Atherosclerosis premature

A family history positive for CHD is important in identifying patients at risk for premature atherosclerosis. If a patient with CHD has elevated triglycerides, the associated abnormality is probably a contributing factor to CHD and should be treated. 

ApoA-1 is the major structural lipoprotein component of HDL particles. Transgenic over-expression of apoA-1 has been well documented to correlate very strongly with antiatherogenic effects seen in a number of animal models [89-91]. The genetic deficiency of apoA-1 in humans has also been linked to low levels of HDL and premature atherosclerosis [90-92]. It is believed that infusion of apoA-1 enhances the ABCAl-mediated cholesterol efflux from macrophages [93]. During the last decade, significant efforts have been spent to find small... 

Patients with both type 1 and type 2 diabetes are prone to complications. The specific chronic diabetic complications are due to microangiopathy and include neuropathy, retinopathy and nephropathy. Recent data stress the vital role of hyperglycaemia and oxidative stress in their pathophysiology. Premature atherosclerosis (which can be considered... 

Rare genetic disorders, including Tangier disease and LCAT (lecithin cholesterol acyltransferase) deficiency, are associated with extremely low levels of HDL. Familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45 mg/dL in women. These patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor. Management should include special attention to avoidance or treatment of other risk factors. Niacin increases HDL in many of these patients. Reductase inhibitors and fibric acid derivatives exert lesser effects. 

Monogenic dyslipoproteinemias can generally be grouped into five categories (1) hypertriglyceridemia with an increase in chylomicrons and the clinical sign of pancreatitis, (2) mixed hyperlipidemia with an increase in chylomicron and VLDL remnants and an increased risk of premature atherosclerosis, (3) hypercholesterolemia with an increase in LDL and an increased risk for premature atherosclerosis, (4) hypoalphalipoproteinemia with low HLD and an increased risk for premature atherosclerosis, and (5) hypolipoproteinemia with a decrease in VLDL and LDL, which may lead to neurological disease. 

Familial dysbetalipoproteinemia (type III) is characterized by the accumulation of chylomicron and VLDL remnants, which are enriched in cholesterol compared to their precursors. The primary molecular cause of familial dysbetalipoproteinemia (type III) is the homozygous presence of the apolipoprotein E2 (apoE2) isoform, which is associated with recessive inheritance of the disorder [62]. However, only 1 in 50 homozygotes for apoE2 will develop type III hyperlipoproteinemia, which is clinically characterized by palmar and tuberous xanthomas, arcus lipoides, and premature atherosclerosis of coronary, peripheral, and cerebral arteries. Precipitating factors include diabetes mellitus, renal disease, hemochromatosis, but also familial hypercholesterolemia. In addition, some rare mutations in the apoE gene have been found to cause dominant and more penetrant forms of type III hyperlipoproteinemia. 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

After binding, the LDL-receptor complex is internalized by endocytosis. [Note A deficiency of functional LDL receptors causes a significant elevation in plasma LDL and, therefore, of plasma cholesterol. Patients with such deficiencies have type II hyperlipidemia (familial hypercholesterolemia) and premature atherosclerosis. The thyroid hormone, T3, has a positive effect on the binding of LDL to its receptor. Consequently, hypothyroidism is a common cause of hypercholesterolemia.]... 

As noted previously, available therapies moderate the hyperglycemia of diabetes, but fail to completely normalize metabolism. The long-stand-hg elevation of blood glucose causes the chronic complications of diabetes—premature atherosclerosis, retinopathy, nephropathy, and neuropathy. Intensive treatment with insulin (see p. 339) delays the onset and slows the progression of these long-term complications. For example, the incidence of retinopathy decreases as control of blood glu-... 

Available treatments for diabetes moderate the hyperglycemia, but fail to completely nor malize metabolism. The long-standing elevation of blood glucose causes the chronic com plications of diabetes—premature atherosclerosis, retinopathy, nephropathy, and neuropathy. 

Phytosterols are safe when consumed in moderate amounts, such as those used in human studies, lu humans, phytosterol intakes of up to 25 g/d for several mouths were uot associated with adverse health effects. Phytosterol-fortilied foods should be avoided by iudividuals with phytosterolemia, an extremely rare genetic disorder characterized by imusuaUy high rates of intestinal absorption of phytosterols and an increased risk of premature atherosclerosis. ... 

C. Familial dysbetalipoproteinemia (Type III pattern). A defect in the remnant particle apoprotein, which results in the loss of ability of remnants to bind to liver ceils. There are xanthomas and marked premature atherosclerosis. Remnant particles accumulate in the plasma, seen as a broad beta band on electrophoresis. There is elevation of both plasma cholesterol and triglycerides. 

D. Familial hypertriglyceridemia (Type IV or V pattern). There is elevated VLDL, but the mechanism is unclear (possibly a defect in VLDL catabolism). There may be xanthomas, pancreatitis and premature atherosclerosis. 

E. Multiple lipoprotein-type hyperlipidemia (Type Ila, Ilb or IV pattern). Elevated LDL, possibly due to excess production of VLDL. There is premature atherosclerosis. 

I. LCAT deficiency. Cholesterol associated with HDL cannot be esterified. There is a buildup of unesterified cholesterol, with comeal opacities, renal insufficiency, hemolytic anemia, and premature atherosclerosis. The diagnosis may be made on enzyme assay for plasma LCAT. 

Apo E consists of 299 amino acids. A genetic disease, called type 111 hyperlipoproteinemia, results from naturally occurring mutations in the apo E gene. The disease results in high plasma cholesterol, high plasma TCs, premature atherosclerosis, and xanthomas. Xanthomas arc lumpy accumulations of choles terol in the wrists, elbows, knees, and other parts of the body. The most common mutation is one that results in the conversion of Arg 158 to Cys 158 (Lohse el al., 1991). Other naturally crecurring mutations result in a truncated polypeptide, or in the complete absence of apo E,... 

Benlian, R, GenneB, J. L Foubert, L, Zhang, IL, Gagne, S., and Hayden, M. (1996). Premature atherosclerosis in patients with familial chylomicroncniia caused by mutations in the lipoprotein lipase gene. W. / Med. 335, 84S- 54. 

Lipoprotein and hepatic lipases are important enzymes involved in the metabolism of chylomicrons and various fractions of lipoproteins. Both have been the subject of attention, as evidenced by numerous reviews (e.g., Garfinkel and Schotz, 1987 Wang eta/., 1992). This interest stems from the fact that abnormal lipoprotein metabolism has been linked to various disorders, including hyperchylomicronemia, hypercholesterolemia, hypertriglyceridemia, obesity, diabetes, and premature atherosclerosis. Genetic defects in both HL and LPL are now known to be the cause of at least some familial disorders of lipoprotein metabolism. 

In 1971, Salen reported (12) that the rare inheirted lipid storage disease, cerebrotendinoux xanthomatosis (CTX), was associated with defective bile acid synthesis. The major and prominent clinical features in CTX syndrome were tendon xanthomas, juvenille cataracts, dementia, pyramidal paresis, cerebellar ataxis, abnormal electroencephalogram (EEC), and cerebral computed tomographic (CT) scans, premature atherosclerosis, pulmonary dysfunction and osteoporosis. Low serum levels of 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were also detected in these patients in association with osteoporosis and frequent bone fractures (13,14). The disease is inherited as an autosomal recessive trait, but is usually detected in adults when cholesterol and cholestanol have accumulated over many years (13-16). Major biochemical... 

This disorder has a late onset it rarely manifests itself in childhood. The most distinctive clinical presentation of dysiipoproteinemia is the presence of palmar xanthomas, the yellow deposits that occur in the creases of the palms. Tuberous and tuberoeruptive xanthomas also occur but are not unique to this syndrome. Premature atherosclerosis develops in 30% to more than 50% of these patients, particularly in the lower extremities. ... 

Karathanasis SK, Ferris E, Haddad lA. DNA inversion within the apolipoproteins AI/CIII/ATV-encoding gene cluster of certain patients with premature atherosclerosis. Proc Natl Acad Sci U S A 1987 84 7198-202. 

Familial homozygous hypercholesterolemia is a rare hereditary monogenic disorder caused by mutations of the LDL receptor gene. Individuals have severe hypercholesterolemia associated with premature atherosclerosis. In a single study, patients were treated with gene therapy... 

In hypobetalipoproteinenia the plasma LDL level is decreased (10-20% of normal), but that of HDL is normal, and that of VLDL is mildly lowered. Of 23 affected individuals from the four known affected families, one had central nervous system dysfunction and fat malabsorption. The others had mild or no pathological changes. The disease is inherited as an autosomal dominant trait. The benign nature of this condition is in sharp contrast with the seriousness of hyperbetalipoproteinemia. In the latter, LDL cholesterol concentrations are two to six times normal, and patients are predisposed to premature atherosclerosis. In another form of hypobetalipoproteinemia, the patient synthesized apo B-48 and secreted chylomicrons but did not produce apo B-lOO or secrete VLDL. 

Another factor that regulates HDL cholesterol levels is the plasma level of cholesteryl ester transfer protein (CETP). CETP, a hydrophobic glycoprotein (M.W. 741,000), facilitates the transfer of cholesteryl esters in HDL and triacylglycerols in LDL and VLDL (see above). In CETP deficiency due to a point mutation (G A) in a splice donor site that prevents normal processing of mRNA, the plasma HDL cholesterol levels of affected individuals are markedly high, with decreased LDL cholesterol. In the affected families, there was no evidence of premature atherosclerosis and, in fact, there was a trend toward longevity. These observations support the role of CETP and the antiatherogenic property of HDL. However, not all factors that elevate HDL levels may be... 

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