMPs) and activate macrophage release of inflammatory cytokines and recruit autoreactive T cells leading to autoimmune vascular injury.
MACROPHAGES also release growth factors that stimulate smooth muscle cell proliferation. Smooth muscle cells in the region of endothelial injury proliferate, produce collagen, and MIGRATE over the fatty streak, forming an atherosclerotic plaque. (3) The plaque may calcify, protrude into the vessel lumen, and obstruct blood flow to distal tissues (especially during exercise), which may cause symptoms (e.g., angina or intermittent claudication) known as a FIBROUS PLAQUE. Many plaques are “unstable,” meaning they are prone to rupture. These plaques are CLINICALLY SILENT and do not affect luminal blood flow significantly until they erode and RUPTURE. Rupture of unstable plaques occurs due to the degradative effects of inflammatory cytokines and enzymes, wall stress, and neurohumoral changes. (4) Plaques that have ruptured are called complicated plaques or COMPLICATED LESIONS. Once rupture occurs, exposure of underlying tissue results in platelet adhesion, initiation of the clotting cascade, and rapid thrombus formation. The thrombus may suddenly occlude the affected vessel, resulting in ischemia and infarction. Aspirin or other antithrombotic agents are used to prevent this complication of atherosclerotic disease.
Endothelium Injury –> Inflammation of endothelium –> Cytokine released –> Cellular proliferation –> Macrophage migration –> LDL oxidation & foam cell formation –> Fatty streak –> Fibrous plaque –> Complicated plaque
Explain the role of gut microbiome dysfunction in the pathogenesis of atherosclerosis
The microbiome impacts atherosclerosis indirectly through diet and lifestyle (i.e., diabetes and autoimmunity) but also directly by function of the microbiota. It is thought that the microbiome regulates homocysteine and lipid metabolism and when dysregulated may result in hyperhomocysteinemia which is linked to cardiovascular risk.
Identify the modifiable and non-modifiable risk factors including the social determinants of health in the development of atherosclerosis and cardiovascular disease
Non-modifiable risk factors:
* advanced age
* male gender or women after menopause (estrogen is protective)
* family history & genetics (shared environmental exposure)
Modifiable risk factors:
* Dyslipidemia
* Hypertension (endothelial injury, increase myocardial demand)
* cigarette smoking (vasoconstriction and increase in LDL/decrease in HDL)
* diabetes and insulin resistance (endothelial damage, thickening of vessel wall)
* obesity and/or sedentary life style
* atherogenic diet (high in salt, fats, trans fat, and carbohydrates)
Non-traditional risk factors:
* markers of inflammation, ischemia, and thrombosis (C-reactive protein)
* adipokines (adiponectin and leptin - released from adipose cells)
* medications (NSAIDs and anti-rejection drugs)
* air pollution and ionizing radiation (may contribute to macrophage activation, oxidation of LDL, inflammation of vessel walls)
* coronary artery calcification, carotid wall thickness
* dysregulated microbiome
* chronic kidney disease: dyslipidemia, endothelial dysfunction, vascular calcification, elevated levels of growth factors, and toxic oxygen radicals all contribute
Treatment includes:
* reducing risk factors
* removing initial cause of vessel damage
* preventing lesion progression
* promoting exercising, smoking cessation, and controlling hypertension & diabetes
* reducing LDL cholesterol levels by diet, drugs or both
Discuss the diagnostics for atherosclerosis
- Laboratory Tests: measurement of lipids, blood glucose, and high-sensitivity CRP (hs-CRP)
- Diagnostic Imaging: x-ray films, electrocardiography, ultrasonography, nuclear scanning, CT, MRI, and angiography to identify affected vessels, particularly coronary vessels
- Physical Assessment & History: complete healthy history (including risk factors and symptoms of ischemia), physical examination may reveal evidence of decreased blood flow to tissues
Explain the pathophysiologic processes associated with dyslipidemia and how it relates to the inflammatory process in the development of atherosclerosis
Serum levels of LDL are normally controlled by hepatic receptors that bind LDL and limit liver synthesis of this lipoprotein. Genetic predisposition to dyslipidemias, in combination with a high dietary intake of saturated fats, result in excess amounts of LDL in the bloodstream. Excess LDL migration into the vessel wall, oxidation, and phagocytosis by macrophages are key steps in the pathogenesis of atherosclerosis. LDL also plays a role in endothelial injury, inflammation, and immune responses that have been identified as being important in atherogenesis.
Low levels of HDL cholesterol are an indicator of increased coronary risk, whereas high levels of HDL are associated with a significant reduction in coronary risk independent of age, smoking history, LDL levels, blood pressure, or weight. HDL is responsible for “reverse cholesterol transport,” which returns excess cholesterol from the tissues to the liver for processing or elimination in the bile. HDL also participates in endothelial repair and decreases thrombosis.
Other lipoproteins associated with increased cardiovascular risk include elevated levels of serum VLDLs (triglycerides) and increased lipoprotein(a) levels. Triglycerides are associated with an increased risk for CAD, especially in combination with other risk factors such as diabetes. Lipoprotein(a) (Lp[a]) is a genetically determined molecular complex between LDL and a serum glycoprotein called apolipoprotein A and has been shown to be an important risk factor for atherosclerosis, especially in women. Lipoprotein(a) potentially contributes to cardiovascular disease through proatherogenic, proinflammatory, and prothrombotic effects.
Explain how inflammation an the atherosclerotic process contributes to the formation of abdominal aortic aneurysms
An aneurysm is a localized dilation or outpouching of a vessel wall or cardiac chamber. True aneurysms involve weakening in all THREE layers of the arterial wall. Most are fusiform and circumferential, whereas saccular aneurysms are basically spherical in shape. False aneurysms are an extravascular HEMATOMA that communicates with the intravascular space. A common cause of this type of lesion is a leak between a vascular graft and a natural artery.
Vascular aneurysms most commonly occur in the thoracic or abdominal aorta, and in the cerebrovascular system. Major risk factors for aneurysm formation include hypertension and atherosclerosis. Atherosclerotic plaque formation causes inflammatory changes that erode the vessel wall and contributes to a loss of smooth muscle cells and accumulation of inflammatory cells.
The aorta is particularly susceptible to aneurysm formation because of constant stress on the vessel wall and the absence of penetrating vasa vasorum in the media layer. Chronic inflammation of the wall of the aorta is considered the primary cause of aortic aneurysms leading to weakening of the intima and medial layers. Aortic aneurysms can be complicated by the acute aortic syndromes, which include aortic dissection, hemorrhage into the vessel wall, or vessel rupture. Abdominal aortic aneurysms may be caused by infections (i.e., syphilis), collagen disorders, traumatic injury, or genetic susceptibility.
Clinical manifestations of aneurysms depend on where the aneurysm is located. Aortic aneurysms often are asymptomatic until they rupture and then cause severe pain and hypotension.
Discuss the diagnostics for aneurysms
Aneurysms are diagnosed through ultrasonography, CT, MRI, or angiography. Treatment includes keep blood volume low and decreasing pressure on the weakened wall. If the client smokes, we will encourage them to stop. We may prescribe a Beta-adrenergic blocker.
Acute aortic syndromes involve a vessel rupture and can lead to a deadly aortic dissection. A type A dissection is an emergency and will require immediate surgery. Type B is less threatening and can be managed with medical therapy. Symptoms will present in a pain behind the neck, jaw, chest, back or abdomen - will require an urgent CT scan, echo and MRI.
Identify the manifestations of peripheral artery disease (PAD)
Peripheral artery disease (PAD) refers to atherosclerotic disease of arteries that perfuse the limbs, especially the lower extremities. The risk factors for PAD are the same as those previously described for atherosclerosis. It is especially prevalent in smokers and older adults with diabetes.
Lower extremity ischemia resulting from arterial obstruction in PAD can be gradual or acute. In most individuals, gradually increasing atherosclerotic changes in arterial walls is associated with endothelial cell dysfunction, decreases in endogenous vasodilators such as endothelin -1, and the tendency for thrombosis. This leads to obstruction to arterial blood flow and exercise-related ischemia. In the iliofemoral vessels, this may result in leg pain with ambulation called intermittent claudication. If a thrombus forms over the atherosclerotic lesion, complete obstruction of blood flow can occur acutely, causing severe pain, loss of pulses, and skin color changes in the affected extremity. Critical limb ischemia may lead to gangrene.
Evaluation for PAD requires a careful history and physical examination that focuses on finding evidence of atherosclerotic disease (e.g., bruits), determining a difference in blood pressure measured at the ankle versus the arm (ankle-brachial index), and measuring blood flow using duplex ultrasound, CT angiography, or magnetic resonance angiography. Treatment begins with risk factor reduction including smoking cessation, exercise, diabetes and hypertension management, and treatment for dyslipidemia. Symptomatic PAD should be managed with vasodilators in combination with antiplatelet medications.
What are Lipoproteins?
Lipoproteins consist of lipids, phospholipids, cholesterol, and triglycerides bound to carrier proteins that are necessary for the formation and repair of plasma membranes. Cholesterol is an important example of a Lipoprotein that plays a role in manufacturing essential substances (e.g., bile acids and steroid hormones) and repairs plasma membranes. We can obtain cholesterol from the diet, but it is primarily manufactured by the body.
There are four types of Lipoproteins:
1. High-density lipoproteins (HDLs)
2. Low-density lipoproteins (LDLs)
3. Very low-density lipoproteins (VLDLs)
4. Chylomicrons (primarily triglycerides)
What are Chylomicrons?
A type of Lipoprotein that transports exogenous lipids from the intestine to the liver and peripheral cells. Dietary fat is packaged into chylomicrons for absorption in the small intestine. They primarily contain triglyceride; triglycerides may be removed and either stored by adipose tissue or used by muscle as an energy source. Their remnants contain cholesterol, which is taken up by the liver.
What are Low-density Lipoproteins (LDLs and VLDLs)?
LDLs carry cholesterol to the tissues and are normally controlled by hepatic receptors that bind LDL and limit liver synthesis of this lipoprotein. If serum concentrations of LDL are high, and an individual also has contributing risk factors such as age, diabetes and/or CKD they may have coronary risk.
Very low-density lipoproteins carry triglycerides.
What are High-density Lipoproteins (HDLs)?
High-density lipoprotein returns cholesterol to the liver through “reverse cholesterol transport”; cholesterol binds to hepatic receptors (including the LDL receptor) and is processed an eliminated as bile or converted to cholesterol-containing steroids. Other functions of HDL include protecting LDL from oxidation, preserving endothelial function, and promoting anti-inflammatory and anti-thrombotic effects.
What are the diagnostic criteria for dyslipidemia?
- Total cholesterol greater than 240, 200 is considered borderline
- LDL greater than 160, 130 is considered borderline and over 190 is very high
- Triglycerides greater than 150, greater than 500 is considered very high
- HDL between 40-60; has a narrow range for health
Discuss the clinical manifestations of Atherosclerosis
Atherosclerosis presents with symptoms and signs that result from inadequate perfusion of tissues because of obstruction of the vessels that supply them. Partial vessel obstruction may lead to transient ischemic events, often associated with exercise or stress. As the lesion becomes complicated, increasing obstruction with superimposed thrombosis may result in tissue infarction. Obstruction of peripheral arteries can cause significant pain and disability. CAD caused by atherosclerosis is the major cause of myocardial ischemia. Atherosclerotic obstruction of the vessels supplying the brain is the major cause of stroke. Often, more than one vessel will become involved with this disease process such that an individual may present with symptoms from several ischemic tissues at the same time, and disease in one area may indicate that the individual is at risk for ischemic complications elsewhere.
Discuss management of lipid disorders
Pharmacotherapy for hyperlipidemia focuses on reducing LDL and increasing HDL, reducing cholesterol in liver cells can contribute to lowering LDL in plasma. Remember, patients with lipid disorders are often asymptomatic until progressing to more serious cardiovascular disorders.
Targets are an LDL of less than 2.5 mmol/L; and total cholesterol: HDL <4.0; Triglyceride <1.7 mmol/L
Non Pharmacological management:
* diet (reduced intake of saturated fats and cholesterol)
* increase intake of soluble fiber and plant sterols
* eliminate tobacco and alcohol
* exercise regularly
* regular monitoring of blood lipids; HDL and LDL
Pharmacological management:
* HMG-CoA reductase Inhibitors
* Antiplatelet (ADP receptor blocker)
* Cyclooxygenase (COX) inhibitors
* Thrombolytics: tissue plasminogen activator (tPA)
* Antidepressants
