Atherosclerosis and hypercholesterolemia

Coronary artery spasm may account for a variety of clinical syndromes such as variant angina, acute myocardial infarction and sudden cardiac death [94]. The mechanisms of vasospasm however are not entirely clear. Atherosclerosis and hypercholesterolemia have been implicated in the pathogenesis of vasospasm [95-97] and a local hyperactivity of the coronary artery may be involved. 

Acaterin (1), isolated from a culture broth of Pseudomonas sp. A92 by Endo and co-workers/ is one of the acyl-CoA cholesterol acyltransferase (ACAT) inhibitors that are expected to be effective for the treatment of atherosclerosis and hypercholesterolemia, and also has remarkable antitumor activity. Since the total synthesis of acaterin reported by Kitahara and co-workers, synthetic strategies based on the MBH reaction have more recently been reported for this molecule almost simultaneously by three different research groups. Franck and Figadere first reported the synthesis of racemic acaterin 1 by condensation of ot,(3-unsaturated y-lactone 2 (99% ee) and octanal via a DABCO-mediated MBH reaction (Scheme 5.1). Unfortunately, using chiral (S)-2 (99% ee) as a reactant. 

Famiiiai hyperchoiesteroiemia (type iia) Defective LDL receptors or mutation in ligand region of apo B-100. Elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease. 

Lipitor (Atorvastatin) Atherosclerosis Dyslipidemia Hypercholesterolemia 3.8 1.3 1997 - UK and US Once daily... 

Ila i i j i Familial hypercholesterolemia Autosomal dominant (Aa 1/500, AA 1/10 ) Cholesterol LDL High risk of atherosclerosis and coronary artery disease Homozygous condition usually death <20 years Xanthomas of the Achilles tendon Tuberous xanthomas on elbows Xanthelasmas Comeal arcus... 

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. 

The measurement of serum cholesterol is one of the most common tests performed in the clinical laboratory. Hypercholesterolemia (high blood cholesterol levels) can be the result of a variety of medical conditions. Among the conditions implicated are diabetes mellitus, atherosclerosis, and diseases of the endocrine system, liver, or kidney. High blood cholesterol levels do not point to a specific disease determination of cholesterol is used in conjunction with other clinical measurements mainly for confirmation of a particular diseased condition, rather than for diagnosis of a specific ailment. 

However, if a man smokes, eats to the point of obesity, and has elevated blood glucose and elevated blood pressure, his peripheral nervous system wires do not respond adequately to the let s have intercourse signal from the brain—in other words, neurological innervation of the penis is rendered faulty, usually by diabetes (Fig. 14—12). Furthermore, there may not be much pressure in the plumbing — there may be atherosclerosis of the arterial supply of the penis from hypertension and hypercholesterolemia—when cGMP says relax the smooth muscle and let the... 

Hereditary dyslipidemias such as familial hypercholesterolemia, type II and type IV hyperlipidemia and Tangiers disease predispose to premature large vessel atherosclerosis and hence stroke (Meschia 2003 Hutter et al. 2004). 

Atherosclerosis and Plasma Lipids - Lipoprotein lipases play a critical role in the metabolism of lipoproteins and thus may be involved in athero-genesis. Hypercholesterolemia in the cholesterol-fed rabbit was attributed to the accumulation of chylomicron remnants, which may be formed on the aorta wall by lipoprotein lipase and deposited in the deep layers of the arterial wall without prior release into the blood stream.13 On this basis, cholesterol-rich lipoproteins in plasma may be the product rather than the cause of the atherogenic process. However, the defect in Type III hyperlipoproteinemia (broad- disease) may be ineffective removal of chylomicron remnant particles from the arterial wall,11 due to a failure of the liver to recognize such particles.15... 

Okuyama H, Eujii Y, Ikemoto A. N-6/n-3 ratio of dietary fatty acids rather than hypercholesterolemia as the major risk factor for atherosclerosis and coronary heart disease. J Health Sci 2000 46 157-177. 

Most of these concepts have arisen from detailed studies in cultured fibroblasts from normal subjects and from patients with the disease, FH. Lack of the above-described regulatory features in FH fibroblasts led to the conclusion that the abnormal phenotype is caused by lack of LDL receptor function, and thus, disruption of the LDL receptor pathway. In particular, the balance between extracellular and intracellular cholesterol pools is disturbed. Clinically, the most important effect of LDL receptor deficiency is hypercholesterolemia with ensuing accelerated development of atherosclerosis and its complications (Chapter 21). In the following sections, a detailed description of the... 

The LDL Receptor and Cholesterol Homeostasis (Figure 18.10) Atherosclerosis Familial hypercholesterolemia... 

The association between atherosclerosis in humans and plasma lipoproteins has led to the development and use of several animal models to help our understanding of familial hypercholesterolemias and atherosclerosis however, the species differences in lipoproteins and their metabolism must be considered when developing models of atherosclerosis and novel therapeutic agents. Dietary manipulations in animals with dominant LDL-C fractions are perhaps more appropriate models for these studies than in animals where HDL is the dominant fraction (Cayen, Givner, and Kraml... 

Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis-associated conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease, and peripheral vascular disease. These conditions account for most morbidity and mortality among middle-aged and older adults. DysUpidemias, including hyperhpidemia (hypercholesterolemia) and low levels of high-density-hpoprotein cholesterol (HDL-C), are major causes of increased atherogenesis both genetic disorders and lifestyle (sedentary behavior and diets high in calories, saturated fat, and cholesterol) contribute to the dysUpidemias seen in developed countries. 

All HMGRIs are approved for the treatment of primary hypercholesterolemia and familial combined hyperlipidemia (Fredrickson s type Ha and lib) (Table 30.2) In patients who have not responded to diet, exercise, and other non pharmacological methods (Table 30.6) (15,21). They may be used either alone or In combination with bile acid sequestrants, ezetimibe, or niacin. As previously mentioned, they should be administered at least 1 hour before or 4 to 6 hours after bile acid sequestrants when this combination Is desired. Fluvastatin, lovastatin, pravastatin, and simvastatin have been specifically Indicated to reduce the mortality of CHD and stroke. By reducing plasma LDL levels, these compounds slow the progression of atherosclerosis and reduce the risk of myocardial Infarction and other ramifications of vascular occlusion. Atorvastatin, rosuvastatin, and simvastatin have been shown to be effective In homozygous familial hyperlipidemia and are Indicated for this use. Additionally, atorvastatin, pravastatin, and simvastatin are Indicated for primary dysbetallpoprotelnemla (Fredrickson s type III) (Table 30.2). Finally, atorvastatin, pravastatin, rosuvastatin, and simvastatin are Indicated for the treatment of hypertriglyceridemia. 

This inborn error of metabolism, familial hypercholesterolemia, is dangerous because high LDL concentrations are linked to atherosclerosis and heart disease. The patients normally die before the age of 25 years. 

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