Definition of Atherosclerosis
Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a specific form of arteriosclerosis in which an artery wall thickens as a result of the accumulation of calcium and fatty materials such as cholesterol and triglyceride. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, caused largely by the accumulation of macrophages and white blood cells and promoted by low-density lipoproteins (LDL, plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high-density lipoproteins (HDL). It is commonly referred to as a hardening or furring of the arteries. It is caused by the formation of multiple plaques within the arteries.
The atheromatous plaque is divided into three distinct components:
- The atheroma (“lump of gruel”, from Greek ἀθήρα (athera), meaning “gruel”), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery
- Underlying areas of cholesterol crystals
- Calcification at the outer base of older/more advanced lesions.
Atherosclerosis is a chronic disease that remains asymptomatic for decades. Atherosclerotic lesions, or atherosclerotic plaques are separated into two broad categories: Stable and unstable (also called vulnerable). The pathobiology of atherosclerotic lesions is very complicated but generally, stable atherosclerotic plaques, which tend to be asymptomatic, are rich in extracellular matrix and smooth muscle cells, while, unstable plaques are rich in macrophages and foam cells and the extracellular matrix separating the lesion from the arterial lumen (also known as the fibrous cap) is usually weak and prone to rupture. Ruptures of the fibrous cap expose thrombogenic material, such as collagen to the circulation and eventually induce thrombus formation in the lumen. Upon formation, intraluminal thrombi can occlude arteries outright (e.g. coronary occlusion), but more often they detach, move into the circulation and eventually occluding smaller downstream branches causing thromboembolism. Apart from thromboembolism, chronically expanding atherosclerotic lesions can cause complete closure of the lumen.
Interestingly, chronically expanding lesions are often asymptomatic until lumen stenosis is so severe (usually over 80%) that blood supply to downstream tissue(s) is insufficient, resulting in ischemia.
These complications of advanced atherosclerosis are chronic, slowly progressive and cumulative. Most commonly, soft plaque suddenly ruptures (see vulnerable plaque), causing the formation of a thrombus that will rapidly slow or stop blood flow, leading to death of the tissues fed by the artery in approximately 5 minutes. This catastrophic event is called an infarction. One of the most common recognized scenarios is called coronary thrombosis of a coronary artery, causing myocardial infarction (a heart attack). The same process in an artery to the brain is commonly called stroke. Another common scenario in very advanced disease is claudication from insufficient blood supply to the legs, typically caused by a combination of both stenosis and aneurysmal segments narrowed with clots.
Atherosclerosis affects the entire artery tree, but mostly larger, high-pressure vessels such as the coronary, renal, femoral, cerebral, and carotid arteries. These are termed “clinically silent” because the person having the infarction does not notice the problem and does not seek medical help, or when they do, physicians do not recognize what has happened.
Cause of Atherosclerosis
The atherosclerotic process is not fully understood. Atherosclerosis is initiated by inflammatory processes in the endothelial cells of the vessel wall in response to retained low-density lipoprotein (LDL) molecules.
Lipoproteins in the blood vary in size. Some data suggests that only small dense LDL (sdLDL) particles are able to get behind the cellular monolayer of endothelium. LDL particles and their content are susceptible to oxidation by free radicals, and the risk may be higher while in the bloodstream. However, LDL particles have a half-life of only a couple of days, and their content (LDL particles carry cholesterol, cholesteryl esters, and tryglycerides from the liver to the tissues of the body) changes with time.
Once inside the vessel wall, LDL particles get stuck and their content becomes more prone to oxidation. The damage caused by the oxidized LDL molecules triggers a cascade of immune responses which over time can produce an atheroma. First the immune system sends specialized white blood cells (macrophages and T-lymphocytes) to absorb the oxidized LDL, forming specialized foam cells. These white blood cells are not able to process the oxidized LDL. They grow and then rupture, depositing a greater amount of oxidized cholesterol into the artery wall. This triggers more white blood cells, continuing the cycle. Eventually, the artery becomes inflamed. The cholesterol plaque causes the muscle cells to enlarge and form a hard cover over the affected area. This hard cover is what causes a narrowing of the artery, reducing blood flow and increasing blood pressure.
Some researchers believe that atherosclerosis may be caused by an infection of the vascular smooth muscle cells. Chickens, for example, develop atherosclerosis when infected with the Marek’s disease herpesvirus. Herpesvirus infection of arterial smooth muscle cells has been shown to cause cholesteryl ester (CE) accumulation, which is associated with atherosclerosis. Cytomegalovirus (CMV) infection is also associated with cardiovascular diseases.
Signs and Symptoms of Atherosclerosis
Clinically, atherosclerosis is typically associated with men over the age of 45. Sub-clinically, the disease begins to appear at early childhood, and perhaps even at birth. Noticeable signs can begin developing at puberty. Though symptoms are rarely exhibited in children, early screening of children for cardiovascular diseases could be beneficial to both the child and his/her relatives. Atheroma in arm, or more often in leg arteries, which produces decreased blood flow is called peripheral artery occlusive disease (PAOD). Typically, atherosclerosis begins as a thin layer of white streaks on the artery wall (usually due to white blood cells) and progresses from there. While coronary artery disease is more prevalent in men than women, atherosclerosis of the cerebral arteries and strokes equally affect both sexes.
According to United States data for the year 2004, for about 66% of men and 47% of women, the first symptom of atherosclerotic cardiovascular disease is heart attack or sudden cardiac death (death within one hour of onset of the symptom).
Most artery flow disrupting events occur at locations with less than 50% lumen narrowing (~20% stenosis is average). The illustration above, like most illustrations of arterial disease, overemphasizes lumen narrowing, as opposed to compensatory external diameter enlargement (at least within smaller arteries, e.g., heart arteries) typical of the atherosclerosis process as it progresses. The relative geometry error within the illustration is common to many older illustrations, an error slowly being more commonly recognized within the last decade.
Cardiac stress testing, traditionally the most commonly performed non-invasive testing method for blood flow limitations, in general, detects only lumen narrowing of ~75% or greater, although some physicians claim that nuclear stress methods can detect as little as 50%.
A famous case study involved autopsies of American soldiers killed in World War II and the Korean War. Although these were mostly young, healthy men in their 20s, many already had evidence of developing atherosclerosis. Other studies done on soldiers in the Second Indochina War showed similar results, although often worse than the ones from the earlier wars. Theories include high rates of tobacco use and (in the case of the Vietnam soldiers) the advent of processed foods after WWII.
Risk Factors for Atherosclerosis
Various anatomic and physiological risk factors for atherosclerosis are known. These can be divided into various categories: congenital vs acquired, modifiable or not, classical or non-classical. The points labelled ‘+’ in the following list form the core components of metabolic syndrome.
Risks multiply, with two factors increasing the risk of atherosclerosis fourfold. Hyperlipidemia, hypertension and cigarette smoking together increases the risk seven times.
- Diabetes or Impaired glucose tolerance (IGT) +
- Dyslipoproteinemia (unhealthy patterns of serum proteins carrying fats & cholesterol): +
- High serum concentration of low-density lipoprotein (LDL, “bad if elevated concentrations and small”), and / or very low density lipoprotein (VLDL) particles, i.e., “lipoprotein subclass analysis”
- Low serum concentration of functioning high density lipoprotein (HDL “protective if large and high enough” particles), i.e., “lipoprotein subclass analysis”
- An LDL:HDL ratio greater than 3:1
- Tobacco smoking, increases risk by 200% after several pack years
- Elevated serum C-reactive protein concentrations
- Vitamin B6 deficiency
- Dietary iodine deficiency and hypothyroidism, which cause elevated serum cholesterol and of lipid peroxidation
- Advanced age
- Male sex
- Having close relatives who have had some complication of atherosclerosis (e.g. coronary heart disease or stroke)
- Genetic abnormalities, e.g. familial hypercholesterolemia
Lesser or uncertain
The following factors are of relatively lesser importance, are uncertain or unquantified:
- Obesity (in particular central obesity, also referred to as abdominal or male-type obesity) +
- Postmenopausal estrogen deficiency
- High intake of saturated fat (may raise total and LDL cholesterol)
- Intake of trans fat (may raise total and LDL cholesterol while lowering HDL cholesterol)
- High carbohydrate intake
- Elevated serum levels of triglycerides +
- Elevated serum levels of homocysteine
- Elevated serum levels of uric acid (also responsible for gout)
- Elevated serum fibrinogen concentrations
- Elevated serum lipoprotein(a) concentrations
- Chronic systemic inflammation as reflected by upper normal WBC concentrations, elevated hs-CRP and many other blood chemistry markers, most only research level at present, not clinically done.
- Hyperthyroidism (an over-active thyroid)
- Elevated serum insulin levels +
- Short sleep duration
- Chlamydia pneumoniae infection
- PM2.5 air pollution, fine particulates less than 2.5 µm in diameter, have been associated with thickening of the carotid artery.
The relation between dietary fat and atherosclerosis is a contentious field. The USDA, in its food pyramid, promotes a low-fat diet, based largely on its view that fat in the diet is atherogenic. The American Heart Association, the American Diabetes Association and the National Cholesterol Education Program make similar recommendations. In contrast, Prof Walter Willett (Harvard School of Public Health, PI of the second Nurses’ Health Study) recommends much higher levels, especially of monounsaturated and polyunsaturated fat. Writing in Science, Gary Taubes detailed that political considerations played into the recommendations of government bodies. These differing views reach a consensus, though, against consumption of trans fats.
The role of dietary oxidized fats/lipid peroxidation (rancid fats) in humans is not clear. Laboratory animals fed rancid fats develop atherosclerosis. Rats fed DHA-containing oils experienced marked disruptions to their antioxidant systems, and accumulated significant amounts of phospholipid hydroperoxide in their blood, livers and kidneys. In another study, rabbits fed atherogenic diets containing various oils were found to undergo the greatest amount of oxidative susceptibility of LDL via polyunsaturated oils. In a study involving rabbits fed heated soybean oil, “grossly induced atherosclerosis and marked liver damage were histologically and clinically demonstrated.” However, Kummerow, a prominent researcher, claims that it is not dietary cholesterol, but oxysterols, or oxidized cholesterols, from fried foods and smoking, that are the culprit.
Rancid fats and oils taste very bad even in small amounts, so people avoid eating them. It is very difficult to measure or estimate the actual human consumption of these substances.
Highly unsaturated omega-3 rich oils such as fish oil are being sold in pill form so that the taste of oxidized or rancid fat is not apparent. The health food industry’s dietary supplements are self regulated by the manufacture and outside of FDA regulations. To properly protect unsaturated fats from oxidation, it is best to keep them cool and in oxygen free environments. Long term exposure to inorganic arsenic can cause atherosclerosis.
Diagnosis of Atherosclerosis
Areas of severe narrowing, stenosis, detectable by angiography, and to a lesser extent “stress testing” have long been the focus of human diagnostic techniques for cardiovascular disease, in general. However, these methods focus on detecting only severe narrowing, not the underlying atherosclerosis disease. As demonstrated by human clinical studies, most severe events occur in locations with heavy plaque, yet little or no lumen narrowing present before debilitating events suddenly occur. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, and potential permanent debility and sometimes sudden death.
Plaques that have ruptured are called complicated plaques. The extracellular matrix of the lesion breaks, usually at the shoulder of the fibrous cap that separates the lesion from the arterial lumen, where the exposed thrombogenic components of the plaque, mainly collagen will trigger thrombus formation. The thrombus then travel downstream to other blood vessels, where the blood clot may partially or completely block blood flow. If the blood flow is completely blocked, cell deaths occur due to the lack of oxygen supply to nearby cells, resulting in necrosis. The narrowing or obstruction of blood flow can occur in any artery within the body. Obstruction of arteries supplying the heart muscle result in a heart attack, while the obstruction of arteries supplying the brain result in a stroke.
Lumen stenosis that is greater than 75% were considered as the hallmark of clinically significant disease in the past because recurring episodes of angina and abnormalities in stress test are only detectable at that particular severity of stenosis. However, clinical trials have shown that only about 14% of clinically debilitating events occur at sites with >75% stenosis. Majority of cardiovascular events that involve sudden rupture of the atheroma plaque do not display any evident narrowing of the lumen. Thus, greater attention has been focused on “vulnerable plaque” from the late 1990s onwards.
Besides the traditional diagnostic methods such as angiography and stress-testing, other detection techniques have been developed in the past decades for earlier detection of atherosclerotic disease. Some of the detection approaches include anatomical detection and physiologic measurement.
Examples of anatomical detection methods include (1) coronary calcium scoring by CT, (2) carotid IMT (intimal media thickness) measurement by ultrasound, and (3) intravascular ultrasound (IVUS). Examples of physiologic measurement methods include (1) lipoprotein subclass analysis, (2) HbA1c, (3) hs-CRP, and (4) homocysteine. Both anatomic and physiologic methods allow early detection before symptoms show up, disease staging and tracking of disease progression.
Anatomic methods are more expensive and some of them are invasive in nature, such as IVUS. On the other hand, physiologic methods are often less expensive and safer. But they do not quantify the current state of the disease or directly track progression. In the recent years, ways of estimating the severity of atherosclerotic plaques is also made possible with the developments in nuclear imaging techniques such as PET and SPECT.
Prevention from Atherosclerosis
Combinations of statins, niacin, intestinal cholesterol absorption-inhibiting supplements (ezetimibe and others, and to a much lesser extent fibrates) have been the most successful in changing common but sub-optimal lipoprotein patterns and group outcomes. In the many secondary prevention and several primary prevention trials, several classes of lipoprotein-expression-altering (less correctly termed “cholesterol-lowering”) agents have consistently reduced not only heart attack, stroke and hospitalization but also all-cause mortality rates. The first primary prevention comparative treatment trial was AFCAPS/TexCAPS with multiple later comparative statin/placebo treatment trials including EXCEL, ASCOT and SPARCL. While the statin trials have all been clearly favorable for improved human outcomes, only ASTEROID and SATURN showed evidence of atherosclerotic regression. Both human and animal trials that showed evidence of disease regression used more aggressive combination agent treatment strategies, which nearly always included niacin.
Treatment of Atherosclerosis
If atherosclerosis leads to symptoms, some symptoms such as angina pectoris can be treated. Non-pharmaceutical means are usually the first method of treatment, such as cessation of smoking and practicing regular exercise. If these methods do not work, medicines are usually the next step in treating cardiovascular diseases, and, with improvements, have increasingly become the most effective method over the long term.
In general, the group of medications referred to as statins has been the most popular and are widely prescribed for treating atherosclerosis. They have relatively few short-term or longer-term undesirable side-effects, and several clinical trials comparing statin treatment with placebo have fairly consistently shown strong effects in reducing atherosclerotic disease ‘events’ and generally ~25% comparative mortality reduction, although one study design, ALLHAT, was less strongly favorable.
The newest statin, rosuvastatin, was the first to demonstrate regression of atherosclerotic plaque within the coronary arteries by IVUS (intravascular ultrasound evaluation). The study was set up to demonstrate effect primarily on atherosclerosis volume within a 2 year time-frame in people with active/symptomatic disease (angina frequency also declined markedly) but not global clinical outcomes, which was expected to require longer trial time periods; these longer trials remain in progress. In the 2011 SATURN study, atorvastatin was also shown to effect regression of atherosclerotic plaque to a degree roughly equivalent to the regression brought about by rosuvastatin. However, for most people, changing their physiologic behaviors, from the usual high risk to greatly reduced risk, requires a combination of several compounds, taken on a daily basis and indefinitely. More and more human treatment trials have been done and are ongoing that demonstrate improved outcome for those people using more-complex and effective treatment regimens that change physiologic behaviour patterns to more closely resemble those that humans exhibit in childhood at a time before fatty streaks begin forming.
The success of statin drugs in clinical trials is based on some reductions in mortality rates, however by trial design biased toward men and middle-age, the data is, as yet, less strongly clear for women and people over the age of 70.
Changes in diet may help prevent the development of atherosclerosis. Researchers at the Agricultural Research Service have found that avenanthramides, which are chemical compounds found in oats, may help reduce the inflammation of the arterial wall, this contributes to the development of atherosclerosis. Avenanthramides have anti-inflammatory properties that are linked to activating proinflammatory cytokines. Cytokines are proteins that are released by the cell to protect and repair tissues. Researchers have found compounds in oats have the ability to reduce inflammation and help prevent atherosclerosis.
Other physical treatments, helpful in the short term, include minimally invasive angioplasty procedures that may include stents to physically expand narrowed arteries and major invasive surgery, such as bypass surgery, to create additional blood supply connections that go around the more severely narrowed areas.
Patients at risk for atherosclerosis-related diseases are increasingly being treated prophylactically with low-dose aspirin and a statin. The high incidence of cardiovascular disease led Wald and Law to propose a Polypill, a once-daily pill containing these two types of drugs in addition to an ACE inhibitor, diuretic, beta blocker, and folic acid. They maintain that high uptake by the general population by such a Polypill would reduce cardiovascular mortality by 80%. It must be emphasized however that this is purely theoretical, as the Polypill has never been tested in a clinical trial.
Medical treatments often focus predominantly on the symptoms. However, over time, clinical trials have shown treatments that focus on decreasing the underlying atherosclerosis processes—as opposed to simply treating symptoms—more effective.
In summary, the key to the more effective approaches has been better understanding of the widespread and insidious nature of the disease and to combine multiple different treatment strategies, not rely on just one or a few approaches. In addition, for those approaches, such as lipoprotein transport behaviors, which have been shown to produce the most success, adopting more aggressive combination treatment strategies has generally produced better results, both before and especially after people are symptomatic.
Because many blood thinners, particularly warfarin and salicylates such as aspirin, thin the blood by interfering with Vitamin K, there is recent evidence that blood thinners that work by this mechanism can actually worsen arterial calcification in the long term even though they thin the blood in the short term.