Which of the following is most related coronary heart disease ?(AIIMS Nov 2010)
a. A large body of evidence supports a direct relationship between LDL cholesterol and the rate of CHD. This includes within-population studies (i.e., Framingham and MRFIT) and between-population studies (i.e., Seven Countries).
b. Familial hypercholesterolemia, a genetic disorder characterized by high levels of LDL cholesterol, has an exceedingly high rate of premature atherosclerosis. Animals with both spontaneous and diet-induced hypercholesterolemia develop lesions similar to human atherosclerosis.
c. There are four major subtypes of lipoproteins which vary in size, density, protein and fat content. Chylomicrons and Very Low Density Lipoproteins (VLDL) are the least dense lipoproteins and are comprised primarily of a triglyceride rich core.
d. Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL) are the smallest and most dense lipoproteins and contain a core comprised primarily of cholesterol.
e. While circulating through the peripheral tissues, both the chylomicrons and VLDL are acted upon by the adipose tissue and muscle by the enzyme lipoprotein lipase which removes triglyceride from these particles for storage in fat or energy consumption in muscle.
f. In this manner, the chylomicron is transformed into a cholesterol-rich remnant particle that is removed from the circulation by the liver through the action of a specific remnant receptor.
g. VLDL is likewise transformed into a cholesterol-rich remnant particle which can be removed by the liver or further metabolized to the more cholesterol rich LDL particleby the action of hepatic lipase.
h. A specific LDL receptor is responsible for the uptake of both the VLDL remnants and LDL particles. As VLDL is metabolized by lipoprotein lipase it is left with excess surface coat as its core diminishes in size.
i. In exchange for surface coat, HDL transfers cholesterol esters to VLDL by the action of Cholesterol Ester Transfer Protein (CETP).
j. The exchanged surface coat allows the HDL particle to continue to absorb cholesterol and grow in size while the exchanged cholesterol ester can then be taken up by the liver as the VLDL remnant particles are metabolized.
k. This represents one of the two mechanisms by which HDL can remove cholesterol from tissues.
l. The other mechanism involves direct uptake of the HDL particle by the liver.
m. The frequency of this gene in the population is ~ 1/500. Individuals with Homozygous Familial Hypercholesterolemia have no functional LDL receptors, have extremely high LDL levels, i.e., 1000 mg/dl and develop atherosclerosis in their teens.
n. The frequency of this disease is 1/1,000,000. The first step in atherogenesis is the infiltratio and entrapment of Low Density Lipoprotein (LDL) in the blood vessel wall. Ground substances such as the glycosaminoglycans (GAGs) have a high affinity for the apo B-100 of the LDL.
o. Other particles containing apo B-100, i.e., VLDL remnants (IDL) are probably atherogenic as well. Chylomicron remnants which contain the truncated form of apo B, apo B-48 may also become similarly involved.
p. Once entrapped in the vessel wall, LDL undergoes modification through oxidation, dramatization or glycosylation. Initially, when minimally modified, endothelial cells react by secreting a chemotactic substance which attracts monocytes to the area.
q. Monocytes then migrate through the vessel wall, transform into macrophages which then begin digesting the LDL particles as they becomes more oxidized.
r. The macrophage lacks the ability to autoregulate the uptake of modified LDL. Modified LDL is cytotoxic and inhibits further migration of the macrophage out of the vessel.
s. Eventually the cytoplasm of the cell is packed with lipid. When a slide preparation is made through an area with nests of these cells, as in a fatty streak, the lipid is removed leaving a foamy like appearance.
t. Fatty Streaks are smooth raised plaques located beneath the endothelium. They represent the initial phase of atherosclerosis.
u. They occur early in life and are present in teen-agers. They are composed primarily of foam cells (lipid laden macrophages) and may regress, remain dormant or progress to a more complicated atherosclerotic lesion.
v. The fibrous plaque represents the second phase. As the fatty streak progresses, smooth muscle cells (not normally present in the subendothelial space) migrate from the media to the subendothelial space where they proliferate and produce connective tissue to form a fibrous cap.
w. The final lesion to develop is the complicated lesion which can manifest calcification, hemorrhage, ulceration and thrombosis.
x. Antioxidant therapy may be useful in preventing atherosclerosis. By inhibiting the oxidation of LDL, chemotactic factors are not secreted thus preventing the migration of monocytes to the vessel wall and subsequent inflammatory reaction.
y. Reference: Franklin L. Murphy, MD, FACC, FACP; Clinical Cardiology and Internal Medicine, Clinical Professor of Medicine, UCLA School of Medicine
z. Although LDL-cholesterol continues to be the principal lipid factor for vascular risk, the atherogenic role of hypertriglyceridemia is today recognized.
aa. In the structured classification of lipid factors for cardiovascular risk, LDL-cholesterol continues to rank number one.
bb. However, increasing epidemiologic clinical and pathophysiological evidence suggest that certain types of hypertriglyceridemia (HTG) are dangerous for the arterial wall: thus some recommendations, which deal little with the role of HTG, would be insufficient.