Atherosclerosis PDF is patchy intimal plaques (atheromas) encroach on the lumen of medium- and large arteries, containing lipids, inflammatory cells, smooth muscle cells, and connective tissue; the plaques comprise lipids, inflammatory cells, smooth muscle cells, and connective tissue. Dyslipidemia, diabetes, cigarette smoking, family history, sedentary lifestyle, obesity, and hypertension are all risk factors. Symptoms appear when plaque formation or rupture limits or obstructs blood flow; symptoms vary depending on which artery is impacted. Angiography, ultrasonography, or other imaging studies are used to confirm the diagnosis. Risk factors, lifestyle, and dietary changes, as well as physical activity, antiplatelet medications, and antiatherogenic therapies, are all used to treat atherosclerosis.
Atherosclerosis is the most common type of arteriosclerosis, which is a term that refers to a group of diseases that cause the arterial wall to thicken and lose elasticity. Because it causes coronary artery disease and cerebrovascular disease, atherosclerosis is the most serious and clinically relevant form of arteriosclerosis. Arteriolosclerosis and Mönckeberg arteriosclerosis are non-atheromatous types of arteriosclerosis.
Atherosclerosis Pathophysiology
The fatty streak is an aggregation of lipid-laden foam cells in the intimal layer of the artery that is the first apparent lesion of atherosclerosis.
The atherosclerotic plaque is the hallmark of atherosclerosis; it is the result of the evolution of the fatty streak and consists of three basic components:
- Lipids
- Smooth muscle cells and inflammatory cells
- A connective tissue matrix may contain calcium deposits and thrombi in various stages of organization.
Formation of atherosclerotic plaque
Atherosclerosis is thought to be an inflammatory response to injury mediated by particular cytokines at all stages, from initiation to plaque formation and complication. Endothelial damage is regarded to be the primary initiator or instigator of the disease.
Atherosclerosis affects specific parts of the arterial tree more than others. Endothelial dysfunction is caused by nonlaminar or turbulent blood flow (for example, at branch sites in the arterial tree), which reduces the endothelial synthesis of nitric oxide, a potent vasodilator, and anti-inflammatory chemical. Endothelial cells are stimulated to create adhesion molecules, which recruit and bind inflammatory cells, as a result of the increased blood flow.
Atherosclerosis risk factors (e.g., dyslipidemia, diabetes, cigarette smoking, hypertension), oxidative stressors (e.g., superoxide radicals), angiotensin II, and systemic infection and inflammation all inhibit nitric oxide production while stimulating adhesion molecules, pro-inflammatory cytokines, chemotactic proteins, and vasoconstrictors; the exact mechanisms are unknown. Endothelial binding of monocytes and T cells, migration of these cells to the subendothelial region, and initiation and maintenance of a local vascular inflammatory response are the net effects.
In the subendothelium, monocytes become macrophages. Lipids in the blood attach to endothelial cells and are oxidized in the subendothelium, notably low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) cholesterol. Fatty streaks are typical early atherosclerosis lesions caused by the uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells. Damaged erythrocyte membranes caused by vasa vasorum rupture and intraplaque bleeding could be a significant additional source of lipids within plaques.
There has been evidence of a link between infection and atherosclerosis, specifically a link between serologic evidence of certain infections (e.g., Chlamydia pneumoniae, CMV) and coronary artery disease (CAD). Indirect effects of chronic inflammation in the bloodstream, cross-reactive antibodies, and inflammatory effects of pathogenic pathogens on the artery wall are all possible pathways.
Plaque stability and rupture
There are two types of atherosclerotic plaques: stable and unstable. Over several decades, stable plaques recede, remain static, or increase slowly until they induce stenosis or occlusion.
Long before they create hemodynamically significant stenosis, unstable plaques are subject to spontaneous erosion, fissure, or rupture, resulting in acute thrombosis, occlusion, and infarction. Plaque stabilization may be a technique to reduce morbidity and mortality by preventing clinical events caused by unstable plaques that do not appear severe on angiography.
The relative balance of collagen deposition and degradation determines the fibrous cap’s strength and resistance to rupture. Metalloproteinases, cathepsins, and collagenases are secreted by activated macrophages in the plaque during plaque rupture. The fibrous cap is digested by these enzymes, especially at the edges, causing the cap to weaken and eventually break. The plaque’s T cells contribute by secreting cytokines. Smooth muscle cells are prevented from generating and depositing collagen, which typically strengthens the plaque, by cytokines.
When a plaque ruptures, the contents of the plaque are exposed to the circulating blood, causing thrombosis; macrophages also cause thrombosis because they carry tissue factor, which stimulates thrombin production in vivo. One of the following five results is possible:
The thrombus that forms as a result of this may organize and become absorbed into the plaque, changing its shape and triggering fast growth.
The thrombus could quickly obstruct the arterial lumen, causing an acute ischemic event.
It’s possible that the thrombus will embolize.
The plaque may fill with blood, expand out, and obstruct the artery immediately.
Rather than thrombus, plaque contents can embolize, occluding arteries downstream.
Plaque composition (relative proportions of lipids, inflammatory cells, smooth muscle cells, connective tissue, and thrombus), wall stress (cap fatigue), size and location of the core, and plaque architecture in respect to blood flow are all factors that influence plaque stability. Intraplaque bleeding may play a key role in the transformation of stable plaques into unstable plaques by promoting fast development and lipid accumulation.
In general, unstable coronary artery plaques have a high macrophage presence, a dense lipid core, and a thin fibrous top; they constrict the conduit lumen by around 50% and rupture in an unpredictable manner. Unstable carotid artery plaques contain the same composition as stable carotid artery plaques, but they generally cause issues due to severe stenosis, occlusion, or platelet thrombi deposition, which embolize rather than burst. Low-risk plaques have a thicker cap and fewer lipids, and they frequently constrict the artery lumen by more than 50%, causing predictable exercise-induced stable angina.
The clinical effects of plaque rupture in coronary arteries are determined by the relative balance of procoagulant and anticoagulant activity in the blood, as well as the myocardium’s vulnerability to arrhythmias.
Atherosclerosis Risk Factors
Atherosclerosis has a number of risk factors (1—see table Risk Factors for Atherosclerosis). The metabolic syndrome, which is growing more common, is caused by a combination of variables. Abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, a prothrombotic state, and a proinflammatory state are all symptoms of this syndrome in sedentary people. Insulin resistance is not the same as metabolic syndrome, but it may play a role in its development.
Hypertension, diabetes, and dyslipidemia (high total, high LDL, or low HDL) all-cause atherosclerosis by amplifying or enhancing endothelial dysfunction and inflammatory pathways in the vascular endothelium.
Subendothelial absorption and oxidation of LDL increases in dyslipidemia; oxidized lipids induce the generation of adhesion molecules and inflammatory cytokines, as well as being antigenic, inducing a T cell-mediated immunological response and inflammation in the arterial wall. Although HDL was once thought to protect against atherosclerosis by transporting reverse cholesterol and antioxidant enzymes that can break down and neutralize oxidized lipids, new evidence from randomized trials and genetics suggests that HDL has a considerably smaller role in atherogenesis. Hypertriglyceridemia plays a complicated function in atherogenesis, while it may have a little independent influence (2).
Angiotensin II-mediated pathways may contribute to vascular inflammation in hypertension. Proinflammatory cytokines, superoxide anions, prothrombotic factors, growth factors, and lectin-like oxidized LDL receptors are all produced when angiotensin II activates endothelial cells, vascular smooth muscle cells, and macrophages to create proatherogenic mediators.
Diabetes causes the creation of advanced glycation end products, which cause endothelial cells to produce more proinflammatory cytokines. Diabetes causes oxidative stress and reactive oxygen radicals, which damage the endothelium and promote atherogenesis.
Nicotine and other compounds in tobacco smoke are harmful to the vascular endothelium. Smoking, including passive smoking, raises platelet reactivity (potentially encouraging platelet thrombosis), as well as plasma fibrinogen and hematocrit levels (increasing blood viscosity). Smoking raises LDL and lowers HDL levels, as well as causes vasoconstriction, which is especially harmful in arteries already constricted by atherosclerosis. Within one month of quitting smoking, HDL levels rise by about 6 to 8 mg/dL (0.16 to 0.21 mmol/L).
Lipoprotein (a) [Lp(a)] is a pro-atherogenic lipid that is a risk factor for cardiovascular disease, including myocardial infarction, stroke, and stenosis of the aortic valve (3, 4). It has a similar structure to LDL, but it additionally has a hydrophilic apolipoprotein(a) component that is covalently attached to a hydrophobic apolipoprotein B100 component (5). Lp(a) levels are determined by genetics and stay relatively constant throughout life. Lp(a) concentrations more than 50 mg/dL are deemed pathogenic.
Apolipoprotein (B) (apoB) is a particle that comes in two different isoforms: apoB-100, which is made in the liver, and apoB-46, which is made in the gut. ApoB-100 is a protein that can attach to the LDL receptor and is involved in cholesterol transport. It also has proinflammatory effects and is involved in the transfer of oxidized phospholipids. The presence of the apoB particle within the artery wall is assumed to be the catalyst for atherosclerotic lesions to form.
Diabetes is associated with a high quantity of tiny, dense LDL, which is extremely atherogenic. Increased oxidative susceptibility and nonspecific endothelium binding are possible mechanisms.
A high level of C-reactive protein (CRP) does not accurately predict the extent of atherosclerosis, but it does suggest an increased risk of ischemic events. Higher levels may indicate an enhanced risk of atherosclerotic plaque rupture, continuing ulceration or thrombosis, or increased lymphocyte and macrophage activity in the absence of other inflammatory illnesses. CRP does not appear to play a direct function in the development of atherosclerosis.
Endothelial dysfunction can be caused by C. pneumoniae infection or other infections (e.g., viral, Helicobacter pylori) by direct infection, endotoxin exposure, or promotion of systemic or subendothelial inflammation.
Chronic kidney illness increases the development of atherosclerosis through a number of mechanisms, including increased lipoprotein(a), homocysteine, fibrinogen, and C-reactive protein levels, as well as increasing hypertension and insulin resistance.
Immune-mediated endothelial damage is thought to be the cause of accelerated coronary atherosclerosis after heart transplantation. Radiation-induced endothelial injury is thought to be the cause of accelerated coronary atherosclerosis after thoracic radiation therapy.
Atherosclerosis and cardiovascular events have been linked to a number of common and unusual genetic variations. Despite the fact that each risk variant has a minor effect on its own, genetic risk scores based on the overall number of risk variants have been linked to more advanced atherosclerosis as well as both main and recurrent cardiovascular events.
Patients with hyperhomocysteinemia (due to a lack of folate or a genetic metabolic abnormality, for example) have a higher risk of developing atherosclerosis. However, evidence from Mendelian randomization trials, as well as outcomes from randomized trials of homocysteine reducing medications that failed to show a reduction in atherosclerotic disease, has led to the conclusion that hyperhomocysteinemia does not cause atherosclerosis. The cause of the link between high homocysteine levels and atherosclerosis is unknown.
Atherosclerosis Symptoms and Signs
Atherosclerosis is generally asymptomatic at first, lasting decades. When lesions obstruct blood flow, symptoms and indicators appear. When persistent plaques build and reduce the artery lumen by more than 70%, transient ischemia symptoms (e.g., stable exertional angina, transient ischemic episodes, intermittent claudication) may emerge. A lesion that does not restrict blood flow can become severe or complete stenosis as a result of vasoconstriction. When unstable plaques burst and acutely occlude a major artery, with superimposition of thrombosis or embolism, symptoms of unstable angina or myocardial infarction, ischemic stroke, or rest pain in the limbs may emerge. Atherosclerosis can also result in rapid death without the presence of angina pectoris, whether stable or unstable.
Aneurysms and arterial dissection can occur as a result of atherosclerotic involvement of the artery wall, and symptoms include pain, a pulsatile mass, absent pulses, and sudden death.
Diagnosis of Atherosclerosis
The presence or absence of symptoms influences how atherosclerosis is diagnosed.
Patients who are experiencing symptoms
Depending on the organ affected, patients with symptoms and signs of ischemia are assessed for the quantity and location of arterial blockage using a variety of invasive and noninvasive techniques (see elsewhere in THE MANUAL). These patients should also be tested for atherosclerosis risk factors.
- History and physical examination
- Fasting lipid profile
- Plasma glucose and glycosylated hemoglobin (HbA1C) levels
- Patients with the documented disease at one site (eg, peripheral arteries) should be evaluated for the disease at other sites (eg, coronary and carotid arteries).
Because not all atherosclerotic plaques are equally prone to rupture, several imaging methods are being investigated as a means of identifying plaques that are more vulnerable to rupture; however, these approaches have yet to be employed therapeutically.
Plaque morphology and features can be assessed using noninvasive imaging techniques.
- Vascular ultrasonography in three dimensions
- Angiography using computed tomography (CT)
- Magnetic resonance angiography (MR angiography) is a type of angiography that uses
Also employed are invasive catheter-based diagnostics. These include the following:
Intravascular ultrasonography produces images of the artery lumen and wall using an ultrasound transducer on the tip of a catheter.
Angioscopy is a procedure that involves the use of special fiberoptic catheters to view the artery surface directly.
Plaque thermography is a technique for detecting elevated temperatures in plaques that are inflamed.
- Optical coherence tomography is a type of imaging that uses infrared laser light.
- Elastography is a technique for detecting soft, lipid-rich plaques.
Immunoscintigraphy is a noninvasive option that use radioactive tracers that target plaque that is susceptible. Another new method for assessing susceptible plaque is positron emission tomography (PET) imaging of the vasculature.
Some doctors examine serum indicators of inflammation in addition to the fasting lipid profile, plasma glucose, and hemoglobin A1C tests. C-reactive protein levels of less than 3.1 mg/L (29.5 nmol/L) are strongly linked to cardiovascular events.
Asymptomatic patients (screening)
The role of additional testing beyond the lipid profile in patients with atherosclerotic risk factors but no symptoms or evidence of ischemia is unknown. Although imaging investigations such as carotid ultrasonography to measure the intimal medial thickness and other studies to detect atherosclerotic plaque are being investigated, they do not improve ischemic event prediction when compared to risk factors or current prediction techniques and are not advised. CT imaging for coronary artery calcium (i.e., to obtain a calcium score) is an exception, for which there is more robust evidence for risk categorization; it may be useful for refining risk estimations and deciding on statin medication in certain patients (eg, those with intermediate-risk, family history of premature cardiovascular disease).
In individuals with any of the following features, most guidelines advocate lipid profile screening:
- Men ≥ 40 years
- Women ≥ 50 years and post-menopausal women
- Type 2 diabetes
- Family history of familial hypercholesterolemia or early cardiovascular disease (onset age 55 years in male 1st-degree relatives or 65 years in female 1st-degree relatives)
- Metabolic syndrome
- Hypertension
- Chronic inflammatory conditions
To predict lifetime and 10-year risk of atherosclerotic cardiovascular disease, the American Heart Association (AHA) currently advises utilizing the pooled cohort risk assessment equations (see Downloadable AHA Risk Calculator). This calculator has taken the place of earlier risk calculators (eg, Framingham score). Sexe, age, race, total and HDL cholesterol levels, systolic blood pressure (and whether high pressure is being treated), diabetes, and smoking status are all factors in the new risk calculation (1). To estimate the 10-year risk of the first fatal atherosclerotic event, the European Cardiovascular Society (ESC) and the European Atherosclerosis Society (EAS) 2016 guideline suggests using the Systemic Coronary Risk Estimation (SCORE), which calculates risk based on age, gender, smoking, systolic blood pressure, and total cholesterol (2). Lipoprotein(a) testing has been suggested to help refine classification for patients regarded to be at moderate risk (3).
Urinary albuminuria (> 30 mg albumin/24 hours) is a substantial predictor of cardiovascular and noncardiovascular morbidity and mortality; nevertheless, there is no direct link between albuminuria and atherosclerosis.
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