Atherosclerosis

hardening of the arteries due to the deposition of atheromas heart disease is the leading cause of death caused by the deposition of cholesteryl esters on the walls of arteries atherosclerosis is correlated with high LDL and low HDL

Photograph of an arterial plaque

blood vessel lumen

endothelial cells

elastic lamina

smooth muscle cells

Cell layers adjacent to the lumen of arterial blood vessel.

Development of an atherosclerotic plaque: Various conditions can initiate formation of a lesion in the endothelium lining the arterial lumen.  Inflammatory response, including cytokine production that may be activated by oxidized lipids present in LDL.  Risk factors include elevated circulating LDL, high blood pressure, exposure to nicotine, etc.

blood vessel lumen

endothelial cells

elastic lamina

smooth muscle cells

Monocytes in the blood adhere to endothelial cells at sites of injury/inflammation, & then pass into the subendothelial space where they differentiate into macrophages. Lipoproteins (e.g., LDL) leak across the endothelium & accumulate in the subendothelial space, in part through binding to proteoglycans. Over time, exposure to oxygen radicals results in oxidation of polyunsaturated fatty acids within LDL & modification of the apolipoprotein.

blood vessel lu en endothelial cells

y y y LDL y y

y foam cell y y yy

s ooth muscle cells

Macrophages have on their surface scavenger receptors that cause them to take up oxidized lipoproteins becoming "foam cells" that have many cytoplasmic lipid droplets. Although in humans foam cells mainly develop from macrophages, smooth muscle cells may also migrate into the subendothelial space & become foam cells.

blood ve el lumen endothelial cells

y y y y

y oam cell y y yy

smooth muscle cells

Foam cells aggregate within the developing arterial plaque. Within the plaque core foam cells eventually undergo necrotic death, releasing harmful cellular contents that can promote plaque rupture & development of blood clots.

blood vessel lumen endothelial cells

y y y y

y oam cell y y yy

smooth muscle cells

Foam cells aggregate within the developing arterial plaque. Within the plaque core foam cells eventually undergo necrotic death, releasing harmful cellular contents that can promote plaque rupture & development of blood clots.

Atherosclerotic Plaque

Atherosclerosis
Obstruction of blood vessels due to pathological accumulation of cholesterol-containing plaques. Heart failure due to occluded coronary arteries is a major cause of death in industrialized societies. Incidence of atherosclerosis correlates with high blood concentrations of cholesterol, especially with high levels of LDL. Incidence of atherosclerosis is negatively correlated with high levels of HDL.

Familial Hypercholesterolemia
Genetic disease that arises from any one of many mutant alleles for the LDL receptor gene. LDL uptake into cells is defective, which results in cholesterol accumulation in the blood.
Homozygotes: 680 mg/dL (atherosclerosis in childhood) Heterozygotes: 300 mg/dL (atheroclerosis in middle age) Healthy Level: 175 mg/dL

Treated with inhibitors of de novo cholesterol biosynthesis and Cholestyramine.

Tangiers Disease and Familial HDL Deficiency

Rare diseases that result from defects in the gene encoding the ABC1 protein. Cholesterol-depleted HDL cannot acquire cholesterol from any cell lacking ABC1. Cholesterol-depleted HDL is rapidly removed from the circulation so plasma HDL levels are 1-5% of normal. Patients accumulate cholesterol in the lymphoreticular system (hepatomegaly and spleenomegaly).

Type 1 Hyperlipidemia
Elevated blood concentrations of chylomicrons. Caused by either of two separate genetic defects:
Deficiency in ApoC-II Deficiency in lipoprotein lipase

Symptoms:
Plasma triacylglycerol levels > 1000 mg/dL Eruptive xanthomas and pancreatitis

Abetalipoproteinemia
Genetic disease characterized by lack of ApoB-100. Patients cannot synthesize chylomicrons, VLDLs and LDLs. Symptoms:

Malabsorption of fat. Accumulation of lipid droplets within cells of the small intestine. Spiny shaped red cells Neurological disease (i.e. ataxia and retardation)

ApoE and Type 3 Hyperlipidemia

Caused by defects in the gene encoding ApoE. Patients show reduced uptake of chylomicrons and VLDL remnants. Symptoms include increased risk of atherosclerosis.

ApoE and Alzheimer s Disease

Three common alleles of the gene encoding apoE:
APOE3 (78% of population) APOE4 (15%) APOE2 (7%)

Individuals homozygous for APOE4 have a 16-fold increased risk of Alzheimer s Disease (mean age of onset = 70 y) Individuals homozygous for APOE3 have a mean age of onset = 90 y (If they get the disease at all.) Second role for apoE in stabilizing the neuronal cytoskeleton?

Frederickson -WHO classification

Type I incr. chylomicrons, reduced HDL, absence of I: lipoprotein lipase; deficiency of apo CII (hyperchylomironemia) Type II-A: raised LDL; decreased catabolism of LDL (receptor IIdeficiency or polygenic) Type II-B: raised VLDL + LDL; often reduced HDL; increased IIproduction of VLDL + impaired LDL catabolism Type III raised IDL (dysbetalipoproteinemia); abnormal III: apolipoprotein E; impaired catabolism of IDL; elevated cholesterol and triglycerides (formerly known as broad beta disease)

Frederickson -WHO classification

Type IV raised VLDL; often reduced HDL; impaired VLDL IV: catabolism; dietary indiscretion ( formerly known as hyperprebetalipoproteinemia) Type V raised chylomicrons + VLDL; reduced HDL; V: reduced lipoprotein lipase + VLDL hypersecretion (formerly known as mixed lipemia)

Factors promoting elevated blood lipids

age men >45 years of age; women > 55 years of age family history of CAD smoking hypertension >140/90 mm Hg low HDL cholesterol obesity >30% overweight diabetes mellitus inactivity/ lack of exercise