Summary of Atherosclerosis
Cardiovascular diseases play an important role in the modern world’s structure of morbidity and mortality. Of all the other underlying causes, atherosclerosis is the most frequent in the development of many cardiovascular diseases (CVDs).
Any artery can be affected by atherosclerosis. When it involves arteries of the heart, it may result in angina or myocardial infarction (MI). In the brain, it can lead to transient ischemic attack (TIA) or stroke while in the peripheral arteries of the limbs, it causes claudication or critical limb ischemia.
Atherosclerosis is a chronic inflammatory disease and involves both innate and adaptive immunity. This article explains the evaluation and treatment of atherosclerosis, its risk factors, and its complications.
Introduction to Atherosclerosis
Atherosclerosis is a multifactorial disease that develops over the course of a long time. It is a chronic inflammatory disease involving arteries (mainly large and medium-sized). Approximately, 50% of all deaths in Western countries have atherosclerosis as an underlying cause. (1)
It is an inflammatory process initiated by endothelial damage and promoted by oxidized low-density lipoprotein (LDL) accumulation particularly affecting arteries having disturbed and non-laminar flow at branch points.
The vessel injury activates thrombo-inflammatory mechanisms that lead to coagulation of blood and thrombus formation. Thrombotic events can cause MI or stroke, or can dislodge from its original place of formation and produce an embolism.
Elevated LDL and cholesterol levels are necessary for atherosclerosis and can be controlled by using statin drugs and lifestyle modifications. (1, 2)
Epidemiology of Atherosclerosis
The determination of the incidence of atherosclerosis is not easy because it is predominantly an asymptomatic disease. It usually presents with associated cardiovascular disease mainly involving the heart and brain.
Ischemic heart disease is the leading cause of death worldwide, while stroke comes fifth in causing deaths. (1) Ischemic heart disease (IHD) makes up 2.2% of all global diseases and 32.5% of cardiovascular diseases. (3) Both developed and developing countries have a high prevalence of this condition.
One out of every four deaths is due to heart disease in the United States. Almost 735,000 patients in the United States have an episode of myocardial infarction (MI) every year, of which 525,000 are the first episode and 210,000 are recurrent myocardial infarctions. (1) Almost 200 billion dollars are spent annually on IHD.
According to the American Heart Association survey, 7.6% of men and 5% of women in the United States had coronary artery disease from 2009 to 2012. (3, 4) Women are comparatively protected from atherosclerosis due to female sex hormones but this protective effect is lost after menopause.
Stroke is the fifth leading cause of death worldwide and is the most common cause of disability in patients. (1, 5) The American Heart Association 2022 update shows that the prevalence of stroke in the United States is 2.7% and it increases as the age of the patient advances. Approximately, 795,000 people in the United States suffer from an episode of new or recurrent stroke, with 140,323 of them resulting in the death of the patient. (6)
Women have a greater lifetime risk of stroke as compared to men. But, men have a higher age-adjusted tendency to stroke. Stroke, in most cases, is ischemic in nature which is due to atherosclerotic cerebrovascular disease (ASCVD).
Etiology and Risk Factors
Atherosclerosis is a multifactorial disease involving both modifiable and non-modifiable risk factors. The clinical importance of these risk factors has been proved by experimental studies and clinical trials.
Various risk factors have been identified, but they do not explain all the outcomes, leading to the conclusion that there may be some unknown risk factors that are responsible for person-to-person variations. The effect of multiple risk factors is multiplicative rather than additive. This makes a patient with multiple risk factors more susceptible to atherosclerotic cerebrovascular disease (ASCVD).
Therefore, it is important to note all the risk factors and manage them accordingly. The risk factors for atherosclerosis are mainly divided into two groups, modifiable and non-modifiable risk factors. (1, 7)
Non-modifiable Risk Factors:
- Genetic factors:
Twin studies have shown the influence of genetic factors in the development of atherosclerosis. A monozygotic twin of an affected person has eight times greater risk for atherosclerosis and cerebrovascular diseases while a dizygotic twin has four times greater risk than the general population. (7)
- Family History:
Positive family history of atherosclerosis is also an important factor due to shared genetic makeup, and lifestyle and environmental factors. It is considered significant when the clinical signs and symptoms of the disease appear in first-degree relatives at a relatively younger age. (7)
- Age and Sex:
Age is the non-modifiable most significant risk factor and has a direct relationship with the development of atherosclerosis. The prevalence of atherosclerosis increases with increasing age. Sex difference in atherosclerosis is also considerable and should be kept in mind while managing the disease. Women are less vulnerable than men at a younger age, especially before menopause. But this protective effect is lost after menopause. While men have more chances of sudden death and MI at a younger age. Lifestyle modifications are also more effective in women than in men regarding risk reduction. (8)
Type A personality is associated with an increased risk of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD). However, there is not much evidence to support this belief and more research is needed.
Modifiable Risk Factors:
It is the most significant modifiable risk factor in the development of atherosclerosis, as basic science studies have shown the high oxidant and inflammatory burden of smoking that can directly cause endothelial damage. Smoking has a direct proportional and dose-dependent association with disease. Moreover, smoking cessation is beneficial at any age and is one of the most important steps for reducing the risks of coronary disease, cancer, and mortality. (8)
Raised serum total cholesterol and low-density lipoprotein (LDL) cholesterol enhances the risk of cardiovascular events. It is the most important factor in the absence of smoking and is preventable in most cases. Dietary changes and physical activity can help reduce serum cholesterol and LDL levels and, in turn, reduces the risk of atherosclerosis. (1, 7)
The risk of atherosclerosis increases with hypertension, both systolic and diastolic. Antihypertensive treatment and good blood pressure control are associated with reduced cardiovascular events and mortality.
- Diabetes mellitus:
This is a potent risk factor for diffused atherosclerosis. It can further lead to coronary artery disease, stroke and even death. Diabetes is a major risk factor for ischemic heart disease (IHD), especially in South Asian people.
- Lifestyle and physical activity:
A sedentary lifestyle is expected to double the risk of coronary artery disease and is associated with an increased risk of atherosclerosis and other ASCVDs. On the other hand, healthy and regular activity (walking, running, cycling, and swimming) has a protective effect as it is associated with low serum cholesterol and LDL levels. It also helps in the management of hypertension and diabetes mellitus.
- Diet and Nutrition:
Consumption of the Mediterranean diet is associated with a reduced risk of cardiovascular diseases. While a diet deficient in fruits, vegetables and polyunsaturated fatty acids leads to an increased risk of atherosclerosis and other cardiovascular diseases.
- Chronic Stress:
Social deprivation and chronic stress are also important factors in atherosclerosis development. Significant evidence supports that chronic stress can cause the release of hormones like cortisol and catecholamines regulating vascular blood flow and causing endothelial injury. That is why this aspect of a patient’s life should also be discussed and managed accordingly. (9)
Pathophysiology of Atherosclerosis
The development of atherosclerosis is a continuous process involving inner arterial wall lesions. It involves trapping of lipids by the intimal layer leading to a structural modification and inflammatory process at susceptible sites in the arterial wall. The process begins with endothelial damage, the formation of isolated foamy macrophages and fatty streaks due to intracellular lipid accumulation, further evolving to fibrous plaques and complex atheroma formation which are vulnerable to rupture. This atheroma can also cause stenosis of arteries by its increasing size resulting in syndromes like acute coronary syndrome and stroke. (1, 7, 10)
The histological changes in the development of atherosclerosis can be divided into the following stages:
The process begins with endothelial damage and intimal thickening, followed by the internalization of low-density lipids (LDL) and the accumulation of lipid droplets in macrophages leading to the formation of foam cells. This lays the groundwork for the formation of fatty streaks within the intimal layer and complex atheroma formation.
Early Fatty Streak Phase:
Fatty streak formation is the second stage of atherosclerosis development. In every individual, adaptive thickening of the intimal layer is present by birth. This gives support to the vessel wall, especially in high-pressure areas. As the age of the individual increases, oxidized LDL adheres to the intimal layer of the blood vessel and causes the formation of fatty streaks. This increased adherence is due to proinflammatory stimuli (such as smoking, diabetes mellitus, and hypertension) leading to increased endothelial dysfunction that can disrupt the endothelial barrier. This, in turn, predisposes to enhanced endothelial permeability and causes the trapping of LDL by proteoglycans. The LDL undergoes oxidative modification, and oxidized LDL is phagocytosed by macrophages to become foam cells, which is characteristic histology of the fatty streak phase.
Early Fibro Atheroma Phase:
Once fatty streaks and foam cells are formed, the smooth muscle cells migrate from the tunica media to the intima and form collagen-rich fibrous plaque located beneath the endothelium. The migration of smooth muscle cells is mediated by angiotensin 2, insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF). The fibrous plaque formation is a protective mechanism to prevent plaque rupture.
This stage usually begins at about age 55 to 65 years. These plaques consist of a thin fibrous cap containing high amounts of lipids and macrophages and abundant tissue factor in cells while being low in smooth muscle cell density. A necrotic core enriched in cholesterol crystals, foamy macrophages and T lymphocytes compose the content of the atheroma making it vulnerable to rupture.
Necrotic Core Development:
It is an important pathogenic process responsible for plaque susceptibility to rupture. Different mechanisms for necrotic core development have been proposed. Many studies have proven that intraplaque hemorrhage is the major factor for the growth of the necrotic core as blood is rich in lipids and free cholesterol, which is the key constituent of ruptured plaques. Another important mechanism is the endoplasmic reticulum stress pathway or unfolded protein response produced in diseased macrophages, as shown in some studies. This response causes the accumulation of dead macrophages within the necrotic core. Moreover, dysregulated neovascularization also contributes to this process as studies show increased microvascular density in advanced plaques. These effects collectively increase the chances of plaque rupture.
The thin fibrous cap makes the atheroma vulnerable to rupture. The exact mechanism of plaque rupture is still unknown, but recent studies have shown that uncontrolled proteolytic activity by matrix metalloproteinases (MMPs) and myeloperoxidases exposes the intima and stimulates platelet aggregation and tissue factor activation leading to thrombus formation. This thrombus can cause obstruction to the blood flow or can dislodge from its original site to form an embolus. In situ thrombus formation and embolism are the main culprits of major cardiovascular events like acute coronary syndrome and stroke.
Thrombi mainly develop as a result of plaque rupture but it can also be the result of plaque erosion and calcified nodule within the plaque. Plaque erosion is characterized by the absence of endothelium, exposed intima at the site of erosion and minimal inflammation. It can be differentiated from plaque rupture as it contains fewer macrophages and T lymphocytes. Calcified nodule formation may also occur but it is rare. (10, 11)
History and Clinical Features
Obtaining a complete medical history is important to assess all the risk factors. History of smoking, sedentary lifestyle, diet and nutrition, and family history should be considered significant as they may contribute to the development of atherosclerosis. Moreover, the management of these patients, either behavioral or medical, is done according to the number of risk factors present and the severity of the disease.
The clinical features of the disease depend upon the type of organ involved. Atherosclerosis causes obstruction to the blood supply of the organ leading to clinical manifestations, including:
- When coronary arteries are affected, the patient can present with acute coronary syndrome (ACS), including angina and even MI. Chest pain, breathlessness, palpitations, dizziness, cold sweats, nausea and weakness are the common presenting complaints in ACS. (3)
- Stroke and transient ischemic attack (TIA) are the manifestations when arteries of the brain are involved. Patients can have weakness or numbness on one side of the body, altered state of consciousness, dizziness, diplopia, dysarthria, and facial drop. (5)
- When a peripheral artery is affected, it can compromise a whole limb, presenting with pain, numbness, heaviness and cramping. It can also cause arterial ulcers in advanced chronic disease. (12)
- When it affects the renal arteries, secondary hypertension may develop through renin-angiotensin pathway activation. (12, 13)
- Involvement of the mesenteric arteries can lead to intestinal ischemia. The symptoms include pain after taking meals, alternating bowel habits, and weight loss. (13)
- Erectile dysfunction is also one of the manifestations of atherosclerosis in males and should be evaluated. (12)
The signs of atherosclerosis include arterial bruits (carotid bruit, renal bruit, aortic bruit), high blood pressure, and parethesias, pain and numbness of the limbs (in peripheral arterial disease).
Atherosclerosis is mainly diagnosed based on risk factors, but investigations can be done to check associated diseases. Investigations can also be done to assess the severity of the disease and evaluate the associated risk factors.
- Lipid profile (including serum cholesterol, triglycerides, low-density lipoproteins, and high-density lipoproteins) is the most important investigation as raised cholesterol and LDL are significant risk factors in the development of atherosclerosis. (1)
- Blood glucose (fasting and random) should be checked to rule out diabetes mellitus as it also contributes to atherosclerosis. (1, 7)
- When coronary artery disease is suspected, several tests can be done to confirm the diagnosis. ECG is the first and most important, followed by troponin levels (Troponin I & T). Angiography is done to evaluate atherosclerotic lesions in coronary arteries and is considered the best method. (14) Although it is an invasive procedure and should be done in selected patients. CT angiography and cardiac MRI can also be done in some cases. (14)
- CT-scan of the brain and MRI can be used to detect stroke along with the clinical signs and symptoms. (15)
- For screening of peripheral arterial disease, the ankle-brachial index is considered the best criterion and can be obtained using a Doppler device. (7, 16)
Treatment of Atherosclerotic Disease
The goal of treatment is to keep all the modifiable factors within a favorable range. This will improve the overall prognosis of the disease and prevent cardiovascular events associated with atherosclerosis. The management involves medical treatment, lifestyle modifications, and diet and nutrition balance.
Serum cholesterol and LDL level can be lowered and maintained at low by using statin therapy. These drugs inhibit 3-hydoxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which prevents the conversion of HMG-CoA to mevalonate. This is the rate-limiting step in cholesterol production. As a result, serum cholesterol production is decreased. Non-stain drugs such as bile acid sequestrants, fibric acid derivatives, niacin, and ezetimibe can also be used. (17)
Hypertension can be treated with the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, vasodilators, calcium channel blockers (CCBs) and diuretics. In severe cases, a combination of two or more drugs is used. The goal is to maintain a blood pressure of less than 130/85. (18)
Good diabetes control is also important for atherosclerosis management. Different groups of drugs are available, each having its own mechanism of action. These include biguanides (metformin), sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, dipeptidyl peptidase IV inhibitors (DPP-4), glucagonlike-peptide-1 agonist, selective, sodium-glucose transporter-2 (SGLT-2) inhibitors, and amylinomimetics. The desired level of glycated hemoglobin (HbA1c) is less than 7%. (19)
Antiplatelet agents (like aspirin or clopidogrel) may also be considered in patients due to the high risk of, or having previous episodes of thrombotic events. It is advised for patients, who are at high risk, to receive a single antiplatelet agent (either acetylsalicylic acid or clopidogrel) while those with a history of an atherothrombotic event, such as stroke or myocardial infarction, are given double antiplatelet therapy (both acetylsalicylic acid and clopidogrel). The duration of therapy is 6-12 months in case of MI history and 6 weeks in stroke. (20)
This is an important step in atherosclerosis management as it reduces morbidity and mortality. This includes smoking cessation, physical activity and exercise, while avoiding a sedentary lifestyle. Daily exercise is recommended even for healthy people to prevent atherosclerosis development. Obesity with a high BMI index is also a major contributor to this disease. Daily exercise for 90 to 150 minutes is recommended, along with medical treatment and a balanced diet. (1)
Diet and Nutrition:
Appropriate diet modification is necessary for patients having atherosclerosis and hypercholesterolemia. The current studies have shown the importance of a personalized approach to diet and nutrition. It is recommended that patients take less saturated fats and processed meats, and more monounsaturated and polyunsaturated fats (fish, walnuts) in their diet. The Keto diet, Mediterranean diet, and DASH diet are usually recommended and are considered to prevent cardiovascular events. However, it may be difficult for consumers to select one of these optimal diets due to geographic, financial, and climatic reasons. (21)
Complications of Atherosclerosis
As described earlier, atherosclerosis can lead to cardiovascular diseases such as acute coronary syndrome (ACS), transient ischemic attack (TIA) and cerebrovascular disease, hypertension, renal artery stenosis, abdominal aortic aneurysms, and peripheral arterial disease. Each of these has a different presentation and management and should be properly evaluated. (1, 7)
The author does not report any conflict of interest.
This information is for educational purposes and is not intended to treat disease or supplant professional medical judgment. Physicians should follow local policy regarding the diagnosis and management of medical conditions.
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Dr. Muhammad Daniyal Haider is a general physician who continuously seeks for platforms to serve the community and utilize his knowledge and abilities to improve the health
system. Dedication to the cure of diseases and, more importantly, prevention and
awareness of people about these diseases is the goal. He is a general physician, author
and a calligrapher. He is passionate about research projects, latest guidelines and
techniques which can lead to a better approach to the patient’s condition.