atHerosClerosis -- heaRth disEase

Atherosclerosis

Atherosclerosis
Classification & external resources


Changes in endothelial dysfunction in atherosclerosis (note text comments about geometry error)
ICD-10
I70.

ICD-9
440

DiseasesDB
1039

MedlinePlus
000171

eMedicine
med/182

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:
1. 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.
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 (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


Severe atherosclerosis of the aorta. Autopsy specimen.
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.
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.

large valve

Large heart valves – small heart valves

What´s the difference?

The heart is a muscular pump. It keeps the blood circulating through the body through its continuous pumping action, allowing the blood to supply the organs with nutrients and oxygen. The left side of the heart pumps blood that is rich in oxygen, while the right side receives blood that is low in oxygen from the veins and pumps it to the lungs to be re-oxygenated. The left and right sides of the heart each consist of two chambers: the upper chamber or atrium, and the lower, main chamber, the ventricle. The atria are thin-walled and serve primarily as reservoirs for blood received from the body and lung, while the two ventricles each have a thick, muscular wall that is responsible for most of the pumping action.

What the four heart valves do?

The four heart valves stand guard at the entry and exit points of the chambers, and keep the blood flowing in one direction. Oxygen-depleted venous blood from the body arrives at the right atrium via the inferior and superior vena cava, passes through the tricuspid valve into the right ventricle, and then from there via the pulmonal valve into the pulmonary artery and the lung, where it is enriched with oxygen and passed back to the left atrium. From the left atrium it flows through the mitral valve into the left ventricle and is pumped through the aortic valve into the aorta, and hence through the systemic circulation.
In a lifetime these valves will open and close more than two billion times.
The four heart valves act like doors which open and close in concert to keep the blood moving in one direction. They consist of flexible, thin but extremely robust flaps of tissue which have to withstand stretching and pressure with every heartbeat.
Each day the human heart beats approximately 100,000 times. In a lifetime this amounts to more than two billion heartbeats.
One or more heart valves can be affected by disease to the point where the flow of blood through the heart is compromised. In the advanced stage of valvular disease, intervention with a cardiac catheter or a heart operation is the only way of remedying this situation.



Mechanical heart valves are minor miracles
Prosthetic heart valves differ from one another in their properties, including their durability, their thrombogenicity (formation of small numbers of thrombi), their haemodynamic profile (the way blood behaves as it passes through the heart valve) and the amount of noise they generate. Since most implanted heart valves are of the mechanical variety, we will deal only with this type of valves.
Mechanical replacement heart valves can be divided into those with peripheral blood flow (where blood flows along the inside edge of the valve) and those with central blood flow (where blood flows through the middle).
Mechanical prostheses with a central closing mechanism and peripheral blood flow are divided into two groups: the caged-ball prosthesis (Starr-Edwards, Smeloff-Cutter) and the caged-disk prosthesis, which is now no longer manufactured.
The caged-ball prosthesis – a first-generation mechanical heart valve with peripheral blood flow – consists of a metal ring and 3 or 4 symmetrically arranged metal struts forming the cage. The ring and struts consist of a polished chromium / nickel / cobalt / molybdenum alloy (stellite). The sewing ring consists of a teflon-polypropylene mesh enveloping the metal ring except for its inner surface which is exposed to the flow of blood. The poppet is a silicone rubber ball impregnated with barium sulphate (2 % by weight).



Mechanical prostheses with central blood flow have tilting disks or bileaflets as the closing system.
Construction of a bileaflet prosthesis; here from St. Jude Medical heart (with central blood flow):

The closing mechanism consists of a graphite core impregnated with tungsten (5-10 % by weight) in order to afford some contrast on x-rays. The graphite core is completely enveloped in pyrolite (carbon). The mounting consists of pyrolite. The closing mechanism is formed by two biplanar semicircular leaflets which, in the closed position, form an obtuse angle of 120° and, when fully opened, are at an angle of 85% to the ring plane. The sewing ring by which the valve is attached in the appropriate position consists of dacron-velours.

Construction of a mono-tilting disk prosthesis, or simply tilting-disk prosthesis; here from Medtronic Hall (with central blood flow):

The circular, biplanar tilting disk consists of pyrolite with a circular central opening and x-ray contrasting impregnation – similar to the tilting disks from St. Jude Medical. The housing and mounting mechanism for the tilting disk are made of titanium (from a single cast). The mounting allows the tilting disk to rotate freely. As it opens, the closing mechanism moves along a raised hook passing through the centre of the disk. In the mitral position this tilting disk has an opening angle of 70° and, in the aortic position, of 75° to the ring plane.

Mechanical heart valves come in different sizes
The valves described come in different sizes. This is all to do with the fact that people of different sizes have variously sized heart valves. Prosthetic heart valves are manufactured in sizes ranging from 19 mm to a maximum size of 31 or 33 mm.

How is valve size measured?
The size quoted for a valve is its external diameter with the sewing ring compressed. An over-size sewing ring is to the detriment of the internal diameter determining the absolute flow rate. Manufacturers of mechanical heart valves are interested, therefore, in achieving maximum blood flow with each size of valve, in order to simulate as closely as possible the situation that existed prior to surgery.
When a heart surgeon replaces a diseased heart valve, he usually removes the diseased areas of tissue and replaces it with an implant as described above.
When choosing the size of a mechanical or biological heart valve, the heart surgeon looks at the size of the annulus (ring) which is created when the human heart valve is excised – i.e. the size of the patient’s natural heart valve.
Manufacturers of prosthetic heart valves have instruments that reproduce the dimensions of the valve, so that it is possible during the operation to determine the size of valve to be implanted. Valve sizes are in mm. .
What effect does the size of the heart valve have on the subsequent course of events?

The heart’s pumping action is measured in terms of the difference in pressure that exists ahead of the prosthetic heart valve compared to the pressure behind it. This pressure gradient is on average between 10 and 20 mmHg. A natural heart valve does not, however, produce any significant pressure gradient ahead of and after the valve. Based on the size of the heart valve it is possible to calculate the pumping force of the heart.
• The larger the internal diameter of the heart valve, the smaller is the force needed to pump the blood.
• The smaller the annulus, the greater is the necessary pumping force of the heart.
• Raised blood pressure causes an increase in the rate of blood flow.
Why patients hear heart valve noises

The annulus of the prosthetic heart valve forms an unnatural barrier to blood flow. This is the reason why there are always slight turbulences behind the mechanical valve in aortic or mitral position. In the same way as with a swollen stream, greater turbulences occur as the flow of blood increases through the artificial valve. Not only the cardiologist can pick this up on his stethoscope; sometimes the wearer himself can hear the blood flowing and the tilting disks opening and closing – even without a stethoscope.
Virtually every mechanical heart valve is responsible for creating a certain level of noise. Often the noise decreases as the size of heart valve increases. In addition to noise actually produced by the valve, the human body’s so-called “resonance board” itself plays a role in propagating the noises produced in the mechanical heart valve. It is understandable, therefore, that patients perceive the noises differently.Based on life quality data obtained in the ESCAT study, it was found that approximately 10% of patients are bothered immediately post-operatively by the heart valve noise. Of this patient collective 80% become accustomed to the noise; only 20% of the collective, i.e. 2% of all patients who have undergone replacement mechanical heart valve surgery, find the noise bothersome. Women suffer more from the valve noise than men. In particular the 20-to-30 age group and the 40-to-50 age group develops a strong aversion to the heart valve noise.
What are the advantages of a mechanical heart valve?

The advantage of a mechanical heart valve is the fact that it will last almost forever and that it has flow characteristics that closely approximate those of natural heart valves. With long-term oral anticoagulant medication, thrombogenesis (formation of thrombi) by the heart valves no longer has any role to play.
Other ESCAT study results showed that, with anticoagulation self-management, the incidence of thrombus formation in the first 2 years is just 0.2% per patient year. This is a very low complication rate.

PD Dr. med. Heinrich Koertke, Heart- and Diabetes-Center North-Rhine Westphalia, Georgstr. 11, 32545 Bad Oyenhausen (Germany) (2004).