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ScienceWeek
MEDICAL BIOLOGY: INFLAMMATION AND CORONARY ARTERY DISEASE
The following points are made by Göran K. Hansson (New Engl. J. Med. 2005 352:1685):
1) Recent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. Atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree.
2) A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world.[1] Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.
3) Atherosclerotic lesions (atheromata) are asymmetric focal thickenings of the innermost layer of the artery, the intima. They consist of cells, connective-tissue elements, lipids, and debris.[2] Blood-borne inflammatory and immune cells constitute an important part of an atheroma, the remainder being vascular endothelial and smooth-muscle cells. The atheroma is preceded by a fatty streak, an accumulation of lipid-laden cells beneath the endothelium.[3] Most of these cells in the fatty streak are macrophages, together with some T cells. Fatty streaks are prevalent in young people, never cause symptoms, and may progress to atheromata or eventually disappear.
4) In the center of an atheroma, foam cells and extracellular lipid droplets form a core region, which is surrounded by a cap of smooth-muscle cells and a collagen-rich matrix. T cells, macrophages, and mast cells infiltrate the lesion and are particularly abundant in the shoulder region where the atheroma grows.[2,4,5] Many of the immune cells exhibit signs of activation and produce inflammatory cytokines.[5] Myocardial infarction occurs when the atheromatous process prevents blood flow through the coronary artery. It was previously thought that progressive luminal narrowing from continued growth of smooth-muscle cells in the plaque was the main cause of infarction. Angiographic studies, however, have identified culprit lesions that do not cause marked stenosis, and it is now evident that the activation of plaque rather than stenosis precipitates ischemia and infarction. Coronary spasm may be involved to some extent, but most cases of infarction are due to the formation of an occluding thrombus on the surface of the plaque.
References (abridged):
1. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349:1436-1442
2. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92:1355-1374
3. Stary HC, Chandler B, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994;89:2462-2478
4. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986;6:131-138
5. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1084-1088
New Engl. J. Med. http://www.nejm.org
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ON LDL-CHOLESTEROL AND CORONARY HEART DISEASE
The following points are made by J.L. Goldstein and M.S. Brown (Science 2001 292:1310):
1) Low density lipoprotein (LDL), the major cholesterol-carrying lipoprotein in human plasma, is the offending agent in coronary heart disease, which causes one-third of all deaths in the US. Originally, LDL was implicated in heart disease through epidemiologic and genetic observations in humans and animal models, and its involvement has now been confirmed by the recent and repeated demonstration that LDL-lowering drugs, called statins, reduce heart attacks and prolong life.
2) In general, LDLs are composed of spherical particles with an average diameter of 22 nanometers. The average LDL particle contains a hydrophobic core of approximately 1500 molecules of cholesteryl ester surrounded by a polar coat composed primarily of phospholipids and a 513-kilodalton protein called apolipoprotein B-100. LDLs circulate in human plasma with a mean life-span of 2.5 days.
3) Important questions for research are a) What determines the amount of LDL in plasma? and b) Why do so many people have enough LDL to cause heart attacks? In medicine, common problems are often solved by studies of uncommon genetic diseases. In the case of LDL, answers have emerged from unraveling the aberrant genes underlying four rare genetic disorders that elevate plasma LDL and cause premature heart attacks, with the final two molecular defects of this quartet described only several years. Remarkably, all four defects raise the amount of plasma LDL by impairing the activity of liver (hepatic) LDL receptors that normally clear LDL from plasma.
Science http://www.sciencemag.org
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GENOMIC MEDICINE: CARDIOVASCULAR DISEASE
The following points are made by Elizabeth G. Nabel (New Engl. J. Med. 2003 349:60
1) Cardiovascular disease, including stroke, is the leading cause of illness and death in the US. There are an estimated 62 million people with cardiovascular disease and 50 million people with hypertension in the US. In 2000, approximately 946,000 deaths were attributable to cardiovascular disease, accounting for 39 percent of all deaths in the US. Epidemiologic studies and randomized clinical trials have provided compelling evidence that coronary heart disease is largely preventable. However, there is also reason to believe that there is a heritable component to the disease. As future genomic discoveries are translated to the care of patients with cardiovascular disease, it is likely that what we can do will change.
2) Our understanding of the mechanism by which single genes can cause disease, even though such mechanisms are uncommon, has led to an understanding of the pathophysiological basis of more common cardiovascular diseases, which clearly are genetically complex. This point can be illustrated by a description of the genetic basis of specific diseases.
3) Low-density *lipoprotein (LDL) is the major cholesterol-carrying lipoprotein in plasma and is the causal agent in many forms of coronary heart disease. Four monogenic diseases elevate plasma levels of LDL by impairing the activity of hepatic LDL receptors, which normally clear LDL from the plasma. Familial hypercholesterolemia was the first monogenic disorder shown to cause elevated plasma cholesterol levels. The primary defect in familial hypercholesterolemia is a deficit of LDL receptors, and more than 600 mutations in the LDLR gene have been identified in patients with this disorder. One in 500 people is *heterozygous for at least one such mutation, whereas only 1 in a million is *homozygous at a single locus. Those who are heterozygous produce half the normal number of LDL receptors, leading to an increase in plasma LDL levels by a factor of 2 or 3, whereas LDL levels in those who are homozygous are 6 to 10 times normal levels. Homozygous persons have severe coronary *atherosclerosis and usually die in childhood from *myocardial infarction.
4) Deficiency of lipoprotein transport abolishes transporter activity, resulting in elevated cholesterol absorption and LDL synthesis. For example, mutations in the APOB-100 gene, which encodes apolipoprotein B-100, reduce the binding of apolipoprotein B-100 to LDL receptors and slow the clearance of plasma LDL, causing a disorder known as familial ligand-defective apolipoprotein B-100. One in 1000 people is heterozygous for one of these mutations; lipid profiles and clinical disease in such persons are similar to those of persons heterozygous for a mutation causing familial hypercholesterolemia.
5) Sitosterolemia, a rare *autosomal disorder, results from loss-of-function mutations in genes encoding two ATP-binding cassette (ABC) transporters, ABC G5 and ABC G8, which act in concert to export cholesterol into the intestinal lumen, thereby diminishing cholesterol absorption. Autosomal recessive hypercholesterolemia is extremely rare (prevalence, less than 1 case per 10 million persons). The molecular cause is the presence of defects in a putative hepatic adaptor protein, which then fails to clear plasma LDL with LDL receptors. Mutations in the gene encoding that protein (ARH) elevate plasma LDL to levels similar to those seen in homozygous familial hypercholesterolemia.(1-5)
References (abridged):
1. NHLBI morbidity and mortality chartbook, 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, May 2002
2. NHLBI fact book, fiscal year 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, February 2003
3, Cooper R, Cutler J, Desvignes-Nickens P, et al. Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the National Conference on Cardiovascular Disease Prevention. Circulation 2000;102:3137-3147
4. Goldstein JL, Brown MS. The cholesterol quartet. Science 2001;292:1310-1312
5. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic & molecular bases of inherited disease. 8th ed. Vol. 2. New York: McGraw-Hill, 2001:2863-913
New Engl. J. Med. http://www.nejm.org
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