AGE-LDL

Diabetic patients are 3 4 times more susceptible to atherosclerosis and vascular insufficiency. The situation is similar for those suffering from renal insufficiency, independent of diabetes. Makita et al.5sl found that there was a direct correlation CP < 0.005) between serum AGE-peptide levels and renal function, as assessed by creatinine clearance. This led Bucala et a/.145 to consider that the modification of the plasma proteins, such as LDL, may arise due to the reaction with reactive, circulating AGE-peptides rather than glucose. AGE-LDL did form readily in vitro when native LDL was incubated with either synthesised AGE-peptides or AGE-peptides isolated directly from the plasma of patients. Such AGE-LDL exhibited markedly impaired clearance kinetics when injected into transgenic mice, expressing human LDL receptor. Their data indicate that AGE modification could contribute to elevated LDL levels in patients with diabetes or renal insufficiency. This hypothesis was further supported by the administration of AG to diabetic patients, when circulating levels of LDL decreased by almost 30%. Levels of Hb-AGE decreased too. 

Hunt, K.J., Baker, N., Cleary, P., Backlund, J.Y., Lyons, T, Jenkins, A., Lopes-Virella, M.F. Oxidized LDL and AGE-LDL in circulating immune complexes strongly predict progression of carotid artery IMT in type 1 diabetes. Atherosclerosis Dec 2013 231(2) 315-22. 

Reduction in semm Hpids can contribute significantly to prevention of atherosclerosis. In 1985 a consensus report indicating that for every 1% reduction in semm cholesterol there is a 2% reduction in adverse effects of coronary heart disease was issued (145). Recommended semm cholesterol concentration was 200 mg/dL for individuals under 30 years of age, and individuals having concentration 240 mg/dL and LDL-cholesterol over 160 mg/dL should undertake dietary modification and possibly pharmacotherapy (146). Whereas the initial step in reducing semm cholesterol is through reduction of dietary cholesterol intake, a number of dmgs are available that can affect semm Hpid profile (see Fat substitutes). The pathway to cholesterol synthesis is shown in Figure 2. 

In Western countries, the total plasma cholesterol in humans is about 5.2 mmol/L, rising with age, though there are wide variations between individuals. The greater part is found in the esterified form. It is transported in hpoproteins of the plasma, and the highest proportion of cholesterol is found in the LDL. Dietary cholesterol equifibrates with plasma cholesterol in days... 

Familial hypercholesterolaemia is characterized by a significant elevation in plasma LDL concentration. The basic metabolic defect appears to be abnormal LDL receptor function, arising from mutations in the LDL receptor gene. Several receptor mutations have been identified and hypercholesterolaemia severity as well as the age of onset of ischaemic heart disease has recently been demonstrated to vary according to the type of LDL receptor gene defect (Moorjani et al., 1993). 

Esterbauer, H., Waeg, G., Puhl, H., Dieber-Rotheneder, M. and Tatzber, F. (1992). Inhibition of LDL oxidation by antioxidants. In Free Radicals and Aging (eds. I. Emerit and B. Chance) pp. 145-157. Birkhauser Verlag, Basel. 

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited disease caused by mutations in the gene for the LDL receptor. Up to now more than 680 distinct mutations, distributed over the entire gene, have been described [42]. Heterozygous FH individuals express only half the number of functional LDL-r and, therefore, have a markedly raised plasma cholesterol and usually present with premature coronary artery disease. Homozygous FH individuals are more severely affected and may succumb before the age of maturity. The prevalence of heterozygous FH is approximately 1 in 500 in Caucasians. 

Recent development of mitochondrial theory of aging is so-called reductive hotspot hypothesis. De Grey [465] proposed that the cells with suppressed oxidative phosphorylation survive by reducing dioxygen at the plasma membrane rather than at the mitochondrial inner membrane. Plasma membrane redox system is apparently an origin of the conversion of superoxide into hydroxyl and peroxyl radicals and LDL oxidation. Morre et al. [466] suggested that plasma membrane oxidoreductase links the accumulation of lesions in mitochondrial DNA to the formation of reactive oxygen species on the cell surface. 

A fasting lipoprotein profile including total cholesterol, LDL, HDL, and triglycerides should be measured in all adults 20 years of age or older at least once every 5 years. 

Age - The risk of cerebrovascular and circulatory disease in OC users is substantially increased in women 35 years of age and older with other risk factors (eg, smoking, uncontrolled hypertension, hypercholesterolemia [LDL 190], obesity, diabetes). 

Positive risk factors for CHD (other than high LDL) include Age (men 45 years of age or older women 55 years of age or older or women who go through premature menopause without estrogen replacement therapy) family history of premature CHD smoking hypertension (greater than 140/90 mm Hg) low HDL cholesterol (less than 35 mg/dL) obesity (more than 30% overweight) and diabetes mellitus. 

Adolescents 10 to 17 years of age with heterozygous familial hypercholesterolemia (immediate-release only)-The recommended dosing range is 10 to 40 mg/day the maximum recommended dose is 40 mg/day. Start patients requiring reductions in LDL cholesterol of 20% or more on 20 mg/day. Consider a starting dose of 10 mg for patients requiring smaller reductions. Adjust at intervals of 4 weeks or more. 

Elderly In patients older than 70 years of age, the AUC of lovastatin, pravastatin, and simvastatin is increased. Pravastatin does not need dosage adjustment. The safety and efficacy of atorvastatin, rosuvastatin, and lovastatin extended-release in patients 70 years of age and older were similar to those of patients younger than 70 years of age. Elderly patients (65 years of age and older) demonstrated a greater treatment response in respect to LDL-C, total-C and LDL/HDL ratio than patients younger than 65 years of age. 

Dramatic elevation of blood LDL-cholesterol levels in FFI leads to a high risk of atherosclerosis at an early age due to deposition on the linings of the coronary arteries. 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

Lipid metabolism. Oil, administered orally to female C57BL/6 mice weaned at 21 d of age at a dose of 15% w/w for 6 weeks, increased the total lipids, triglycerides, LDL and VLDL cholesterol, and thioharhituric acid-reactive substances (TEARS) and reduced glutathione concentrations, without changes in phospholipids or total cho-... 

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