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.
Pathologically, the atheromatous plaque
is divided into three distinct components:
- The atheroma ("lump of porridge", from Athera, porridge in Greek,) 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.
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 (in 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.
Alternatively, 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, e.g. 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 also occur 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 who 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, over emphasizes lumen narrowing as opposed to compensatory external diameter
enlargement (at least within smaller, e.g. heart arteries) typical of the atherosclerosis process as it progresses, see Reference
1, Glagov S, below 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 generally only detects lumen narrowing of ~75%
or greater, although some physicians advocate 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 are made of excess fat, collagen, and elastin. Initially, 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.[1]
Visible features
Although arteries are not typically studied microscopically, two plaque types can be distinguished[2]:
- 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.
- 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 fibres (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, while 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
Microphotography of arterial wall with calcified (violet colour) atherosclerotic plaque (haematoxillin & eosin stain)
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 medial 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":
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.
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 which have proved 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).
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 evaluation,[3] see the Effect of Very High-Intensity Statin Therapy reference below. 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 which demonstrate improved outcome for those people using more complex
and effective treatment regimens which change physiologic behaviour patterns to more closely resemble those humans exhibit in
childhood at a time before fatty streaks begin forming.
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 and 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, generally far less effective and less widely adhered to with
success.
Evidence has increased that people with diabetes, despite not having clinically
detectable atherosclotic disease, have more severe debility from atherosclerotic events over time than even non-diabetics who
have already suffered atherosclerotic events. Thus diabetes has been upgraded to be
viewed as an advanced atherosclerotic disease equivalent.
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.
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.
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 which go
around the more severely narrowed areas.
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. [citation needed]
On the other hand, 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 who had Diabetes Mellitus, the mortality rate reduction between statin
and placebo was 54%. 4S was a 5.4 year trial which 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, mentioned above and in reference 3, 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.
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. Additionally, 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.
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[4] to propose a Polypill, a
once-daily pill containing these two types of drugs in addition to an ACE inhibitor,
diuretic and 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.
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.[3]
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 by 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. Generally 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 which 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.
References
- ^ Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis
GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N
Engl J Med 1987;316:131-1375. PMID
- ^ Deepak L. Bhatt, MD;
Eric J. Topol, MD Need to Test the Arterial Inflammation Hypothesis, 2002, referenced on 4/1/06
- ^ [1], "Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis".
- ^ Wald NJ, Law MR. A strategy to reduce cardiovascular
disease by more than 80%. BMJ 2003;326:1419. PMID.
5. Stevens, Karen M.J. Douglas, Athanasios N. Saratzis and George D. Kitas Inflammation and atherosclerosis in rheumatoid
arthritis Robert J. Expert Rev. Mol. Med. Vol. 7, Issue 7
6. Mol, A 2002 _The Body Multiple: Ontology in medical practice_ London: Duke University Press
External links
See also
