Atheroma

Atheroma
Specialty	Cardiology

An atheroma (plural: atheromata) is an abnormal inflammatory accumulation of macrophage white blood cells within the walls of arteries. These anatomic lesions typically begin in later childhood, well before age 10, and progress over time. Veins do not develop atheromata, unless surgically moved to function as an artery, as in bypass surgery. The accumulation is always between the endothelium lining and the smooth muscle wall of the arterial tube. While the early stages, based on gross appearance, have traditionally been termed fatty streaks by pathologists, they are not composed of fat, i.e. adipose cells. In the context of heart or artery matters, atheroma are commonly referred to as "plaque" in modern laguage.

Collectively, the process of atheroma development within an individual is called atherogenesis and the overall result of the disease process is termed atherosclerosis.

Stages

In humans, atheroma usually begin in later childhood, about ages 5-9, as fatty streaks. These, and older, larger atheroma lesions have long been observed in autopsy examinations of people who have died for unrelated reasons; they are so common, more so with increasing age, they were long considered normal, even though clearly unhealthy.

More advanced atheroma develop multiple different internal tissue characteristics within the same atheroma. By light microscopy visualization, pathologists have characterized as many as 10 different tissue subtypes within a single advanced atheroma. Generally, these range from collections of macrophage cells, always the initiating cells in the newest sections of atheroma, to more complex structures including living cells, cellular debris of cells which have died and extracelluar deposits of fibrous tissue & calcified crystals, within the oldest, outermost portions of atheroma structures.

Atheroma typically progress silently for decades and remain undetected by most clinical diagnostic approaches, including cardiac stress testing and angiography. Eventually, their presence is revealed by disastrous clinical events and permanent disability, such as heart attack or stroke, with the majority of people assuming they were healthy until finally proven otherwise by events. For some individuals, warning symptoms do occur before the onset of major debility or death, however these are the minority.

Historically physicians, who are primarily trained to treat symptoms and avoid treatment before onset of clear enough symptoms and physical abnormalities, have just considered the process a normal part of ageing, even though unhealthy.

Difficulty of Tracking, Researching and Better Understanding Atheroma

For most people the first clinical symptoms result from atheroma progression within the heart arteries, most commonly resulting in a heart attack and ensuing debility. However, the heart arteries, because (a) they are small (from about 5 mm down to invisible), (b) they are hidden deep within the chest and (c) they never stop moving, have been a difficult target organ to track, especially clinically in individuals who are still asymptomatic. Additionally all mass applied clinical strategies focus on both (a) minimal cost and (b) the overall safety of the procedure. Therefore existing diagnostic strategies for detecting atheroma and tracking response to treatment have been extremely limited. The methods most commonly relied upon, patient symptoms and cardiac stress testing, do not detect any symptoms of the problem until atheromatous disease is very advanced.

Evolving Concepts and Understanding

In First World countries, with improved public health, infection control and increasing life spans, atheroma processes have become an increasingly important problem and burden for society. Atheroma continue to be the number one underlying basis for disability and death, despite a trend for gradual improvement since the early 1960s (adjusted for patient age). Thus, increasing efforts towards better understanding, treating and preventing the problem are continuing to evolve.

In the mid-twentieth century, it was assumed (incorrectly) that atheromata simply expanded into the lumen and produced stenoses as they grew, since the disease always developed between the inner endothelial lining and the muscular wall. This belief was based on angiography views of the blood column within arteries and a belief that the smooth muscle wall of an artery (the thickest and strongest portion of the artery wall in a healthy artery) would not change in size and structure over time. This belief continued despite increasing contradicting evidence that this was an overly simplistic theory and did not explain many empiric observations. Most artists' illustrations of atheromata and the atherosclerosis process in 2004 still portray this concept, even though quite incorrect. By the late 1980s and early 1990s, careful pathology work and research using intravascular ultrasound (IVUS) showed clearly that this angiographic assumption was incorrect.

Since the early to mid 1990s, better research has led to a somewhat wider recognition that one of two changes typically occur in the artery wall structure as an atheroma develops and progresses: (a) wall thickening and external enlargement with associated lumen preservation until late in the process; or (b) wall thickening with both external and lumen enlargement. These processes both have survival value, as they reduce and hide some of the effects of the atheroma process and help prevent symptoms, for a time. However they also prevent detection of the disease process by most conventional diagnostic tests, (e.g. cardiac stress tests and angiography), until advanced stages.

According to United States data, 2004, for about 65% of men and 47% of women, the first symptom of cardiovascular disease is heart attack or sudden death (death within one hour of symptom onset.)

Most artery flow disrupting events occur at locations with less than 50% lumen narrowing. From elegantly performed clinical studies published in the late 1990s, and using IVUS to better visualize disease status, the typical heart attack occurs at locations with about 20% stenosis, prior to sudden lumen closure and resulting heart attack. 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 sometimes detect as little as 50%.

Actual Artery/Atheroma Behavior:

1. External Artery Enlargement; Eventual Possible Stenosis and/or Closure

Over time, atheroma usually progress in size and thickness and induce the surrounding muscular wall of the artery to stretch out, termed remodeling, typically just enough to compensate for their size such that the opening of the artery remains unchanged until typically over 40-50% of the artery wall cross sectional area consists of atheromatous tissue (see: Glasgov, below).

If the muscular wall enlargement eventually fails to keep up with the enlargement of the atheroma volume, then the lumen of the artery begins to narrow, commonly as a result of repeated ruptures of the covering tissues separating the atheroma from the blood stream. This becomes a more common event after decades of living, increasingly more common after people are over 40 years old.

If a rupture occurs, a rupture of the endothelium and covering tissue, termed fibrous cap, which separates an atheroma from the blood in the lumen, then a platelet and clotting response over the rupture rapidly develops. Additionally, the rupture may result in a shower of debris. Platelet and clot accumulation over the rupture may produce narrowing/closure of the lumen and tissue damage may occur due to either closure of the lumen and loss of blood flow beyond the ruptured atheroma and/or by occlusion of smaller downstream vessels by debris. See vulnerable plaque.

This is the principal mechanism of heart attack, stroke or other related cardiovascular disease problems. As research has shown, this process is not a result of stenosis. Prior to the rupture, there may have been no lumen narrowing, even aneurysmal enlargement, at the atheroma. On average, by clinical research using IVUS, there is a minor stenosis, about 20%, present over those unstable atheroma which rupture and result in major disability or death. Comparatively, stenoses of about 75% are required to produce detectable abnormalities during cardiac stress tests.

2. External Artery Enlargement and Lumen Enlargement

If the muscular wall enlargement is overdone over time, then a gross enlargement of the artery results, usually over decades of living. This is a less common outcome. Atheroma within aneurysmal enlargement can also rupture and shower of debris of atheroma and clot downstream. If the arterial enlargement continues to 2 to 3 times the usual diameter, the walls often become weak enough that with just the stress of the pulse, a loss of wall integrity may occur leading to sudden hemorrhage, major symptoms and debility; often rapid death. The main stimulus for aneurysm formation is pressure atrophy of the underlying muscle layers. This causes thinning and the weaker wall balloons allowing gross enlargement to occur.

Evolution of Strategies and Changing Focus

The sudden nature of the complications of pre-existing atheroma, vulnerable plaque, have led, since the 1950s, to the development of intensive care units and complex medical and surgical interventions. Angiography and later cardiac stress testing was begun to either visualize or indirectly detect stenosis. Next came bypass surgery, to plumb transplanted veins, sometimes arteries, around the stenoses and more recently angioplasty, now including stents, most recently drug coated stents, to stretch the stenoses more open.

Yet despite these medical advances, with success in reducing the symptoms of angina and reduced blood flow, atheroma rupture events remain the major problem and still sometimes result in sudden disability and death despite even the most rapid, massive and skilled medical and surgical intervention available anywhere today. According to some clinical trials, bypass surgery and angioplasty procedures have had only a minimal effect, some would argue no effect, on improving overall survival. Additionally, these treatments are often done only after an individual is symptomatic, often already partially disabled, as a result of the disease.

The older methods for understanding atheroma, dating to before WWII, relied on autopsy data. Autopsy data has long shown initiation of fatty streaks in later childhood with slow asymptomatic progession over decades.

Since the later 1980s, the best way to see atheroma and better understand atheroma behaviour in living individuals has been IVUS technology. Angiography does not visualize atheroma; it only makes the blood flow within blood vessels visible. Alternative methods that are non or less physically invasive and less expensive per individual test have been used and are continuing to be developed, such as those using computed tomography (CT; lead by the EBT form given its greater speed) and magnetic resonance imaging (MRI). The most promising since the early 1990s has been EBT, typically detecting and recognizing advanced calcification within the base of atheroma about 10 years before most individuals start having clinically recognized symptoms and debility. However, though these methods are used in research, they are not widely available to most patients, still have mild to significant technical limitations, have not been widely accepted and generally are not covered by medical insurance carriers.

From human clinical trials, it has become increasingly evident that a more effective focus of treatment is slowing, stopping and even partially reversing the atheroma growth process. However, this effort has been slow, partly because the asymptomatic nature of atheromata make them especially difficult to study.

Additionally, understanding what drives atheroma development is complex with multiple factors involved, only some of which, such as lipoprotein patterns, blood sugar levels and hypertension are best known and researched. More recently, some of the complex immune system patterns that promote, or inhibit, the inherent inflammatory macrophage triggering processes involved in atheroma progression are slowly being better elucidated in animal models of atherosclerosis.

Treatment Options

Many approaches, including food choices, staying slender (especially in the abdominal area), aerobic exercise and many different supplements have been promoted as methods to reduce atheroma progression. For most people, changing their internal physiologic behaviors, mostly hidden within, from the usual ones which promote atheroma progression (i.e. high risk, meaning high event rates for symptomatic cardiovascular disease) to reduced risk, requires a combination of strategies, including taking several compounds, 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 behavior patterns to more closely resemble those which humans more commonly exhibit in childhood at a time before fatty streaks begin forming. Calculated LDLipoprotein cholesterol levels at this time of life are usually in the 20 to 40 mg/dL range, far below what are usually considered "normal" adult concentrations.

The group of medications referred to as statins, originally discovered in 1972 by a Japanese researcher as a compound produced by certain strains of fungi, e.g. Aspergillus terreus, Monascus ruber and Monascus purpureus, have been the most successful single approach, with the lowest rates of undesirable side-effects, to reducing atherosclerotic disease events. However, current research evidence continues to support using a combination of several approaches, including: (a) food choices, (b) abdominal fat reduction, (c) low normal blood glucose levels (glycosylated hemoglobin, also called HbA1c, values < 5.0), (d) aerobic exercise and (e) supplements (most Rx, some OTC) to improve the odds of maintaining better health with absence of either symptoms or worse, catastrophic disease events.

Use of the newest approved statin within the United States market, rosuvastatin, especially as an addition to several other treatment strategies, has been the first to demonstrate regression of atherosclerotic plaque within the coronary arteries by IVUS evaluation. See the [|ASTEROID] trial, especially page 8, which shows a single IVUS image view of one individual's heart artery before and after about 2 years of 40 mg/day treatment; the total wall volume is reduced to about half due to a major decrease in the volume of atheroma.

References

• Steven Glasgov: Compensatory Enlargement of Human Atherosclerotic Coronary Arteries, N Engl J Med, 316:131-1375, 1987
• Nissen, et. all. Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis JAMA. 2006;295:(doi:10.1001/jama.295.13.jpc60002)[1], publication pending

See also

• Atherogenesis
• Atherosclerosis
• Artery
• Heart
• Coronary circulation
• Coronary catheterization
• Angiogram
• IVUS
• EBT
• Lipoprotein
• LDL, HDL, IDL and VLDL