Plasma levels, cardiovascular diseases

It has been already pointed out that nitric oxide exhibits antioxidant effect in LDL oxidation at the NO/ 02 ratio 1. Under these conditions the antioxidant effect of NO prevails on the prooxidant effect of peroxynitrite. Although some earlier studies suggested the possibility of NO-mediated LDL oxidation [152,153], these findings were not confirmed [154]. On the other hand, at lower values of N0/02 ratio the formed peroxynitrite becomes an efficient initiator of LDL modification. Beckman et al. [155] suggested that peroxynitrite rapidly reacts with tyrosine residues to form 3-nitrotyrosine. Later on, Leeuwenburgh et al. [156] found that 3-nitrotyrosine was formed in the reaction of peroxynitrite with LDL. The level of 3-nitrotyrosine sharply differed for healthy subjects and patients with cardiovascular diseases LDL isolated from the plasma of healthy subjects contained a very low level of 3-nitrotyrosine (9 + 7 pmol/mol 1 of tyrosine), while LDL isolated from aortic atherosclerotic intima had a 90-fold higher level (840 + 140 pmol/moD1 of tyrosine). It has been proposed that peroxynitrite formed in the human artery wall is able to promote LDL oxidation in vivo. 

A 42-year-old man presents with a chief complaint of intermittent claudication during exercise. His fomHy history is significant for the presence of cardiovascular disease on his fether s side, but not on his mother s side. Physical exam reveals xanthelasmas and bilateral tendon xanthomas. A plasma lipid profile reveals a cholesterol level of 340 mg/dL, with a high LDL/HDL ratio. He is given instructions for dietary modifications and a prescription for Zocor (simvastatin). 

For people who are at risk of cardiovascular disease due to high plasma LDL cholesterol levels, lifestyle changes to control plasma cholesterol levels are the first and best place to start. When efforts to control plasma cholesterol levels by diet and exercise fail, people frequently turn to drugs, some of which are effective in producing substantial lowering of cholesterol levels and realizing associated clinical benefits. 

These studies demonstrate that optimal doses of statins reduce the incidence of clinical events in patients with established coronary artery disease, in patients with elevated plasma LDL levels but without existing coronary artery disease, in individuals with normal plasma LDL levels without existing coronary artery disease, and in diabetics, a patient population at high risk of cardiovascular disease. ... 

An elevated level of plasma cholesterol, particularly that carried in LDLs, is an independent risk factor for developing cardiovascular disease. Cholesterol comes from dietary sources and is made in the body, largely in the liver. 

The role of the antioxidant properties of vitamins C, E, and p-carotene in the prevention of cardiovascular disease has been the focus of several recent studies. Antioxidants reduce the oxidation of low-density lipoproteins, which may play a role in the prevention of atherosclerosis. However, an inverse relationship between the intake or plasma levels of these vitamins and the incidence of coronary heart disease has been found in only a few epidemiological studies. One study showed that antioxidants lowered the level of high-density lipoprotein 2 and interfered with the effects of lipid-altering therapies given at the same time. While many groups recommend a varied diet rich in fruits and vegetables for the prevention of coronary artery disease, empirical data do not exist to recommend antioxidant supplementation for the prevention of coronary disease. 

While normal concentrations of ET-1 and ET-3 in human plasma are relatively low (pg/ml, ET-2 concentrations are below detectable limits), plasma levels of ET-1 are elevated in many cardiovascular diseases. Therefore, ET receptor antagonists are utilized in the treatment of these diseases, and a number of... 

LDL and HDL The level of plasma cholesterol is not precisely regulated, but rather varies in response to the diet. Elevated levels result in an increased risk for cardiovascular disease (Figue 27.9). The risk increases progressively with higher values fa-serum total cholesterol. A much stronger correlation exists between the levels of blood LDL cholesterol and heart disease. In contrast, high levels of HDL cholesterol have been associated... 

Although elevated levels of cholesterol and LDL in human plasma are linked to an increased incidence of cardiovascular disease, recent data have shown that an increase in concentration of HDL in plasma is correlated with a lowered risk of coronary artery disease. Why does an elevated HDL level in plasma appear to protect against cardiovascular disease, whereas an elevated LDL level seems to cause this disease The answer to this question is not known. An explanation currently favored is that HDL functions in the removal of cholesterol from nonhepatic tissues and the return of cholesterol to the liver, where it is metabolized and secreted. The net effect would be a decrease in the amount of plasma cholesterol available for deposit in arteries (see... 

Considerable discussion has arisen in the lay press about cholesterol and its link to cardiovascular disease because of the correlation between elevated levels of cholesterol in the plasma and the incidence of heart disease. Experts generally agree that people who have total plasma cholesterol levels above 240 mg/dl (6.2 mmole/1) for many years are at increased risk of having a heart attack compared with people whose plasma cholesterol level is below 200 mg/dl (5.2 mmole/1). Because of this it is generally recommended that adults should endeavor to achieve levels of total cholesterol (including both free cholesterol and choles-teryl ester) in plasma of 200 mg/dl (5.2 mmole/1) or less. As discussed in the text, plasma cholesterol is largely carried in LDL as cholesteryl ester. The cholesteryl ester carried by LDL is sometimes referred to in the lay press as bad cholesterol. 

In case LDL oxidation is considered as an important risk factor, the dosage of vitamin E may be important to determine a clinical effect. However, with respect to inhibition of protein kinase-C and the release of proinflammatory cytokines the intracellular transfer of RRRT (natural vitamin E) by the tocopherol-associated protein may be a crucial point. Consequently, natural vitamin E is considered more effective than the synthetic one. Since the activity on LDL oxidation was pointed out as important for the prevention of cardiovascular disease, most of the long-term trials with vitamin E were conducted at dosages >200 mg/day (about 200 lU/d). In a recent meta-analysis the association of plasma levels and mortality was studied in 1168 elderly European men and women (25). No association was found between the plasma concentration and all-cause or cause-specific mortality. 

It is important to note that an elevated and/or altered plasma lipid level is only one of a wide range of risk factors that contribute to the clinical manifestations of cardiovascular disease in humans (Lusis, 2000). Consequently, in some studies, the reduced incidence of atherosclerosis in animals fed CLA was not accompanied by an improvement in the plasma lipid profile during the CLA feeding phase (Wilson et al, 2000). Reasons for these effects are not understood fully. However, atherosclerosis can also be considered as a chronic inflammatory disease (Libby, 2002) and several important anti-inflammatory effects have been associated with the use of RA these include a reduction in the expression of COX-2, PGE2, reduced release of nitric oxide, a decreased production of pro-inflammatory cytokines, and PPARy activation (Urquhart et al, 2002 Yu et al, 2002 Toomey et al, 2003). 

In postmenopausal women estrogen provides a protective effect against cardiovascular disease, causing a decrease in LDL and an increase in HDL levels in plasma. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

Amino acids (AA) have also been studied on microdevices for development of microclinical analysis devices. In urine, normal ranges for standard amino acids and their metabolites range from 0 to 24 mM, with abnormal concentrations indicative of a number of disease states. Plasma concentrations of certain amino acids can also be used for disease detection. Elevated homocysteine levels in plasma is an independent risk factor for cardiovascular disease. Microdevices employing end-column amperometric detection were used for the determination... 

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