Atherosclerosis -- Drug Companies - Pipeline Drugs -- Clinical Trials

Atherosclerosis

Atherosclerosis is a disease of arterial blood vessels. veins are not involved unless surgically moved to function as an artery. Atherosclerosis is commonly referred to as a "hardening of blood vessels", but this is an over-simplification. Vascular lesions known as atheromatous plaques or atheromata (singular: atheroma) are formed in the vessel wall, and in late stages may reduce or restrict blood flow in the lumen. When the inner covering of an unstable atheroma breaks, compromising the structural integrity of the internal artery wall, the break may allow hemorrhage into the plaque, generate stenosis, embolism, (very rarely even hemorrhage beyond the artery wall), sometimes leading to severe morbidity and even death.

Atherosclerosis typically begins in later childhood, is usually found in most major arteries, yet is asymptomatic and not detected by most diagnostic methods during life. 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.

According to United States data, 2004, for about 65% of men and 47% of women, the first symptom of atherosclerotic 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 (~20% stenosis is average). 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%.

Name

Athero is porridge in Latin, as the plaque changes have a foamy appearance under high power light microscopy. Sclerosis denotes hardening.

Atherogenesis

Atherosclerosis refers to the state of having many atheroma lesions present in many arteries. It is characterized by a remodeling of arteries involving an accumulation of macrophage cells forming atheroma or atheromatous plaques, which contain an excess of fatty cellular membranes within the arterial wall. The plaques are always located between the intima lining and muscular portion of the artery wall, typically without producing any narrowing, stenosis, of the artery opening, called the lumen.

In the most widely accepted mechanism of atherosclerosis pathogenesis, the resident cells within the artery wall seem to signal an intrusion, "call for help", an inflammation response. Monocytes, one of the 5 main types of white blood cells circulating in the blood, enter the artery wall. Within tissues, monocytes change characteristics and are called macrophages. The macrophages ingest oxidized cholesterol, slowly turning into large "foam cells" – so described because of the appearance numerous vesicles take on to accommodate their high lipid content. The early stages are called fatty streaks. Foam cells eventually die, and further propagate the inflammatory process.

Intracellular microcalcification deposits 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 wall by LDL particles (low density lipoprotein), especially by the smaller LDL particles, if they are plentiful, because they can pass through the intracellular gaps between the intima lining cells more easily. To attract and stimulate macrophages, the cholesterol must be released from the LDL particles and oxidized, a key step in the ongoing inflammatory process. Additionally, the macrophages must be unable to remove excess cholesterol fast enough, into functioning HDL particles (high density lipoprotein) to avoid becoming foam cells and dying. As of 2004, the only known mechanism by which macrophages can export excess lipid is into HDL particles.

A protective fibrous cap normally forms between the fatty deposits and the artery lining (the intima). These capped fatty deposits (called atheromas) produce enzymes which 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 and egg shaped, still with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an aneurysm is created.

This process of atheroma formation and progressive artery enlargement, or remodeling, usually starts in childhood and continues for many decades, thereby masking either symptoms or any evidence of the disease by any detection methods, such as angiography, which only evaluate the artery lumen.

In effect, small aneurysms of the muscular portion of the artery wall form aneurysms just large enough to hold the atheroma which 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, stiffening, of the artery as a whole.

The calcification deposits, after they have become sufficiently advanced, are partially visible by some high resolution X-Ray imaging systems 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 IVUS imaging.

Although the disease process tends to be slowly progressive over decades, in later stages, it also becomes unstable with repetitive sudden problems, most without obvious symptoms at the time of occurrence but some producing sudden major debility or death. These problems result from instability of the newer, soft atheromas with thinner/weaker fibrous caps.

If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, atheroma 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. Atheroma tissue fragments are very clot promoting; they attract blood platelet accumulation and activate the blood clotting system proteins. This leads to both clotting on the released debries and a clot temporary patch covering over the rupture with narrowing (stenosis) within the artery lumen. Though this is often a repetitive and progressive process over time, it is typically without symptoms until a severe enough event, in a critical enough location, occurs.

Fibrous cap ruptures usually result in only a partial narrowing, stenosis, of the artery lumen, a narrowing which usually partially re-opens with healing and regrowth of the intima lining. However, sometimes the combination of atheroma material release, bleeding into the atheroma bed, platelet accumulation and accumulation of blood clotting proteins quickly builds to the point of creating a complete, or near complete obstruction. The obstruction, either at the site of rupture, or as a result of debris sent downstream, impeeds adequate blood flow to cells downstream. Cells starved for adequate blood supply are injured and may die.

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 heart disease and cardiovascular disease in general. However, these methods focus only on detecting 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.

75% lumen stenosis used to be considered by cardiologists as the hallmark of clinically significant disease because it is 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, as of the later 1990s, greater attention is been focused on the vulnerable plaque.

Though any artery in the body can be involved, usually only severe narrowing or obstruction of some arteries, those which 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%.

Risk factors

These anatomic, physiological & behavioral risk factors for atherosclerosis are known:

documented atheroma in any artery (unfortunately not detected by most medical tests)
having diabetes or just upper normal blood glucose and insulin levels, even though not considered to be in the diabetes range (any glycosolated hemoglobin, HbA1c, above 5.0 according to a European trial reported in 2001)
dyslipidemia (cholesterol and triglyceride level disturbances):
- having a high blood concentration of low density lipoprotein (LDL, "bad cholesterol") particles, elevated lipoprotein little a, a variant of LDLipoproteins and very low density lipoprotein (VLDL) particles
- having a low concentration of functioning high density lipoprotein (HDL, "good cholesterol") particles. HDL particles can transport cholesterol from the tissues back to the liver, however they vary considerably in their actual performance.
higher fibrinogen blood concentrations
homocysteine in the upper half of the normal range, and especially elevated levels
aging and being male (women have more problems after menopause, but hormone replacement therapy worsens rather than improves the event rates)
tobacco smoking, even just once a day
having close relatives who had heart disease or a stroke at a relatively young age
having high blood pressure
having trouble managing stress, especially anger
being obese (especially central obesity, i.e. fat at waist level, especially intra-abdominal (around the intestines) more than subcutaneous fat
being physically less active, especially aerobic exercise
several internal chemical markers indicating ongoing inflammation may also relate to relative risk

these risk factors, judging from clinical trials, operate synergistically to promote earlier and more severe disease yet still miss many who become disabled from the consequences of atherosclerosis

Most humans develop atherosclerosis. Usually only "high-risk" patients are advised to change dietary choices, exercise, lose weight, take cholesterol-lowering mediation and lower blood sugar levels. Most of the proven, more effective cholesterol medications are only available by prescription. There is ongoing debate about what dietary changes are wisest and how to adjust these for different people.

Treatment

If atherosclerosis leads to symptoms, the symptoms (such as angina pectoris) can be treated. Medicines are usually the first step in treating cardiovascular diseases, and with improvements, have increasingly become the most effective method over the long term. However, medicines are critised 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 platelets, taking Omega 3 oils from salt-water fish meats, exercising and losing weight are the usual focus of treatments which have proved to be helpful in clinical trials.

Dramatic lowering of lipoprotein levels, including to very abnormally low levels for adults (especially of the smaller lipoprotein particles), and elevating the large particle (HDL) can slow, stop, or even partially reverse the buildup of plaque, as demonstrated in clinical trials. LDL lowering can reduce the macrophage and lipid content and size of unstable plaques, making them more stable and less prone to rupture. Lowering lipoprotein little a, a genetic variant of the LDLipoproteins, can be achieved with large daily doses of vitamin B3, niacin. Niacin also tends to shift LDLipoprotein particle distribution to larger particle size and improve HDLipoprotein 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 improving clinical outcomes. Dietary changes to achieve this 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.

Aerobic exercise, weight loss, and dietary changes can also help in major ways, but are often more problematic for many to achieve and continue long term.

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.

Unfortunately, high dose supplements of vitamin E and/or C, with the goal of improving antioxidant protection, have failed to produce any beneficial trends in human, double blind, clinical research trials. On the other hand, the statins, and some other medications have been shown to have significant antioxidant effects, perhaps part of their basis for theraputic success.

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 (2003) 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%.

Recent research

Progress on methods to improve HDLipoprotein particle concentrations and function, which in some animal studies largely reverses and remove atheromas, are being developed and researched. The most dramatic demonstrations of potential HDL efficacy to reverse atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of the HDL protein.

Genentic 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 with the proteins which form the lipoprotein transport particles, is progressing.

Some controversial research has suggested a link between atherosclerosis and the presence of nanobacteria in the arteries, though trials of current antibiotic treaments have not been successful in improving outcomes. If this suspicion should be verified in further research, then additional bases for inflammation and options for treatment of the disease may be found.

References