About Cholesterol

Lower Your Cholesterol in 30 Days

Since Scott Davis released the Beat Cholesterol In 30 Days program, many people used it to learn how to manage their hypercholesterolemia quickly and naturally. Due to his personal fight with the disease and the desire to completely avoid prescription meds, he discovered the most effective techniques to overcome this condition and live longer, happier life. While IP6 is well known for its cancer-fighting properties, Davis points to its use to lower blood cholesterol. Indeed, the U.S. National Institutes for Health (NIH) actually performed research that actually drew the same conclusion in 1999. IP6 is also known to actually reduce the presence of calcium deposits in arteries, another benefit which will delay or prevent the onset of heart disease. Davis' ability to collect such an astounding array of oftentimes obscure information and arrange it in a way that is easy for people of all ages to follow and apply to their lives immediately is itself quite an achievement. Read more...

Natural Cholesterol Guide Summary

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Melting Properties of Triglycerides

Triglycerides are the basis for the production of spreads such as margarine and butter, as well as confectionery fats and chocolate. An important triglyceride property in this type of product is their melting behavior and contribution to product texture. The latter is easily recognized in product properties as softness, spreadability, and mouth feel. The melting behavior of oils and fats is the result of complex interactions among large numbers of triglycerides, all different in the type and position of the fatty acids they contain. Thus modification of the fatty acid composition or distribution will result in a change in the melting behavior. To date, the main application of enzymatic TAG modification is probably the production of cocoa but-terfat equivalents. Cocoa butterfat has a very special melting behavior, which is characterized by a rapid melting within a narrow temperature range. This behavior is related to its high content of POSt- and StOSt-type triglycerides (P palmitic O...

Structured Triglycerides

Acidolysis using a 1,3-specific lipase is most commonly applied to produce structured triglycerides. A good example of such a process is the production of Betapol, an additive for infant formulas (81). This product predominantly consists of OPO, which is a major triglyceride in human milk fat (82). Hydrolysis of OPO by human pancreatic lipase will result in free oleic acid and 2-monopalmitin, which are both easily absorbed. As opposed to this, vegetable oils in infant formulas generally contain the POO-type triglycerides, the hydrolysis of which results in free palmitic acid. The latter will form insoluble calcium soaps, thereby preventing absorption of both the palmitic acid and the calcium (83). Another example is the MLM triglycerides (M medium-chain C6-C12 L long-chain), preferably with an unsaturated fatty acid at the 2-position. Because of the improved digestibility of these types of triglycerides (84, 85), they are of interest for individuals suffering from pancreatic...

Familial hypercholesterolemia and statins

Perhaps the most dramatic example of monogenic diseases leading to treatments for common disease concerns familial hypercholesterolemia (FH) and the development of statins (Goldstein et al., 2001). FH is a relatively common dominant condition affecting 1 500 of the population. Individuals with FH have high levels of cholesterol at birth and will develop atherosclerosis and vascular disease in childhood. The risk of fatal heart disease before the age of 40 years is significantly higher than among the general population. Approximately one-third of patients with FH show no symptoms until sudden cardiac death. Through the pioneering work of Brown and Goldstein, we know that FH is caused by loss of function mutations in the LDL receptor gene (LDLR). The LDL receptor removes cholesterol from the blood stream. This piece of genetic detective work proved that high cholesterol is the cause of coronary disease in these patients. Extrapolating from this monogenic condition, these findings...

Monogenic hypercholesterolemias

Important insights into CHD pathogenesis have come from the study of monogenic hypercholes-terolemias, and have led to the development of the most widely used class of lipid-lowering drugs, the HMG-CoA-reductase inhibitors (statins). Among the many known risk factors for atherosclerosis, very high low density lipoprotein (LDL) cholesterol levels are probably unique in their ability to lead to the development of premature atherosclerosis in humans in the absence of other additional risk factors. Table 24.2 summarizes the main characteristics of the known Mendelian disorders of severe hypercholesterolemia, all of which are associated with premature CHD. Autosomal dominant hypercholesterolemias Familial hypercholesterolemia (FH) was the first genetic disease of lipid metabolism to be clinically and genetically characterized and it represents the most common and most severe form of Mendelian hypercholesterolemia (Goldstein et al., 2001). The disease is caused by mutations in the LDL...

Secretion of Glucose Triglycerides and Ketone Bodies

As you may recall from chapter 5, the liver helps to regulate the blood glucose concentration by either removing glucose from the blood or adding glucose to it, according to the needs of the body. After a carbohydrate-rich meal, the liver can remove some glucose from the hepatic portal blood and convert it into glyco-gen and triglycerides through the processes of glycogenesis and

Statins Lipidlowering drugs

Theoretically statins f 3,6-8 NFV simvastatin (20 mg) f 506 SQV r 400 400 BID simvastatin (40 mg) f 3059 10 Case report rhabomyolyse, acute renal failure with ATV 400, sim-vastatin (80 mg) 17 NFV < FPV r < TPV r atorvastatin f (10 mg) 75 - 936 EFV statins 4 40 - 58 3,7,13 Theoretical alternatives NVP theoretically statins 4 pra tatin flw tatin 4,14,15 3. Fichtenbaum CJ, Gerber JG, Rosenkranz S. Pharmacokinetic interaction between protease inhibitors and statins in HIV seronegative volunteers ACTG Study A5047. AIDS 2002 16 569-77.

Project Title Cholesterol Lowering By Nurses To Control Heart Disease

Summary The purpose of this study is to evaluate the effectiveness of a nurse-managed, case-management system of individualized lifestyle modification and pharmacologic intervention to manage lipid disorders in adults who have undergone coronary artery bypass graft surgery (CABG). Clinical trials have provided strong scientific evidence that lowering serum cholesterol will reduce morbidity and mortality from coronary heart disease (CHD) in patients with established CHD.1 Despite the clear benefits of cholesterol-lowering treatment, many patients with clinical evidence of atherosclerosis are not being treated effectively .2-4 Changes in the delivery of health care, including care for and after coronary events, mandate that we consider more effective and economical strategies for the management of lipid disorders in those with CHD so that the benefits of lipid lowering can be achieved outside of clinical drug trials. The primary aims of this study are to 1. compare the effectiveness of...

Modification Of Triglycerides A Modifying the Fatty Acid Composition

Chemical interesterification is one of the major modification techniques and basically involves a random rearrangement of the sn-1, sn-2, and sn-3 fatty acids over the triglycerides present in the mixture (Fig. 1). A similar result can be obtained when using a random lipase such as that from Candida rugosa* (38, 67), Pseudomonas fluorescens (68), or Pseudomonas cepacia (69). Using a 1,3-specific lipase, only the fatty acids on the outer positions of the triglyceride molecules will be randomized. In this case the sn-2 position remains intact, which implies that a different triglyceride mixture will result, as compared to the random process. In both cases the rearrangement process can be regarded as a statistical process, and hence the final, equilibrium composition of the product can be easily calculated. For example, assuming only three fatty acids X, Y, and Z present in a TAG mixture, the molar concentration of an individual types of triglycerides follows from The overall- and...

Coronary Heart Disease

Based on their review of 43 studies that examined the relationship between physical inactivity and CHD incidence, Powell and colleagues (1987) concluded that the risk of incident CHD due to physical inactivity ranges from 1.5 to 2.4 (median 1.9). These values are similar in magnitude to other CHD risk factors, such as hypertension, hypercholesterolemia, and smoking. These data are consistent with recent evidence from the Nurses Health Study, in which physical inactivity (< 1 h of exercise per week) was found to be associated with increased risk (RR 1.58 95 CI, 1.39-1.80) of incident coronary heart disease in 88,393 women followed for 20 years (Li et al, 2006). Data from the Womens' Health Study also indicate that the health benefits of physical activity are not limited to vigorous activity, such that participating in light to moderate physical activity, such as walking for at least 1 h per week, is associated with lower CHD risk (RR 0.49 95 CI, 0.28-0.86) (Leeetal, 2001).

Energy And Nitrogen Requirements

Contain whole protein as a nitrogen source, energy derived from triglycerides and glucose polymers, while electrolytes, trace elements and vitamins are included in recommended amounts. Standard polymeric diets contain approximately 6g nitrogen l with an energy density of 1kcal ml. Other energy, nitrogen-dense diets (containing between 8 and 10 g nitrogen l and an energy density of 1-1.5 kcal ml) are used for those with higher requirements.

The use of functional foods to meet dietary guidelines

Margarines and yogurts have been enriched with plant stanols or sterols, which lower low-density lipoprotein (LDL) cholesterol by 10 per cent and could thus make an important contribution to prevention of coronary heart disease.40 Many well-controlled trials have documented the efficacy of sterols and stanols for lowering LDL, and no major adverse effects have been noted. However, long-term safety and clinical efficacy have not been evaluated in large-scale clinical trials of the size and duration customary for new drugs. The Health Council of The Netherlands therefore discourages the use of plant sterols by consumers who would not benefit from a cholesterol-lowering effect, e.g. children and pregnant women, and other regulatory agencies have suggested similar limitations.

Transfer of Cholesterol to the Mitochondrion

Steroid-synthesizing cells have at least three metabolically active pools of cholesterol (1) a small, metabolically active pool of free cholesterol (2) a large storage pool in which cholesterol is stored as cholesterol esters of free fatty acids and (3) a fixed pool of membrane cholesterol, which is not available for steroid synthe-sis.9 The free cholesterol pool is formed from endogenous conversion of acetate to cholesterol via a complex series of reactions and by hydrolysis of cholesterol esters, including those that are part of the storage pool and those that are constituents of low-density lipoprotein (LDL) and high-density lipoprotein (HDL). After cellular uptake of these lipoproteins, LDL is processed through lysozymes, whereas HDL enters the cy-tosolic pool directly. Dietary cholesterol incorporated into LDL is most commonly used for steroid hormone biosynthesis. Although free cholesterol represents only a small fraction of the total cholesterol pool, this fraction can be...

Increasing consumption what is being done

In several programmes, emphasis is placed on the education and involvement of children, because many of the processes linked to the development of chronic disease begin in childhood. Evidence from the Bogalusa Heart Study, tracking early risk of heart disease among American children, suggests that eating habits in childhood have a potential lifelong effect on cholesterol levels and on adult coronary heart disease.32 A study of British schoolchildren found that children who ate fruit more than once per day had better lung function compared with those who did not. The difference was evident even after controlling for possible confounding factors such as social class and passive smoking.33 A further study in Italy found that even low intakes of fruit can reduce wheezing and asthma with effects being most noticeable in children with a history of respiratory problems.34 Continued attention to increasing fruit and vegetable consumption in children is viewed as a practical and important way...

Triglyceride Triacylglycerol

Only one hydrogen atom, the fatty acid is said to be unsaturated. Triglycerides contain combinations of different saturated and unsaturated fatty acids. Those with mostly saturated fatty acids are called saturated fats those with mostly unsaturated fatty acids are called unsaturated fats (fig. 2.17). Within the adipose cells of the body, triglycerides are formed as the carboxyl ends of fatty acid molecules condense with the hydroxyl groups of a glycerol molecule (fig. 2.18). Since the hydrogen atoms from the carboxyl ends of fatty acids form water molecules during dehydration synthesis, fatty acids that are combined with glycerol can no longer release H+ and function as acids. For this reason, triglycerides are described as neutral fats.

Dairy consumption energy intake and body weight

The association between increased dairy product consumption and healthier body weights has been attributed to several milk components, including conjugated linoleic acid (Wang and Jones, 2004), medium-chain triglycerides (St-Onge and Jones, 2003), and particularly calcium (Heaney et al., 2002 Zemel, 2004). Surprisingly, the role of milk proteins has received little attention, despite the fact that protein makes up a major fraction of milk and is the most satiating among the three macronutrients (Anderson and Moore, 2004).

Common diseasecommon variant or not

At the time of writing, there are not enough data to be able to evaluate the extent to which the CD-CV hypothesis is true. There are a number of examples of common variants for complex diseases that are known (Lohmueller et al., 2003), and also clear examples of moderate allelic heterogeneity (at NOD2 CARD15, involved in Crohn's disease Hugot et al., 2001) and functional rare variants (associated with plasma levels of HDL cholesterol and LDL, and rates of sterol absorption Cohen

Dietary prevention of sudden cardiac death SCD the role of dietary fatty acids alcohol and antioxidants

Whereas PUFA of either the n-6 or n-3 family reduce that risk.4-6 Many (but not all) epidemiological studies have shown consistent associations between the intake of saturated fatty acids and CHD mortality.26 However, the SCD endpoint is usually not analysed in these studies. In addition, a clear demonstration of a causal relationship between dietary saturated fatty acids and SCD would require the organisation of a randomised trial, which is not ethically acceptable. Thus, besides the effect of saturated fatty acids on blood cholesterol levels, the exact mechanism(s) by which saturated fats increase CHD mortality remain unclear. If animal data, demonstrating a proarrhythmic effect of saturated fatty acids, are confirmed in humans, the first thing to do in order to prevent SCD in humans would be to drastically reduce the intake of saturated fats. In fact, this has been done in randomised dietary trials and, as expected, the rate of SCD decreased in the experimental groups.18'19...

Cardiovascular Disease

Regarding etiology and risk factors, three major types of stroke have to be distinguished ischemic stroke (IS), intracerebral hemorrhage (ICH), and sub-arachnoid hemorrhage (SAH), accounting for about 88 , 9 , and 3 of all strokes, respectively (American Heart Association, 2005). Major modifiable risk factors for IS identified in large-scale epidemiologic case-control and cohort studies include hypertension, diabetes, lack of physical activity, smoking and coronary artery disease (Boden-Albala and Sacco, 2004). Hypertension is clearly the most important modifiable risk factor for IS, but other factors, including heavy alcohol consumption, anticoagulant therapy and potentially low cholesterol levels may also play a role. For SAH, smoking appears to be a particularly strong risk factor (Longstreth et al., 1992).

Evidence That Exosomes Play A Role In Stressinduced Hsp72 Release

Independently of the classical secretory pathway (based on the inability of Brefeldin A treatment to inhibit stress-induced HSP72 release), and that non-specific processes such as cell lysis could not account for stress-induced release of HSP72 (Lancaster and Febbraio, 2005). However, and in contrast to the results of Broquet and coworkers, we were unable to confirm a role for lipid rafts in stress-induced HSP72 release. Using methyl- -cyclodextrin (the cholesterol depleting agent) to disrupt lipid raft function, our results demonstrate that lipid rafts do not play a role in stress-induced HSP72 release from human peripheral blood mononuclear cells (PBMCs) (Lancaster and Febbraio, 2005). Importantly, our data demonstrate that methyl- -cyclodextrin highly effectively depleted intracellular cholesterol levels in a dose-dependent manner, confirming that our methyl- -cyclodextrin treatment regimen was efficacious.

Dietary strategies to prevent the development of heart disease

For several decades, the prevention of CHD (including the prevention of ischaemic recurrence after a prior AMI) has focused on the reduction of the traditional risk factors smoking, HBP, hypercholesterolaemia. Priority was given to the prevention (or reversion) of vascular atherosclerotic stenosis. As discussed above, it has become clear in secondary prevention that clinical efficiency needs to primarily prevent the fatal complications of CHD such as SCD. This does not mean, however, that we should not try slowing down the atherosclerotic process, and in particular plaque inflammation and rupture. Indeed, it is critical to prevent the occurrence of new episodes of myocardial ischaemia whose repetition in a recently injured heart can precipitate SCD or CHF. Myocardial ischaemia is usually the consequence of coronary occlusion caused by plaque rupture and subsequent thrombotic obstruction of the artery.

What should be clarified beforehand

Interactions are important in the choice of combination regimens. Whereas interactions between antiretroviral drugs are well known, interactions with other concomitant medications are often less well characterized (see Interactions). The urgent need for more research was demonstrated in a study investigating the interactions between HAART and statins. In healthy volunteers, the measurement of plasma levels showed that levels of simvastatin were elevated by 3.059 after concurrent dosing with ritonavir or saquinavir (Fichtenbaum 2002). One fatal rhab-domyolysis on simvastatin and nelfinavir has been described (Hare 2002). Many drugs should not be combined with particular antiretroviral drugs, as incalculable interactions may occur. These include certain contraceptives. Even drugs that seem unproblematic at first glance can have unfavorable effects for example, the plasma levels of saquinavir can be reduced by half due to concurrent administration of garlic capsules (Piscitelli 2002)....

Dietary control of conventional risk factors cholesterol blood pressure type 2 diabetes and obesity

Cholesterol is a determinant of CHD mortality, and its blood level is at least partly regulated by diet. However, few epidemiological studies have prospec-tively included analyses of the dietary habits of the studied populations in the evaluation of their risk.119 In the Seven Countries Study, marked differences in CHD mortality, dietary habits and cholesterol distribution were observed in the different cohorts.119 Cholesterol levels were high in Northern Europe and in the USA (an average level of 7mmol L), and low in rural Japan (an average of 4mmol L), and population cholesterol levels were positively associated with CHD mortality. Secondary prevention trials with statins in Northern Europe120 and Australia121 confirmed the importance of cholesterol by demonstrating a reduction by 25-30 per cent of the relative risk of CHD death in patients taking these drugs. Whether the effect of statins was entirely related to their effect on cholesterol remains unknown. This was the basis of a...

Medical Decision Making

Directly from disease or indirectly through treatments of disease (via mechanisms such as hypoperfusion of the brain or systemic inflammation). Moreover, these decrements in executive function are associated with poor treatment adherence, which may serve to perpetuate or exacerbate the disease processes. For example, executive function has been associated with poor adherence to medication regimens for cholesterol lowering (Stilley et al, 2004) and HIV AIDS (Hinkin et al, 2003). Other cognitive functions, such as attention, prospective memory, and visuospatial-constructional ability, are also implicated in poor adherence to medication regimens (Hinkin et al, 2003 Stilley et al, 2004 Woods et al, 2008). Decisions to adhere poorly to prescribed treatments should therefore be understood as potential end-products of decrements in various cognitive functions.

Metabolism of Lipids and Proteins

Triglycerides can be hydrolyzed into glycerol and fatty acids. The latter are of particular importance because they can be converted into numerous molecules of acetyl CoA that can enter Krebs cycles and generate a large amount of ATP Amino acids derived from proteins also may be used for energy. This involves deamination (removal of the amine group) and the conversion of the remaining molecule into either pyruvic acid or one of the Krebs cycle molecules.

Breakdown of Fat Lipolysis

When fat stored in adipose tissue is going to be used as an energy source, lipase enzymes hydrolyze triglycerides into glycerol and free fatty acids in a process called lipolysis. These molecules (primarily the free fatty acids) serve as blood-borne energy carriers that can be used by the liver, skeletal muscles, and other organs for aerobic respiration. A few organs can utilize glycerol for energy by virtue of an enzyme that converts glycerol to phosphoglyceraldehyde. Free fatty acids, however, serve as the major energy source derived from triglycerides. Most fatty acids consist of a long hydrocarbon chain with a carboxyl, or carboxylic acid group (COOH) at one end. In a process known as P-oxidation (P is the Greek letter beta), enzymes

Fatty Acid Enrichment

Nutritionally interesting triglycerides can also be obtained by enrichment or removal of certain fatty acids from a TAG mixture, independent of the TAG structure involved. Especially in this area the fatty acid selectivity of certain lipases is rather important. Figure 3 Two-step synthesis of structured triglycerides. (Adapted from Ref. 89.) Figure 3 Two-step synthesis of structured triglycerides. (Adapted from Ref. 89.) A two-step enzymatic process was described, exploiting the high selectivity of Geotrichum candidum lipase B for cis-A-9 unsaturated fatty acids (20, 21). In the first step of the process this lipase was used to preferentially hydrolyze oleic and linoleic acid from sunflower oil at 40 C. This resulted in > 99 unsaturated fatty acids in the free fatty acid fraction (91). After separation of the free fatty acids by conventional distillation, reesterification with glycerol was carried out using immobilized Rhizomucor miehei lipase (Fig. 4). Running the process at 60 C...

Partial Glyceride Production A Monoglycerides

Monoglycerides are widely applied as emulsifiers or surfactants and are normally produced by high-temperature glycerolysis using an inorganic catalyst (4). The product is a mixture of mono- and diglycerides (1 1 w w) and residual triglycerides. Moreover, because of the reaction conditions applied, the crude product is often dark in color and has a burnt flavor. Obviously, this requires extensive purification during further down stream processing, generally involving molecular distillation. Because of the ambient reaction temperatures applied, lipase catalyzed processing has widely been investigated as the more natural process, with fewer byproducts and lower energy consumption. Another option is the use of Penicillium camembertii lipase (lipase G), which is a mono- and diglyceride specific lipase and not able to react upon triglycerides. Moreover, it was shown that the selectivity to produce monoglycerides over diglycerides is determined by the water activity applied during the...

The impact of cardiovascular disease

Owing to the enormous worldwide impact of cardiovascular disease it must be emphasized that even very modest reductions in risk factors, brought about by the appropriate design and use of functional foods, can have very important health related and economic significance. Statistics from the American Heart Association (see http www.americanheart.org statistics 03cardio.html) indicate the enormous impact of CVD. Over 61 million Americans have one or more types of CVD. CVD causes more mortality each year than the next seven leading causes of death combined and the estimated cost of cardiovascular diseases and stroke in the United States in 2003 was 352 billion. In developed countries, childhood obesity has reached epidemic proportions and this will certainly translate into a dramatic increase in type 2 diabetes which is characterized by elevated levels of triglycerides, LDL-C (low-density lipoprotein-cholesterol) and decreased levels of HDL-C (high-density lipoprotein-cholesterol), i.e....

Fortifying the Bile Acid Binding Ability

It is well known that soybean proteins have a cholesterol lowering effect in human serum (65,66). Several mechanisms for the regulation of serum cholesterol have been proposed. As a major one, an undigested insoluble fraction of soybean protein interacts with cholesterols and bile acids in the intestine, and they are excreted into an easing (67,68). Most probably, hydrophobic interactions play an important role in these interactions. Makino et al. found that the 114-161 residues in A1aB1b, one of the peptides generated by trypsin digestion of glycinin, have a bile acid binding ability (69). On the other hand, Iwami et al. confirmed that peptides generated by hydrolysis of mild acids contain residues having highly hydrophobic properties derived from -conglycinin, and these peptides actually bind bile acids (70).

Significance of Lipase

The first three factors damage the MFGM, making the core triglycerides accessible to lipase. Some casein micelles probably adsorb on exposed fat surfaces. Pipeline milking machines cause more damage to the MFGM than hand milking or bucket milking machines. Suction of air at teat cups (which causes foaming), risers, and change of dimensions in the pipeline and the hose connecting the clawpiece to the receiving jar are major potential sites for damage. Homogenization causes total replacement of the natural MFGM by a membrane composed of casein micelles or submicelles and whey proteins. Unless indigenous LPL is inactivated by pasteurization before or immediately after homogenization, rancidity will develop very rapidly. Minimal high temperature short time (HTST 72 C for 15 sec) pasteurization of milk causes extensive inactivation of LPL but pasteurization at 80 C for 10 sec is required for complete inactivation.

Management of Side Effects

It must be stressed that the majority of patients are able to tolerate HAART well, even over years. Nevertheless, the monitoring of treatment by an HIV clinician, is recommended in at least three-monthly intervals, even in asymptomatic patients, and more often at the beginning of a new HAART, when it should be weekly or fortnightly. Standard evaluations include a thorough history (allergies , other side effects ), physical examination and measurement of vital signs and body weight. Routine investigations include a full blood count, liver, pancreas and renal function tests, electrolytes (plus phosphate in patients on tenofovir) as well as fasting cholesterol, triglycerides and glucose levels.

Other Applications of Lipases

An important new application of lipases is in the trans interesterification of fatty acids on triglycerides (75). This approach can be used to modify the melting point of triglycerides, and hence their rheological properties. An important application of this technology is in the production of cocoa butter substitutes for chocolate manufacture. Mono- or polyunsaturated fatty acids may also be introduced to relatively saturated milk lipids to improve their nutritional qualities. Immobilized lipase systems have been developed for these applications (74).

Liver X and Farnesoid X Receptors

In addition, FXR activates expression of yet a fourth orphan receptor, SHP-1, which then dimerizes with the constitutively active LRH-1 and attenuates LRH LXR-mediated transcription of CYP7A, preventing further synthesis of bile acids from cholesterol.417 Despite its crucial role in gating bile acid biosynthesis and cholesterol clearance, LXRa is apparently not essential for survival as deletion of mouse LXRa yields phenotypically normal mice.418 However, when challenged with a high-cholesterol diet, these animals accumulate cholesterol in the liver due to failure to induce CYP7A activity, in spite of the presence of functional LXRp. Oxysterols apparently also upregulate expression of proteins involved in sterol lipid transport. For example, certain ABC transporters involved in lipid transport and cholesterol ester transfer proteins are activated through LXR signaling.419-421 An additional level of regulation may include transcriptional induction of...

Relationship to Classical Indexes

It is important to analyze whether the previous analysis methodology for parameterizing the vessel behavior during the flow-mediated dilation test is linked to other clinical parameters and CVD risk factors traditionally used in the medical literature. Serum lipids, particularly cholesterol and the cholesterol fraction carried by low-density lipoproteins (LDL cholesterol) are recognized as a main causal factor of atherosclerosis 34 . In this disease lipids accumulate in the vessel wall, disturbing the vascular function of delivering sufficient blood flow to the affected territories, which ends with the manifestation of a vascular clinical event like heart attack or stroke. Moreover, knowing patients' lipid levels and modifying them with drugs and diet is the main preventive tool against cardiovascular diseases. From this point of view, cholesterol and LDL cholesterol are considered as risk factors, as higher levels identify individuals with higher risk whereas the cholesterol fraction...

Clinical manifestation

Frequently, complex metabolic alterations are associated with the described body shape alterations. These include peripheral and hepatic insulin resistance, impaired glucose tolerance, type 2 diabetes, hypertriglyceridemia, hypercholesterolemia, increased free fatty acids (FFA), and decreased high density lipoprotein (HDL). Often these metabolic abnormalities appear or deteriorate before the manifestation of fat redistribution. The prevalence of insulin resistance and glucose intolerance has been reported in the literature at 20 to 50 depending on the study design and measurement methods. Frank diabetes is less frequent with a prevalence of between 1 and 6 . Lipodystrophic patients present with the highest rates of metabolic disturbances. The therapy-induced dyslipidemias are characterized by increased triglyceride-rich very low density lipoproteins (VLDL) and to a lesser extend by raising low density lipoproteins (LDL). Detailed characterization revealed an increase of...

FMD Response Eigen Parameterization

As can be concluded from Table 5.7, a weak but significant correlation was found between AFMDc and LDL cholesterol in a damaging way and between AFMDc and HDL cholesterol in a protective way. This had been previously reported when studying dyslipidemic populations with a similar correlation magnitude, association that could be slightly attenuated in our population due to a narrower range of lipids variation. For instance, Kuvin et al. 38 found a correlation coefficient of HDL cholesterol and AFMDc of 0.3. The correlation between classical flow-mediated dilation and LDL cholesterol (r -0.40) had been previously reported by Aggoun et al. 39 in hypercholesterolemic patients. Other studies report one of these associations but rarely both or with stronger association coefficients 40 and never in natural large populations with normal lipid levels 41 . Triglycerides correlated significantly with baseline diameter, 0basal. The presence of wider vessels has been described for high-risk 38 and...

NRTI and lipodystrophy

The patterns of fat redistribution in patients who are exclusively receiving NRTIs are unlike those observed in patients during PI therapy. Peripheral fat loss is the major symptom observed in NRTI therapy (particularly using stavudine and di-danosine combinations), although a few clinical studies have described a minimal intra-abdominal fat increase in these patients, which is clearly less than under PIs. Given that, commonly, only a mild increase in triglycerides has been observed, exclusive NRTI therapy seems to be of minor impact on lipid metabolism. Postpran-dially elevated FFA in patients with lipodystrophy, together with in vitro experiments, have led to the hypothesis that NRTIs could impair fatty acid binding proteins (FABP) which are responsible for cellular fat uptake and intracellular fat transport. In contrast, addition of stavudine (Zerit ) to a dual PI regimen does not result in a further increase in the total cholesterol or triglyceride levels. It is well established...

Protease inhibitors and lipodystrophy

PIs account for the majority of metabolic abnormalities associated with lipodystrophy syndrome. Numerous studies report increases in the levels of total triglycerides and triglyceride-rich lipoproteins (VLDL) accompanied by raised LDL levels after initiation of PI therapy (Walli 1998). Conversely, these parameters improved substantially in most studies after discontinuation of the PI or on switching to abacavir (Ziagen ) or nevirapine (Viramune ). The hyperlipidemic changes are frequently associated with hyperinsulinemia and or insulin resistance.

Specific interventions

Given the extensive indications that PIs are the culprits substantially contributing to the metabolic side effects, numerous attempts have tried to substitute the PI component of a regimen with nevirapine, efavirenz, or abacavir. Similarly, given the close association of stavudine-based therapy with lipoatrophy, replacement of this thymidine nucleoside analogue by, for example, abacavir or tenofovir has been evaluated in several studies. Indeed, these switch studies have demonstrated substantial improvement, although not normalization, of serum lipids (total and LDL cholesterol, triglycerides) and or insulin resistance in many patients. In patients with hy-perlipidemia, substitution of PIs with alternative PIs that have less metabolic side effects (e.g. atazanavir) has also been proven to be a successful strategy (Martinez 2005, Moebius 2005). Protease inhibitor cessation has not been shown to improve lipoatrophy. However, stopping administration of the thymidine nucleoside analogue...

Vitamin E and Creactive protein

C-reactive protein (CRP) is extremely important because it is emerging as a major risk factor for atherosclerosis and cardiovascular disease (Folsom, 1999). Patrick and Uzick (2001) have written an excellent review on the relationship of cardiovascular disease to CRP. The association between atherosclerosis and CRP is strong even in the absence of classical risk factors such as high cholesterol, triglycerides, and blood pressure (Ridker et al., 2001).

Pathogenesis of mitochondrial toxicity

NRTIs are prodrugs (Kakuda 2000) because they require activation in the cell through phosphorylation before they are able to inhibit their target, e.g. HIV reverse transcriptase. In addition to impairing the HIV replication machinery, the NRTI-triphosphates also inhibit a human polymerase called polymerase-gamma, which is responsible for the replication of mitochondrial DNA (mtDNA). Thus, the inhibition of polymerase-gamma by NRTIs leads to a decline (depletion) in mtDNA, a small circular molecule normally present in multiple copies in each mitochondrion and in hundreds of copies in most human cells (Lewis 2003). The only biological task of mtDNA is to encode for enzyme subunits of the respiratory chain, which is located in the inner mitochondrial membrane. Therefore, by causing mtDNA-depletion, NRTIs also lead to a defect in respiratory chain function. An intact respiratory chain is the prerequisite for numerous metabolic pathways. The main task of the respiratory chain is to...

Reactive protein and the etiology of atherosclerosis

Additional evidence suggesting that the lowering of CRP could be important in preventing CVD comes from recent research on the use of statin therapy in the primary prevention (i.e. in people who have no obvious heart disease when enrolled in the study) of acute coronary events (Ridker et al., 2001). Statins are very popular and effective drugs that reduce plasma-cholesterol and LDL-C levels. It is very interesting, however, that statins also reduce CRP levels. Work by Ridker et al. (2001) found that statin therapy could reduce the risk of acute coronary events associated with CRP even in the absence of elevated blood lipids.

Project Title Cvd Risk Health In Postmenopausal Phytoestrogen Users

Summary (Adapted from Investigator's Abstract) In the United States, heart disease is the leading cause of death in postmenopausal women. Estrogen replacement therapy is beneficial for heart disease risk factors as well as for bone density. However, a large proportion of postmenopausal women are not compliant with therapeutic regimens. Phytoestrogens are naturally occurring compounds found in plants and soy products that have estrogenic effects, and may represent an alternative treatment for the prevention of heart disease and osteoporosis in postmenopausal women. However, few intervention trials have examined the extent to which it is possible to improve heart disease risk factors, bone density, and quality of life in postmenopausal women through use of a dietary supplement of Phytoestrogen. The proposed randomized, double-blind, placebo controlled study is designed to determine the acceptability and benefits of use of a dietary supplement of Phytoestrogen (genistein) versus placebo...

Bacterial Cholesterol Metabolism

The intestinal tract has a major impact on cholesterol metabolism (34-36). A major source of intestinal cholesterol comes from the de novo synthesis of the sterol compound. Cholesterol also can enter the intestine from dietary sources. It has been estimated that 34-57 of dietary cholesterol is absorbed from the intestine (37). In humans cholesterol synthesized by the intestinal cells is introduced into the lumen by exfoliation of these cells. An additional source of intestinal cholesterol is via biliary excretion.

Protease inhibitors PIs

All protease inhibitors can be used in combination with 2 NRTIs. PIs differ from each other in respect to their tolerability and side effects. As with adults, dyslipide-mia is associated with the use of protease inhibitors (Lainka 2002). It includes elevated total cholesterol, triglycerides (TG), and low density lipoprotein cholesterol (LDL-c) and decreases in high density lipoprotein cholesterol (HDL-c) In lipodys-trophy, there is a loss of subcutaneous fat (lipoatrophy) and or a deposition of fat tissue subcutaneously or in visceral stores (lipohypertrophy) including the presence of dorsocervical fat accumulation (buffalo hump) and increased waist-to-hip ratio. Lipoatrophy is marked by thinning of subcutaneous fat in the face, buttocks, and extremities associated with a prominent appearance of peripheral veins. The body habitus changes usually occur gradually over months to years. The exact prevalence of lipodystrophy in children is unknown and there are no clear diagnostic...

Monogenic genes as genetic risk factors in common disease

Figure 10.1 Mortality from familial hypercholesterolemia according to sex and time. Mortality was estimated among 250 persons with 0.5 probability of carrying the V408M. Probands and the first 20 years of life were ignored. From Sijbrands et al., 2001. Figure 10.1 Mortality from familial hypercholesterolemia according to sex and time. Mortality was estimated among 250 persons with 0.5 probability of carrying the V408M. Probands and the first 20 years of life were ignored. From Sijbrands et al., 2001. Goldstein, J., Hobbs, H. and Brown, M. (2001). Familial hypercholesterolemia. In Scriver, C., Beaudet, A., Sly, W. and Valle, D., eds., The Metabolic and molecular bases of inherited disease. New York McGraw-Hill. pp. 2863-913. in Alzheimer's disease. Annu Rev Med, 47, 387-400. Rozmahel, R., Wilschanski, M., Matin, A. et al. (1996). Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet, 12, 280-87....

Risk factors for coronary heart disease CHD the role of oxidative stress

There is experimental and clinical evidence indicating that hypercholesterolemia is associated with enhanced oxidative stress. Oxygen free radicals, such as O2*, and F2-isoprostanes, have been found elevated in the artery of hypercholesterolaemic animals and in the urine of patients with high serum cholesterol respectively.28'29 The relevance of these findings in the context of the pathophysiology of atherosclerosis is unclear, even if there is some evidence that in this setting oxidative stress may have a role in reducing the vasodilation of endothelium.30 Conversely, these is no evidence yet that the increase of these markers actually represents a marker of progression of atherosclerotic disease. Two hypotheses can be suggested to explain why hypercholesterolaemia enhances oxidative stress (Fig. 5.1, panel A,B). Cholesterol has been recently shown to activate the metabolism of the arachidonic acid pathway,31 which in turn seems to be associated with NAD(P)H oxidase activation.26...

Race Ethnic Heterogeneity in Health Status

Highest triglyceride and fasting plasma glucose levels, the lowest concentration of high density lipoprotein (HDL) cholesterol, and the lowest median blood pressure levels (Bhopal et al, 1999). CVD risk factor prevalence varies further among Indians. For example, Punjabi Sikhs from North India have lower rates of smoking compared to Gujarati Hindu men from West India, largely because of religious prohibitions on smoking. Punjabis, however, have higher blood pressure and cholesterol levels (Forouhi and Sattar, 2006).

EGCG Modulation of Food Intake and Endocrine Systems

In male rats treated with EGCG for one week, the serum level of protein, fatty acids, and glycerol were not altered, but significant reductions in serum glucose (-32 ), lipids (-15 ), triglycerides (-46 ) and cholesterol (-20 ) were observed. Based on proximate composition analysis, there was no change in water and protein content, a moderate decrease in carbohydrate content, but a very large reduction in fat content, decreasing from 4.1 in control to 1.4 in EGCG-treated group. EGCG treatment also decreases subcutaneous fat by 40 to 70 , and abdominal fat by 20 to 35 in male rats (1, 26). Reduction of body fat may also influence the hormonal levels in animals and influence tumor growth.

Cholesterol Lowering Conjugates Designed to Function Through the Hepatic Lectin

In contrast to the approaches described above in which molecules designed to function within the liver are delivered through their interaction with the hepatic lectin, a strategy to use the hepatic lectin to eliminate unwanted species from serum has also been investigated. Specifically, Biessen et al. attempted to take advantage of hepatic lectin mediated endocytosis and subsequent ligand proteolysis to lower serum cholesterol levels 134 . It was anticipated that targeting the proteins responsible for serum cholesterol transport, high-density lipoprotein (HDL) and low-density lipo-protein (LDL), to hepatocytes via the hepatic lectin would lead to their degradation, thereby lowering serum cholesterol. Bifunctional ligand 29 was designed, in which cholesterol was linked to a trivalent galactose derivative (Fig. 20). When added to serum, compound 29 formed complexes with HDL and LDL. Intravenous injection of 29 into rats resulted in a decrease in detected serum cholesterol levels by 44 ....

Project Title Evaluating Reasons For Variations In Ldl Levels

Summary (provided by applicant) Ischemic heart disease is a major health problem in the United States where secondary prevention therapies have been demonstrated to improve morbidity and mortality. Multiple guidelines have been published which recommend cholesterol lowering for patients with ischemic heart disease. Despite these recommendations, wide variations exist in the achievement of these target LDL levels. The purpose of the current project is to identify patient characteristics, processes of care and structures of care that are associated with these variations in compliance of target LDL levels. A cross-sectional study design will be used. Information will be gathered from secondary data sources, using the Veterans Health Administration databases and through primary data collection, by surveying care providers. Thirty clinics or facilities and approximately 10, 000 patients will be included in the sample. Once identified, these factors can serve as the focus for future quality...

In Situ Profiling Of Transcription In The Gi Tract

Fucose and coordinates the decision to generate a signal for production of host fucosylated glycans when environmental fucose is limited or to induce expression of the bacteria's fucose utilization operon when fucose is abundant (68). Additional studies have evaluated the global intestinal response to colonization of gnotobiotic mice with B. thetaiotaomicron. This colonization dramatically affected the host's gene expression, including several important intestinal functions such as nutrient absorption, mucosal barrier fortification, and postnatal intestinal maturation (9). From the in situ global transcription profiles mentioned above and follow-up experiments it could be established that the production of a previously uncharacterized angiogenin is induced when gnotobiotic mice are colonized with B. thetaiotaomicron, revealing a mechanism whereby intestinal commensal bacteria influence GI-tract bacterial ecology and shape innate immunity (69). In addition, the cellular origin of the...

Clinical Relevance and Disease Prediction

As described by McCarthy and colleagues (McCarthy et al, 2008) clinical translation of recent GWA successes in the identification of susceptibility variants for complex diseases can take two routes. In the first, detection of novel loci - even with small effect sizes - may reveal new insights into disease pathogenesis leading to identification of new therapeutic targets. Such treatments may well be effective in individuals without the specific genetic variant that led to its discovery. Perhaps the best example is the development of HMG-CoA reductase inhibitors (statins) that effectively lower cholesterol levels in nearly everyone, except in individuals with homozygous absence of LDL-receptors who were instrumental in identifying this key metabolic pathway (Manolio et al, 2008).

Pharmacological Toxicological Effects 51 Cardiovascular Effects

A recent meta-analysis using multiple databases, from inception until November 1998, compiled all randomized, double-blind, placebo-controlled trials using monopreparations of garlic, to test the effectiveness of garlic in lowering total cholesterol (TC) (15). Inclusion criteria included trials in which participants had elevated TC, defined as 5.17 mmol L (200 mg dL) at baseline, and reported TC levels as an end point. Studies were excluded if they did not contain enough data to compute effect size. Of the 39 garlic-in-hyperlipi-demia studies identified, 21 were excluded because they were not placebo-controlled, randomized, double-blinded, did not use a monopreparation of garlic, did not report TC, or have a baseline TC meeting inclusion criteria. An additional five trials did not include enough data to perform statistical pooling. Of the 13 studies cited in the meta-analysis, 10 used Kwai powder tablets in doses of 600, 800, and 900 mg day. One study used 700 mg of spray-dried powder...

Examples of Gene Environment Interaction

Many examples of gene-environment interactions involving health-related behaviors may be cited. For instance, high density lipopro-tein cholesterol (HDL) concentrations have been shown to vary by interaction of dietary fat intake and genetic variation in hepatic lipase, a key enzyme in HDL metabolism (0rdovas et al, 2002 Tai et al, 2003). In addition, the degree of cholesterol lowering achieved by consumption of a polyunsaturated, compared to saturated, fat diet may be predicted by polymorphic variation in genes encoding the cholesterol ester transfer protein (CETP) and lipopro-tein lipase (LPL) (Wallace et al, 2000). An asparagine aspartic acid substitution in LPL has also been shown to magnify effects of cigarette smoking on risk of incident ischemic heart disease (Talmud et al, 2000). Likewise, the e4 allele of the apolipoprotein E gene (APOE) increases smoking-related risk for coronary disease events in prospective investigations (Humphries et al, 2001, 2003). A third health...

Project Title Homocysteine Diet Study Effects Of Different Folate Sources

Summary Homocysteine is a factor found in blood that has been found to be elevated among adults with heart disease, similar to elevated blood cholesterol levels. This relatively risk factor for heart disease has been found to respond to the dietary vitamin known as either folate or folic acid. There are three different sources of folate in the diet.

Consumption of soybean and reduced incidence of disease

Soybean consumption has also been linked to a reduced risk for cardiovascular disease (47). Addition of soybean to foods has been shown to result in reduced cholesterol (67). In 1999, the US Food and Drug Administration reported that the consumption of soy protein as part of a healthy diet could help reduce the risk of coronary heart disease by lowering blood cholesterol levels (68). Soy protein isolates typically contain soybean isoflavonoids, which are believed to be largely responsible for the health benefits assigned to soy protein. Related herbal flavanoids prevented in vitro platelet aggregation and in vivo thrombogen-esis in mouse arteries (69). Inclusion of isoflavonoid rich soybean in diets was also reported to protect against coronary heart disease by causing reductions in blood lipids, oxidized LDL, homocysteine, and blood pressure (7).

The present regulatory framework 1221 The US

Although a functional food is not necessarily a novel food, several functional products (mainly products, including dairy products, containing cholesterol-lowering phytosterols or -stanols) have been authorized according to the procedures outlined in the Novel Food Regulation (http ec.europa.eu comm

Project Title Impact Of Chd Risk Perception On Health Behaviors And O

Summary (Applicant's abstract) The overall goal of the proposed study is determine if perceived risk of heart disease among postmenopausal women enrolled in the Observational Study (OS) of the Women's Health Initiative (WHI) in the New York Clinical Center, differs by race, and if risk perception is related to health behaviors. The applicant's long-term career goals are to become an independent investigator with special scientific interest in determining the key psychosocial contributors to racial and gender disparity in heart disease morbidity and mortality. In the proposed study, the first phase will be to develop and pilot test a methodologically sound instrument that measures perceived risk of heart disease. The second phase will be to administer this instrument to 300 White, African-American and Hispanic women at higher risk of heart disease because of smoking status, hypertension, diabetes or high cholesterol (requiring pills) and to determine the relationship of risk perception...

Using Hormonal Strategies To Improve Mammographic Density And Sensitivity Of Screening Mammograms

There may be women in whom reducing hormone levels will not result in reduced density. For such women and for women who due to medical (high cholesterol) or other reasons do not wish to reduce their hormone levels, alternative imaging techniques, currently being developed and tested, may be a good alternative.52

Early Adversity and Health Outcomes Tests of the Model

Metabolic functioning is a complex of risk factors for coronary artery disease and diabetes and is typically defined by fasting glucose, cholesterol, triglycerides, and abdominal obesity, among other indicators. High levels of these variables contribute to metabolic syndrome, which is prognostic for heart disease, diabetes, inflammatory disorders, and all-cause mortality (see Chapter 46). The prevalence of metabolic syndrome in the United States is approximately 22 (McEwen and Seeman, 1999), making it an important contributor to chronic illness.

Children Of Centenarians

Offspring of centenarians have been found to have lipid profiles associated with lower risk for cardiovascular disease (Barzilai, Gabriely, Gabriely, Iankowitz, and Sorkin, 2001). Other findings show that middle-aged sons of long-lived parents had better systolic pressures, cholesterol levels, and decreased frequencies of the apoE fi-4 allele, compared to middle-aged sons of shorter-lived parents. Using a questionnaire-based cross-sectional study design, Terry and colleagues (2004) assessed the

Results and Discussion

Commensurate with the lower FAS protein expression, FAS RNAi resulted in a 4.0-fold decrease of FAS activity in LNCaP extracts, and reduced total lipogenesis as quantified by measuring the incorporation of 2- 14C -labeled acetate into cellular lipids of growing LNCaP cells (27). To investigate the impact of the decreased lipid synthesis by silencing the different lipid species, lipid extracts were analyzed by TLC for phospholipids and neutral lipids, respectively. The majority of 14C -label in control cells was incorporated into phospholipids (80 ), specifically in phospholipids partitioning into detergent-resistant membrane microdomains (28). FAS RNAi caused 2.0- to 3.0-fold decrease in the synthesis ofthese phospholipids, suggesting that FAS plays an important role in the control of membrane microdomain biology. Smaller amounts oflabel were found in triglycerides and free cholesterol (Figure 3). FAS RNAi caused a 7.0-fold decrease in the synthesis of triglycerides in LNCaP cells. In...

Biomarkers of Disease State

Epidemiology has been used to identify many risk factors for disease, including high blood pressure, elevated cholesterol levels, and excessive adiposity in CHD. In some cases, the information is valuable because it may help identify serious problems that have not been diagnosed clinically, so allowing researchers to estimate the clinical iceberg. For example, results from the English Longitudinal Study of Ageing (ELSA) found that 77 of men and 84 of women had total cholesterol levels above the UK recommended level of 5.00 mmol l (193 mg dl), even though in many cases no medical advice or treatment had been given. A significant proportion of respondents (18 men, 16 women) had blood pressure levels in the hypertensive range even though hypertension had never been diagnosed (Pierce et al, 2006). These findings point to failures in primary prevention and unmet clinical needs.

Project Title Osteoblastogenesis In Aortic Valve Calcification

Summary (provided by applicant) This proposal is for a new K08 application which proposes a detailed plan for the candidate's research and a 4-year goal driven plan for further career development. The candidate's career goal is to become a successful independent scientific investigator. A career development plan is described that delineates the specific goals over the award period and the mechanisms that will be used to achieve them. Through didactic training and ongoing supervision through mentors and advisory committee, the candidate expects to 1) further develop as a basic science investigator, 2) conduct the proposed study with the highest degree of quality 3) present and publish studies in valvular heart disease at National conferences and leading journals 5) compete for advanced sources of funding and 6) develop insights in to the pathogenesis of valvular heart disease. The underlying mechanism for the pathogenesis of calcific aortic stenosis is unknown. This trend is becoming...

Other Targets for AntiHDV Therapy

Because the production of mevalonate by the enzyme HMG-CoA reductase is a committed step in both the cholesterol and prenyl lipid biosynthetic pathways (Zhang and Casey 1996), it has been suggested that HMG-CoA reductase inhibitors-which are in widespread clinical use to treat hypercholesterolemia-might be used to inhibit prenylation. Prenylation can indeed be inhibited in vitro by an HMG-CoA reductase inhibitor, but the doses required are cytotoxic (Sinensky et al. 1990). Because cellular needs for cholesterol can be exogenously supplied via the low density lipoproteins receptor system, synergy between HMG-CoA reductase inhibitors and FTIs can be considered. Similar potential synergistic effects might also be achieved by combining FTIs with other classes of drugs which inhibit additional steps in the pathway of prenyl protein synthesis. For example, most prenylated eukaryotic proteins are further processed by the sequential activity of the products of the Rce-1 (CXXX-box...

Project Title Premenopausal Risk Factors For Coronary Heart Disease In Black White Women

Summary Premenopausal black women have a 2- to 3-fold greater rate of coronary heart disease (CHD) than premenopausal white women. The purpose of this study was to provide greater insight into the reasons for this difference, which are currently unclear. We compared CHD risk factors in 99 black and 100 white, healthy, premenopausal women, aged 18 to 45 years, and of relatively advantaged socioeconomic status. Compared with white women, black women had a higher body mass index (32.0 _ 9.2 vs 29.0 _ 9.4 kg m2, p 0.021), and higher systolic (124 _17 vs 115 _ 14 mm Hg, p< 0.0001) and diastolic (79 _ 14 vs 75 _ 11 mm Hg, p 0.048) blood pressures. The mean plasma lipoprotein(a) concentration was markedly higher in the black women (40.2 _ 31.3 mg dl) than in the white women (19.2 _ 23.7 mg dl, p< 0.0001). The plasma total homocysteine level was also higher in the black women (8.80 _ 3.38 vs 7.81 _ 2.58 umol L, p 0.013). The black women, however, had lower plasma triglyceride levels (0.91...

Osteoporosis and Cardiovascular Disease in the Elderly

Osteoporosis and cardiovascular disease are common disorders that increase with aging. Accumulating evidence indicates that both disorders may share common pathophysiologic mechanisms as well as risk factors. Besides age and sedentary lifestyle, diabetes, hypertension, dyslipidemia, estrogen deficiency, and hyperhomo-cysteinemia are common risk factors for both disorders. Furthermore, therapeutic agents for osteoporosis have antiatherosclerotic properties and agents such as statins that are atheroprotective, and appear to increase bone mass and perhaps protect against fractures.

Pathophysiology of the Metabolic Syndrome

Increased circulating FFA has been hypothesized to lead to tissue-specific lipotoxicity (Kusminski et al, 2009 Unger, 2003). Elevated FFA levels inhibit insulin-stimulated skeletal muscle glucose uptake and increase hepatic glucose production (Boden, 1999), thus contributing to peripheral insulin resistance. Further, the increase in FFA levels promotes increased hepatic triglyceride synthesis and storage, and the excess triglycerides are secreted as very low-density lipoproteins (VLDL) (Lewis, 1997), which lead to an increased production of LDL. Elevated plasma triglycerides are inversely correlated with HDL-C levels (Austin, 1989), which is thought to occur by the action of cholesteryl ester transfer protein (Sandhofer et al, 2006). This leads to smaller, triglyceride-rich HDL particles with higher catabolic rate due to increased renal clearance, which results in reduced HDL levels (Ji et al, 2006). In similar fashion, elevated triglyceride levels lead to formation of atherogenic...

Gh Treatment Of Patients With Abdominal Obesity

We have learned that GH can improve several of the aberrations that occur both in GH deficiency and Syndrome X. Thus, in GH-deficient adults the lipolytic effects of GH results in a preferential reduction in visceral adipose tissue (66). Furthermore, GH reduces the diastolic blood pressure (103), reduces total cholesterol, LDL-cholesterol (57,104-106), and increases HDL-cholesterol concentrations (78,105,107). Furthermore, long-term GH treatment does not impair insulin sensitivity (82). With this background we have studied the effects of GH on the metabolic, circulatory, and anthropodometric aberrations associated with abdominal visceral obesity and Syndrome X (108).

Genetic and environmental contributions to CHD pathogenesis

Whilst environmental influences account for a significant part of individual and population susceptibility to CHD, the longevity of some individuals with multiple risk factors (e.g. smoking, hypercholesterolemia, hypertension), and the consistent and highly significant risk conferred by a positive family history of CHD, point to the importance of genetic factors in CHD pathogen-esis. Genes which control plasma lipids and lipoproteins are amongst the clearest examples of genetic risk factors for CHD (Table 24.1). Raised LDL cholesterol, triglycerides reduced HDL cholesterol

Etiology and Pathogenesis

The relationship between depression and cardiovascular disorders also provides insight into the mechanisms of depression. Abnormalities in neurotransmitters (including serotonin), platelet-activating factor, and nitric oxide, which are involved in atherosclerotic processes, have been implicated in the pathogenesis of depression (Plante, 2005). Moreover, vascular consequences of depression such as heart rate and pulse pressure variations may lead to endothelial dysfunction in critical microcirculation networks (cerebral, myocardial, and renal) and initiate physicochemical alterations in interstitial compartments adjacent to vital organs. Worsening depressive symptoms after a coronary event were associated with impaired autonomic control of the heart, and mortality was almost three times higher among the patients with MDD at the time of the initial event compared to those without depression (de Guevara et al., 2004). The finding of higher rates of relapse of depression among patients...

Evidence for the genetic basis of CHD

Family history of the disease is one of the strongest and most consistent risk factors for CHD. Relative risk estimates of between 1.5 and 5 have been derived from a range of family and population studies (Hawe et al., 2003 Lusis, 2003). At least a part of the risk of family history is conferred by the monogenic dyslipidaemias, including familial hypercholesterolemia (FH) (Goldstein et al., 1973), which carry a high penetrance of CHD. However, since the frequency of the FH heterozygous state, and of other monogenic dyslipidaemias, is only at

Genetics of monogenic and complex dyslipidemias

Disorders of lipid metabolism, both monogenic and more genetically complex, are powerful risk factors for CHD. The major circulating lipids, cholesterol, phospholipids and triglycerides, are carried in the blood by several lipoprotein particles serving the physiological task of transporting dietary and endogenously produced lipids to peripheral tissues. The major pathways of lipoprotein metabolism in humans are illustrated in (Figure 24.1). Mutations in many of the lipoproteins, receptors and enzymes shown in the figure have been described in humans or engineered in rodents. Studies of these mutations have yielded the molecular basis of a wide range of dyslipidemias and in many cases elucidated the mechanism by which dysfunction of these proteins predispose to, or protect against, atherosclerosis and CHD.

Monogenic disorders causing impaired reverse cholesterol transport

Low HDL cholesterol is a common finding in patients with premature CHD and usually precedes clinically apparent CHD (Goldbourt et al., 1997). Low HDL concentrations are most frequently associated with the components of the metabolic syndrome X and are rarely due to single-gene disorders (Durrington, 2003). The rare Tangier disease, characterized by very low or even Conversely, cholesterol ester transfer protein deficiency, which is a common cause for high HDL concentrations (> 2.5 mmol l) in Japan is thought to be a state of impaired reverse cholesterol transport, which may lead to premature CHD (Nagano et al., 2002). Thus, HDL cholesterol levels, efflux of cellular lipids as well as the kinetics of HDL metabolism are important determinants of the antiatherogenic effect of HDL (Tall, 1998 von Eckardstein, 2001).

Oligopolygenic complex genetic hyperlipidemias

Combined hyperlipidemia, characterized by increased serum triglyceride and or cholesterol and decreased HDL cholesterol is the most common disorder of lipid metabolism affecting 1-2 of individuals in Western societies. The term familial combined hyperlipidemia (FCHL) was coined by Goldstein et al. to describe a pattern of lipid abnormalities (Goldstein et al., 1973) in survivors of myocardial infarction who had raised blood cholesterol and triglyceride levels. Originally, FCHL was described as a dominant disorder with a primary effect on blood triglyceride levels, a secondary effect on cholesterol levels, and with incomplete penetrance until the third decade (Goldstein et al., 1973). However subsequent segregation analyses (Austin, 1992

Genetics of human coronary heart disease

The heritability of known risk factors that were included in this linkage study (including type 2 diabetes mellitus and hypertension) was high, suggesting that these intermediate phenotypes are genetically determined to a moderately high extent. However, whereas age, gender, diabetes and hypertension contributed significantly to the myocardial infarction phenotype, high cholesterol levels did not. Since many of the individuals in the study were on lipid-lowering therapy, this suggests that hypercholesterolemia now appears to be a less significant risk factor for myocardial infarction than diabetes and hypertension. The possibility that Cd36 deficiency in humans might be a cause of insulin resistance arose initially from rodent studies (Aitman et al., 1997b 1999 Pravenec et al., 2001). Cd36 is a multi-functional protein and belongs to the scavenger receptor family typified by SrB1 and mediates the specific uptake of long chain-free fatty acids by adipocytes and muscle cells. Cd36 is...

Project Title Reducing Heart Disease Risk With Getthefatout

Summary (provided by investigator) Despite enormous public health efforts, heart disease remains the number one killer, partly due to the prevalence of high dietary fat intake and sedentary lifestyles. At the same time and for many of the same reasons, obesity is becoming increasingly prevalent, bringing with it increased risk of heart disease, hypercholesterolemia, diabetes, hypertension, and some forms of cancer. In an effort to address the dietary behaviors that promote both heart disease and obesity, Health Management Consultants of Virginia proposes to develop Get-the-Fat-Out, an Internet data based behavior modification program targeted for at-risk adults at varying stages of readiness for changing dietary fat intake and physical activity level. The ultimate goal of Get-the-Fat-Out is to facilitate life-long habits of maintaining a healthy weight, an active lifestyle, and a low-fat diet. Specific aims for Phase I are 1) Develop initial and on going intervention-integrated...

Insights from rodent models

Early loss-of-function studies focused on molecules previously identified as potentially important modifiers of lipid handling. From these studies, apoE (Plump et al., 1992 Zhang et al., 1992) and the LDL receptor (Ishibashi et al., 1993) were confirmed as important modifiers of cholesterol levels. Mice lacking either apoE or the LDL receptor develop significant atherosclerotic lesions when fed a high fat diet. This observation paved the way for a deluge of studies looking at genetic influences on atherosclerosis lesion size in apoE and LDL receptor knockout mice (Glass and Witztum, 2001). Consequently, a solid body of new information has emerged on the mechanisms regulating plasma lipoprotein levels and controlling the initial stages of atherogenesis. The obvious advantage of studying the effect of a gene in mice predisposed to developing atherosclerosis is that anti-atherogenic effects of a gene may be more readily detected (Table 24.3). QTL studies of atherosclerosis with...

Potential risks of PEP

The risks of PEP mainly concern the adverse effects of the antiretroviral substances, most frequently gastrointestinal symptoms such as nausea, vomiting or diarrhea. Changes of hematology, transaminases or creatinine are also possible. Additionally, there have been reports of elevated triglycerides and cholesterol levels, and insulin resistance even in short term use of protease inhibitors (Parkin 2000). It is unknown whether the temporary use of antiretroviral substances may lead to long term side effects, but this seems to be secondary since the main emphasis is to prevent a chronic and potentially life-threatening disease. For pregnant women particular caution is required since data concerning teratogenicity are lacking.

The Role Of Fibrinogen In Hemostasis

Fibrinogen is the principal substrate of the coagulation and fibrinolytic system. This clotting factor has the highest molecular weight of all of the clotting factors, and it is the substrate upon which the coagulation system is centered. This factor is heat labile but stable in storage. When fibrinogen is transformed to fibrin under the influence of thrombin, it is the onset of solid clot formation. The formation of fibrin occurs within minutes due in part to a positive feedback mechanism within the hemostasis system. Once clotting factors are activated, they accelerate the activity of the next factor, pushing the reaction to conclusion. Negative feedback occurs when the activity of the reaction is delayed. This is the role played by naturally occurring inhibitors within the hemostatic system. With the assistance of factor XIII and thrombin, the fibrinogen molecule is stabilized by cross-linked fibrin. Within hours, the fibrinolytic system swoops in to dissolve the clots that have...

The Composition of the Waste

The initial problem was to decolorize the complex waste-water from an industrial site. The waste originated in a pigment plant and advice indicated that it contained low molecular weight alkyd (sic) polyester resins derived from the reaction of triglycerides and anhydrides like phthalic anhydride along with epoxide resins, derived from bisphenol, and epichlorohydrin and amine resins from melamine and formaldehyde. Lesser quantities of higher molecular weight materials, from polymerization of vinyl, acrylate, or methacrylate monomers were also present. The effluent had a total organic carbon content (TOC) of 2770 mg l and a total suspended content (TSC) of 7429 mg l.

Project Title Sitostanol N3 Fatty Acids On Sterols Fatty Acids Lipoproteins Cholesterol

Summary Participants in this research study will consist of 2 groups. One group will have a moderately high blood cholesterol level. The purpose of this study is to provide a nutritional, non-drug therapy to lower blood cholesterol levels and reduce the risk for heart disease. A substance in plants called sitostanol has been shown to block the absorption of dietary cholesterol that leads to a lower blood cholesterol level. Several companies have developed sitostanol-containing products. They have put sitostanol into margarine for use in this study. Another food that has been shown to decrease the risk of heart disease is fish oil. Fish oil contains omega-3 fatty acids. These fatty acids lower the blood triglyceride level, decrease the formation of blood clots that can block an artery and cause a heart attack and keep the heart beating in a normal rhythm. This study will show if sitostanol and fish oil are a good combination therapy to decrease the risk of heart disease. The second...

Apolipoprotein E APOE

Specifically, reduction in cellular cholesterol availability results in significant changes in APP trafficking and processing, with the resultant reduction in Ab formation (Runz et a ., 2002). In addition, patients who have taken statins for hypercholester-olemia appear to have a reduced incidence of Alzheimer's disease (Fassbender et a ., 2001 Jick et a ., 2000 Wolozin et a ., 2000).

Production of Plasma Proteins

Plasma albumin and most of the plasma globulins (with the exception of immunoglobulins, or antibodies) are produced by the liver. Albumin constitutes about 70 of the total plasma protein and contributes most to the colloid osmotic pressure of the blood (chapter 14). The globulins produced by the liver have a wide variety of functions, including transport of cholesterol and triglycerides, transport of steroid and thyroid hormones, inhibition of trypsin activity, and blood clotting. Clotting factors I (fibrinogen), II (prothrombin), III, V, VII, IX, and XI, as well as angiotensinogen, are all produced by the liver.

Atherosclerosis and Aging

There are two explanations for the increased prevalence of vascular disease in the elderly (1) the increased risk represents a longer duration of exposure to conditions that promote atherosclerosis (i.e., the time-dose product of the risk factors) and (2) atherosclerosis is a specific aging-associated process. It is important to note that these possibilities are not mutually exclusive and that from the perspective of a given elderly individual at risk for vascular disease, this distinction may not matter much. However, discrimination between these hypotheses has important implications for prevention of vascular disease, particularly at the population level. In the former case, preventive therapies should focus on early interventions on established risk factors such as hypercholesterolemia, hypertension, diabetes, obesity, and smoking in the latter case, specific therapies may be required to target the aging-associated mechanisms that accelerate atherosclerosis in the elderly.

Endothelium Derived Vasoactive Substances

Endothelium-derived hyperpolarizing factors appear to play important roles, especially in the microvascula-ture (82). The chemical identity of EDHF has been related to several factors, such as epoxyeicosatrienoic acid (EET) (83), K+ (84), and anandamide (85). There is an emerging consensus that EDHF is unlikely to be a single factor and that considerable tissue and species differences exist for the nature and cellular targets of the hyperpolarizing factors. One of the potential targets is a KCa channel. Randall and Kendall (85) showed that anandamide, an endogenous cannabinoid derived from arachidonic acid, causes vasodilatation via opening of KCa channels. Hayabuchi et al. (86) demonstrated that EET also opens KCa channels via G-protein without changes in cAMP or cGMP. It is of interest that aging and hypercholesterolemia impair EDHF-mediated relaxation however, the mechanisms of impairment are not clear (82).

Milk Composition and Purification of the Target Protein

It is important from a purification point of view that the fat is present in globular form in the size range of 0.1-10 (xm and with a density higher than the other constituents. The fat globule is enclosed in a membrane of polar lipids and proteins. Triglycerides make up 97 of the fat.

Digestion and Absorption of Carbohydrates Lipids and Proteins

Polysaccharides and polypeptides are hydrolyzed into their subunits. These subunits enter the epithelial cells of the intestinal villi and are secreted into blood capillaries. Fat is emulsified by the action of bile salts, hydrolyzed into fatty acids and monoglycerides,and absorbed into the intestinal epithelial cells. Once inside the cells, triglycerides are resynthesized and combined with proteins to form particles that are secreted into the lymphatic fluid. Triglycerides

Digestion and Absorption of Lipids

The salivary glands and stomach of neonates (newborns) produce lipases. In adults, however, very little lipid digestion occurs until the lipid globules in chyme arrive in the duodenum. Through mechanisms described in the next section, the arrival of lipids (primarily triglyceride, or fat) in the duodenum serves as a stimulus for the secretion of bile. In a process called emulsification, bile salt micelles are secreted into the duodenum and act to break up the fat droplets into tiny emulsification droplets of triglycerides. Note that emulsification is not chemical digestion the bonds joining glycerol and fatty acids are not hydrolyzed by this process.

Transport of Lipids in the Blood

Once the chylomicrons are in the blood, their triglyceride content is removed by the enzyme lipoprotein lipase, which is attached to the endothelium of blood vessels. This enzyme hydrolyzes triglycerides and thus provides free fatty acids and (triglycerides) (triglycerides) (triglycerides) (triglycerides) Step 2 Hydrolysis of triglycerides in emulsified fat droplets into fatty acid and monoglycerides Step 3 Dissolving of fatty acids and monoglycerides into micelles to produce mixed micelles Figure 18.35 Fat digestion and emulsification. The three steps indicate the fate of fat in the small intestine. The digestion of fat (triglycerides) releases fatty acids and monoglycerides, which become associated with micelles of bile salts secreted by the liver. Triglycerides Triglycerides Triglycerides + Protein- Figure 18.36 The absorption of fat. Fatty acids and monoglycerides from the micelles within the small intestine are absorbed by epithelial cells and converted intracellularly into...

Test Your Knowledge ofTerms and Facts

Triglycerides are hydrolyzed by the action of pancreatic lipase. c. Triglycerides are resynthesized from monoglycerides and fatty acids in the intestinal epithelial cells. d. Triglycerides, as particles called chylomicrons, are absorbed into blood capillaries within the villi.

Models for the Study of Stroke

Stroke is a devastating disease that represents the third leading cause of death in the United States. Vessel occlusions account for 85 of all strokes, and primary intracerebral bleeding accounts for about 15 . There are several different risk factors for ischemic stroke including genetic factors, aging, hypertension, hypercholesterolemia, diabetes mellitus, atrial fibrillation, coagulation disorders, and smoking. The pathophysiological processes in stroke are complex and involve disruption of the blood-brain barrier, energy failure, loss of cell ion homeostasis, acidosis, increased intracel-lular calcium levels, excitotoxicity, free radical-mediated toxicity, generation of arachidonic acid products, cytokine mediated cytotoxicity, complement activation, activation of glial cells, and infiltration of leukocytes. Animal models have been developed that closely resemble stroke injury seen in human patients. Many experimental models are used to study stroke injury. Mechanisms of cell...

Ivutility Of This Enzyme In Foods

Heavy-metal poisoning antidote and reductor of serum cholesterol and serum triglycerides (17). Garlic extract pills claiming extraordinary health benefits are very popular in the nutraceutical industry. Most of these extracts, however, depending on the methods used for preparation, may or may not contain the desired Allium organosulfur compounds due to their instability (thermodynamic) and reactivity (kinetic) (9).

Coronary Heart Disease 21 Risk Factors

The leading cause of death worldwide is CHD (WHO, 2008). Although atherosclerosis, the preclinical antecedent of CHD, begins in childhood, the clinical manifestations of CHD occur in adulthood and include angina pectoris, MI, heart failure, and sudden death. Major cardiovascular risk factors are those that independently influence the development of atherosclerosis and CHD. More than a half century ago the Framingham Heart Study identified cigarette smoking, elevated serum cholesterol, hypertension, and advancing age as major risk factors (Dawber et al, 1951). Since then, conventional wisdom has come to accept that four modifiable traditional cardiovascular risk factors (i.e., smoking, hypertension, hypercholesterolemia, type 2 diabetes mellitus) account for only 50 of the risk for CHD (Braunwald, 1997 Hennekens, 1998). However, some investigators have contended that the 50 figure is a myth and that traditional risk factors account for far more than half the prevalence of CHD (Canto...

Antilipemic and Hypoglycemic Effects

Because bilberry has traditionally been used to treat diabetes, which is associated with alteration of lipid metabolism, the effects of a bilberry leaf extract on plasma glucose and triglycerides were studied in various rat models (1). The study preparation was made by percolation of bilberry leaf powder with ethanol 40 (Indena, Milano, Italy). All statistical comparisons were done using unpaired t-tests. In Sprague-Dawley rats made diabetic with streptozocin, plasma glucose levels were 26 lower (p < 0.05) 4 days after streptozocin administration, and 26.6 lower (p < 0.01, unpaired t-test) 3 weeks after streptozocin administration in rats treated with bilberry extract at a dose of 3 g kg twice daily for five doses compared with untreated diabetic rats. Triglycerides were also 38.8 (p < 0.05) lower in the treated rats. The extract did not affect glucose levels in control animals, and did not affect weight (1). In rats with diet-induced hyperlipidemia, triglycerides were lower in...

Isoflavones and coronary heart disease

This lack of efficacy has been attributed to the fact that synthetic oestrogens are associated with increased likelihood of blood clot formation and a rise in circulating concentrations of triglycerides and the inflammatory marker C-reactive protein (CRP), which are independent risk factors for CHD (Manson et al., 2003). Of concern is evidence from recent large-scale studies that demonstrate, conclusively, that HRT is associated with increased incidence of endometrial and breast cancer (Beral et al., 1999). Lack of efficacy of HRT with respect to CHD progression, and clear evidence of increased risk of hormone-dependent cancers, has led to interest in the search for alternative therapies to counteract this loss of natural oestrogens at the menopause. The oestrogenicity of isoflavones was first documented over 50 years ago, when isoflavones present in the diet of sheep were found to be responsible for the permanent infertility induced in these animals. Subsequent epidemiological...

Health benefits of CLA

Comprised of 85-90 rumenic acid (Lock and Bauman, 2004). Some studies do however focus on rumenic acid primarily, and in this regard rumenic acid has been associated with improving cardiovascular health, anti-carcinogenic properties and improved immune function. Studies in hamsters showed that dietary rumenic acid improved the ratio of non-high density lipoprotein (HDL) cholesterol to HDL cholesterol (Valeille et al., 2005), improved HDL cholesterol and the ratio of HDL cholesterol to LDL cholesterol (Valeille et al., 2004) and significantly reduced plasma triglyceride concentrations (Wilson et al., 2006). The anti-atherogenic effects of the ingestion of high CLA milkfat (2.59 rumenic acid, which also contained a low concentration of saturated fat (67 )) versus a low CLA milkfat (0.39 rumenic acid, which contained a high concentration of saturated fat (72 )) were compared in hamsters (Valeille et al., 2006). It was found that hamsters on the high CLA milkfat diet had 25 less aortic...

Mechanisms of CLA production in lactating ruminants and starter bacteria

The presence of CLA in the milk of lactating ruminants is a direct result of the action of the ruminal microbiota on dietary linoleic and linolenic acids. These fatty acids are primarily delivered in the form of glycolipids, phospholipids, and triglycerides from forages and seed oils (Bauman et al., 1999), which are released by indigenous and endogenously produced lipases following ingestion (Bauman et al., 1999 Dawson et al., 1977 Dawson and Kemp, 1970 Keeney, 1970) and subsequently undergo microbial biohydrogenation in the rumen by various ruminant bacteria of which Butyrivibrio fibrisolvens is the foremost (Fujimoto et al., 1993 Harfoot and Hazlewood, 1988 Kepler et al., 1966). The biohydrogenation process, which results in the conversion of linoleic and linolenic acids to stearic acid, consists of several steps (see Fig. 21.1). Rumenic acid is formed as the first intermediary in the biohydrogenation of linoleic acid via the activity of the microbial enzyme, linoleic acid...

Epidemiological studies weakening the iron hypothesis

Possible confounding factors are important to be taken into account before concluding any results from epidemiological studies. For atherosclerosis studies, it is necessary to involve an older population, since atherosclerosis progresses with age and the effect of iron on the incidence of severe atherosclerotic events can only be expected in such a population. In addition, excess iron alone as a risk factor may not be sufficient to demonstrate statistically significant different in cardiovascular events, as atherosclerosis is a multifactorial disease. The most recent study (Wolff et al. 2004) identified a relationship between serum ferritin levels and carotid atherosclerosis, and this correlation was even stronger when low-density lipoprotein (LDL)-cholesterol levels were taken into account.

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