Arteriosclerosis

Atherosclerosis is a disease affecting arterial blood vessels. It is a chronic inflammatory response in the walls of arteries, in large part due to the deposition of lipoproteins (plasma proteins that carry cholesterol and triglycerides). 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:
 * 1) The atheroma ("lump of porridge", from Athera, porridge in Greek,), 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
 * 2) Underlying areas of cholesterol crystals
 * 3) Calcification at the outer base of older/more advanced lesions.

The following terms are similar, yet distinct, in both spelling and meaning, and can be easily confused: arteriosclerosis, arteriolosclerosis, and atherosclerosis. Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries (from the Greek Arterio, meaning artery, and sclerosis, meaning hardening), arteriolosclerosis is atherosclerosis mainly affecting the arterioles (small arteries), atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque. Therefore, atherosclerosis is a form of arteriosclerosis.

Atherosclerosis causes two main problems. First, the atheromatous plaques, though long compensated for by artery enlargement, see IMT, eventually lead to plaque ruptures and stenosis (narrowing) of the artery and, therefore, an insufficient blood supply to the organ it feeds. If the compensating artery enlargement process is excessive, then a net aneurysm results.

These complications are chronic, slowly progressing 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, that is, within 5 minutes, leading to death of the tissues fed by the artery. 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). Another common scenario in very advanced disease is claudication from insufficient blood supply to the legs, typically due to a combination of both stenosis and aneurysmal segments narrowed with clots. Since atherosclerosis is a body-wide process, similar events occur also in the arteries to the brain, intestines, kidneys, legs, etc.

Symptoms
Atherosclerosis typically begins in early adolescence, and is usually found in most major arteries, yet is asymptomatic and not detected by most diagnostic methods during life. Autopsies of healthy young men that died during the Korean and Vietnam Wars showed evidence of the disease. It most commonly becomes seriously symptomatic when interfering with the coronary circulation supplying the heart or cerebral circulation supplying the brain, and is considered the most important underlying cause of strokes, heart attacks, various heart diseases including congestive heart failure, and most cardiovascular diseases, in general. Atheroma in arm, or, more often, leg arteries, and producing decreased blood flow, is called Peripheral artery occlusive disease (PAOD).

According to United States data for the year 2004, for about 65% 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 reader might reflect that 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, see Glagov and the ASTEROID trial, the IVUS photographs on page 8, as examples for a more accurate understanding. 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%.

Atherogenesis
Atherogenesis is the developmental process of atheromatous plaques. It is characterized by a remodeling of arteries involving the concomitant accumulation of fatty substances called plaques. One recent theory suggests that, for unknown reasons, leukocytes, such as monocytes or basophils, begin to attack the endothelium of the artery lumen in cardiac muscle. The ensuing inflammation leads to formation of atheromatous plaques in the arterial tunica intima, a region of the vessel wall located between the endothelium and the tunica media and tunica adventitia. The bulk of these lesions is made of excess fat, collagen, and elastin. At first, as the plaques grow, only wall thickening occurs without any narrowing, stenosis of the artery opening, called the lumen; stenosis is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not the just atherosclerosis process by itself.

Cellular
The first step of atherogenesis is the development of fatty streaks, small subendothelial deposits of lipid. The exact cause for this process is unknown, and fatty streaks may appear and disappear.

LDL in blood plasma poses a risk for cardiovascular disease when it invades the endothelium and becomes oxidized. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of free-radicals in the endothelium or blood vessel lining.

The initial damage to the blood vessel wall results in a "call for help," an inflammation response. Monocytes (a type of white blood cell) enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This may be promoted by redox signaling induction of factors such as VCAM-1, which recruit circulating monocytes. The monocytes differentiate into macrophages, which ingest oxidized LDL, slowly turning into large "foam cells" – so-described because of their changed appearance resulting from the numerous internal cytoplasmic vesicles and resulting high lipid content. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die, and further propagate the inflammatory process. There is also smooth muscle proliferation and migration from tunica media to intima responding to cytokines secreted by damaged endothelial cells. This would cause the formation of a fibrous capsule covering the fatty streak.

Calcification and lipids
Intracellular microcalcifications form within vascular smooth muscle cells of the surrounding muscular layer, specifically in the muscle cells adjacent to the atheromas. In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques.

Cholesterol is delivered into the vessel wall by cholesterol-containing low-density lipoprotein (LDL) particles. To attract and stimulate macrophages, the cholesterol must be released from the LDL particles and oxidized, a key step in the ongoing inflammatory process. The process is worsened if there is insufficient high-density lipoprotein (HDL), the lipoprotein particle that removes cholesterol from tissues and carries it back to the liver.

The foam cells and platelets encourage the migration and proliferation of smooth muscle cells, which in turn ingest lipids, become replaced by collagen and transform into foam cells themselves. A protective fibrous cap normally forms between the fatty deposits and the artery lining (the intima).

These capped fatty deposits (now called atheromas) produce enzymes that cause the artery to enlarge over time. As long as the artery enlarges sufficiently to compensate for the extra thickness of the atheroma, then no narrowing, stenosis, of the opening, lumen, occurs. The artery becomes expanded with an egg-shaped cross-section, still with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an aneurysm is created.

Visible features
Although arteries are not typically studied microscopically, two plaque types can be distinguished:
 * 1) The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris.  In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger "foamy" cells and capillaries. These plaques usually produce the most damage to the individual when they rupture.
 * 2) The fibrous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic) and, rarely, lipid-laden cells.

In effect, the muscular portion of the artery wall forms small aneurysms just large enough to hold the atheroma that are present. The muscular portion of artery walls usually remain strong, even after they have remodeled to compensate for the atheromatous plaques.

However, atheromas within the vessel wall are soft and fragile with little elasticity. Arteries constantly expand and contract with each heartbeat, i.e., the pulse. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall, as they progress, lead to a loss of elasticity and stiffening of the artery as a whole.

The calcification deposits, after they have become sufficiently advanced, are partially visible on coronary artery computed tomography or electron beam tomography (EBT) as rings of increased radiographic density, forming halos around the outer edges of the atheromatous plaques, within the artery wall. On CT, >130 units on the Hounsfield scale {some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. These deposits demonstrate unequivocal evidence of the disease, relatively advanced, even though the lumen of the artery is often still normal by angiographic or intravascular ultrasound.

Rupture and stenosis
Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until an atheroma obstructs the bloodstream in the artery. This is typically by rupture of an atheroma, clotting and fibrous organization of the clot within the lumen, covering the rupture but also producing stenosis, or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis. Stenoses can be slowly progressive, whereas plaque rupture is a sudden event that occurs specifically in atheromas with thinner/weaker fibrous caps that have become "unstable."

Repeated plaque ruptures, ones not resulting in total lumen closure, combined with the clot patch over the rupture and healing response to stabilize the clot, is the process that produces most stenoses over time. The stenotic areas tend to become more stable, despite increased flow velocities at these narrowings. Most major blood-flow-stopping events occur at large plaques, which, prior to their rupture, produced very little if any stenosis.

From clinical trials, 20% is the average stenosis at plaques that subsequently rupture with resulting complete artery closure. Most severe clinical events do not occur at plaques that produce high-grade stenosis. From clinical trials, only 14% of heart attacks occur from artery closure at plaques producing a 75% or greater stenosis prior to the vessel closing.

If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released, and blood enters the atheroma within the wall and sometimes results in a sudden expansion of the atheroma size. Tissue fragments are very clot-promoting, containing collagen and tissue factor; they activate platelets and activate the system of coagulation. The result is the formation of a thrombus (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen and nutrients. If this is the myocardium (heart muscle), angina (cardiac chest pain) or myocardial infarction (heart attack) develops.

Diagnosis of plaque-related disease
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.

Greater than 75% lumen stenosis used to be considered by cardiologists as the hallmark of clinically significant disease because it is typically only at this severity of narrowing of the larger heart arteries that recurring episodes of angina and detectable abnormalities by stress testing methods are seen. However, clinical trials have shown that only about 14% of clinically-debilitating events occur at locations with this, or greater severity of narrowing. The majority of events occur due to atheroma plaque rupture at areas without narrowing sufficient enough to produce any angina or stress test abnormalities. Thus, since the later-1990s, greater attention is being focused on the "vulnerable plaque."

Though any artery in the body can be involved, usually only severe narrowing or obstruction of some arteries, those that supply more critically-important organs are recognized. Obstruction of arteries supplying the heart muscle result in a heart attack. Obstruction of arteries supplying the brain result in a stroke. These events are life-changing, and often result in irreversible loss of function because lost heart muscle and brain cells do not grow back to any significant extent, typically less than 2%.

Over the last couple of decades, methods other than angiography and stress-testing have been increasingly developed as ways to better detect atherosclerotic disease before it becomes symptomatic. These have included both (a) anatomic detection methods and (b) physiologic measurement methods.

Examples of anatomic methods include: (1) coronary calcium scoring by CT, (2) carotid IMT (intimal media thickness) measurement by ultrasound, and (3) IVUS.

Examples of physiologic methods include: (1) lipoprotein subclass analysis, (2) HbA1c, (3) hs-CRP, and (4) homocysteine.

The example of the metabolic syndrome combines both anatomic (abdominal girth) and physiologic (blood pressure, elevated blood glucose) methods.

Advantages of these two approaches: The anatomic methods directly measure some aspect of the actual atherosclerotic disease process itself, thus offer potential for earlier detection, including before symptoms start, disease staging and tracking of disease progression. The physiologic methods are often less expensive and safer and changing them for the better may slow disease progression, in some cases with marked improvement.

Disadvantages of these two approaches: The anatomic methods are generally more expensive and several are invasive, such as IVUS. The physiologic methods do not quantify the current state of the disease or directly track progression. For both, clinicians and third party payers have been slow to accept the usefulness of these newer approaches.

Physiologic factors that increase risk
Various anatomic, physiological & behavioral 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":


 * Advanced age
 * Male sex
 * Having 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"), Lipoprotein(a) (a variant of LDL), 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"
 * Tobacco smoking
 * Having high blood pressure +
 * Being obese (in particular central obesity, also referred to as abdominal or male-type obesity) +
 * A sedentary lifestyle
 * Having close relatives who have had some complication of atherosclerosis (eg. coronary heart disease or stroke)
 * Elevated serum levels of homocysteine
 * Elevated serum levels of uric acid (also responsible for gout)
 * Elevated serum fibrinogen 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.
 * Stress or symptoms of clinical depression
 * Hyperthyroidism (an over-active thyroid)
 * High intake of trans-fats and saturated fats in diet

Prognosis
Lipoprotein imbalances, upper normal and especially elevated blood sugar, i.e., diabetes, high blood pressure, homocysteine, stopping smoking, taking anticoagulants (anti-clotting agents), which target clotting factors, taking omega-3 oils from fatty fish or plant oils such as flax or canola oils, exercising and losing weight are the usual focus of treatments that have proven to be helpful in clinical trials. The target serum cholesterol level is ideally equal or less than 4mmol/L (160 mg/dL), and triglycerides equal or less than 2mmol/L (180 mg/dL).

Evidence has increased that people with diabetes, despite their not having clinically-detectable atherosclotic disease, have more severe debility from atherosclerotic events over time than even non-diabetics that have already suffered atherosclerotic events. Thus diabetes has been upgraded to be viewed as an advanced atherosclerotic disease equivalent.

Treatment
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. However, medicines are criticized for their expense, patented control and occasional undesired effects.

Statins
In general, the group of medications referred to as statins has seen popularity yet they are not approved in most jurisdictions for treating atherosclerosis. They have relatively few short-term undesirable side-effects, and have shown some effect in reducing atherosclerotic disease 'events' in some but not all studies such as ALLHAT.

The newest statin, rosuvastatin, has been the first to demonstrate regression of atherosclerotic plaque within the coronary arteries by IVUS (intravascular ultrasound evaluation), The study was not set up to demonstrate clinical benefit or harm. 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 statins, and some other medications, have been shown to have antioxidant effects, possibly part of their basis for some of their therapeutic success in reducing cardiac 'events'.

The success of statin drugs in clinical trials is based on some reductions in mortality rates, however never in women or people over the age of 70 CMAJ. For example, in 4S, the first large placebo controlled, randomized clinical trial of a statin in people with advanced disease who had already suffered a heart attack, the overall mortality rate reduction for those taking the statin, vs. placebo, was 30%. For the subgroup of people in the trial that had Diabetes Mellitus, the mortality rate reduction between statin and placebo was 54%. 4S was a 5.4-year trial that started in 1989 and was published in 1995 after completion. There were 3 more dead women at trial's end on statin than in the group on placebo drug. The ASTEROID trial has been the first to show actual disease volume regression (see page 8 of the paper, which shows cross-sectional areas of the total heart artery wall at start and 2 years of rosuvastatin 40 mg/day treatment); however, its design was not able to "prove" the mortality reduction issue since it has no placebo group.

Diet and dietary supplements
Lowering lipoprotein little a, a genetic variant of LDL, can be achieved with large daily doses of vitamin B3, niacin. Niacin also tends to shift LDL particle distribution to larger particle size and improve HDL functioning. Work on increasing HDL particle concentration and function, beyond the niacin effect, perhaps even more important, is slowly advancing. 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 dyslipidemia patterns but, in the case of inhibitors and fibrates without improving clinical outcomes in secondary prevention. In primary prevention, cholesterol-lowering agents have not reduced the mortality rates, for example, the AFCAPS/TexCAPS and EXCEL trials and the 2 main trials with atorvastatin, Lipitor, as in the ASCOT and SPARCL studies. Dietary changes to achieve benefit have been more controversial, in general, far less effective and less widely adhered to with success.

Lowering homocysteine levels, including within the normal range and dietary supplements of Omega-3 oils, especially those from the muscle of some deep salt water living fish species, also have clinical evidence of significant protective effects as confirmed by 6 double blind placebo controlled human clinical trials.

High dose supplements of vitamin E or C, with the goal of improving antioxidant protection, have failed to produce any beneficial trends in human, double blind, clinical research trials. However, these trials have consistently used lower doses than those claimed to be effective and have ignored the short half-life of high intakes of vitamin C in the body.

Surgical intervention
Other physical treatments, helpful in the short term, include minimally invasive angioplasty procedures 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.

Prophylaxis
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, the treatments which focus on decreasing the underlying atherosclerosis processes, as opposed to simply treating the symptoms resulting from the atherosclerosis, have been shown by clinical trials to be 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. However, treating asymptomatic people remains controversial in the medical community.

Recent research
Methods to increase high-density lipoprotein (HDL) particle concentrations, which in some animal studies largely reverses and remove atheromas, are being developed and researched. Niacin has HDL raising effects (by 10 - 30%) and showed clinical trial benefit in the Coronary Drug Project; however, the drug torcetrapib most effectively raising HDL (by 60%) also raised deaths by 60%, and all studies regarding this drug were halted in December 2006.

An indication of the role of HDL on atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of this HDL protein. Ongoing work starting in the 1990s may lead to human clinical trials probably by about 2008, on using either synthesized Apo-A1 Milano HDL directly or gene-transfer methods to pass the ability to synthesize the Apo-A1 Milano HDL protein.

The ASTEROID trial used a high-dose of a powerful statin, rosuvastatin, and found plaque (intima + media volume) reduction; see the Effect of Very High-Intensity Statin Therapy reference below. No attempt has yet been made to compare this drug with placebo regarding clinical benefit.

Since about 2002, progress in understanding and developing techniques for modulating immune system function so as to significantly suppress the action of macrophages to drive atherosclerotic plaque progression are being developed with considerable success in reducing plaque development in both mice and rabbits. Plans for human trials, hoped for by about 2008, are in progress. In general, these techniques are termed immunomodulation of atherosclerosis.

Genetic expression and control mechanism research, including (a) the PPAR peroxisome proliferator-activated receptors known to be important in blood sugar and variants of lipoprotein production and function and (b) of the multiple variants of the proteins that form the lipoprotein transport particles, is progressing.

Some controversial research has suggested a link between atherosclerosis and the presence of several different nanobacteria in the arteries, e.g., Chlamydophila pneumoniae, though trials of current antibiotic treatments known to be usually effective in suppressing growth or killing these bacteria have not been successful in improving outcomes.

The immunomodulation approaches mentioned above, because they deal with innate responses of the host to promote atherosclerosis, have far greater prospects for success.