Reduce Cholesterol Naturally

Beat Cholesterol By Scott Davis

Scott Davis' e-Book Beat Cholesterol in 30 Days is a useful compendium of information about natural methods and foods to avoid to lower LDL (bad) cholesterol. While the book is extremely useful in categorizing what helps and harms people in terms of diet, it's not so much a full-fledged system as opposed to a guidebook on foods that will improve and worsen your cholesterol levels. This program reveals to people 10 foods that they can use to keep their heart strong, and 3 drinks that can lower their cholesterol levels. The program also provides people with 11 dieting tips to prevent a heart attack, and a collection of delicious and easy-to-make recipes to fight cholesterol. In addition, Scott Davis will provide people with an instruction book and some special gifts when they order this program. When you download the e-book you learn how to be in control of your cholesterol and live a longer and more fulfilling life. Youll also learn diet tips, discover supplements that can help you and even learn how to avoid toxins found in most water. However, the most important thing that youll get is a 30 day action plan. More here...

Natural Cholesterol Guide Overview


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Author: Scott Davis
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My Natural Cholesterol Guide Review

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I've really worked on the chapters in this book and can only say that if you put in the time you will never revert back to your old methods.

Overall my first impression of this book is good. I think it was sincerely written and looks to be very helpful.

Dietary Cholesterol Intake Patterns

Dietary cholesterol intakes in the United States have been declining, from an average of 500 mg per day in men and 320 mg per day in women in 1972 to levels in 1990 of 360 mg per day in men and 240 mg per day in women. This decline is due in part to dietary recommendations to the US public to reduce total and saturated fat intake and to reduce dietary cholesterol daily intake to less than 300 mg and in part from the increased availability of products with reduced fat and cholesterol content. Major efforts in the early 1970s by public health agencies and advertising emphasized reducing dietary cholesterol as a means to lower plasma cholesterol levels, leading to a high degree of consumer concern regarding cholesterol-containing foods and demand for low-cholesterol products. Today, practically all foods sold in the United States are labeled for their cholesterol content and their percentage contribution to the daily value of 300 mg for cholesterol.

Safety of cholesterol reduction

The uncertainty concerning the excess mortality from hem-orrhagic stroke at low serum cholesterol concentrations is unresolved, as discussed above. This apart, there are no material grounds for concern about hazard. Trials of statin drugs, particularly informative on safety because of the large reduction in serum cholesterol that they achieve, have resolved the issue of safety because they show no excess mortality from non-circulatory causes.1'7-11 The excess mortality from cancer and accidents and suicide at very low serum cholesterol in observational studies is attributable to cancer or depression lowering serum cholesterol, not the reverse.19 Further reassurance on safety is provided by the condition of heterozygous familial hypobetalipoproteinemia, in which serum cholesterol levels are as low as 2-3 mmol l. Life expectancy is prolonged because coronary artery disease is avoided, and no adverse effects from the low cholesterol are recognized24,25 - an important natural experiment....

Statins as potential antiischemic drugs

Statins have made a considerable difference to the mortality of patients with ischemic heart disease in several studies. In the West of Scotland Coronary Prevention Study (WESCOPS), pravastatin was able to reduce hard end points in middle-aged hypercholesterolemic men without prior MI. In this group, the occurrence of angina pectoris was highly correlated (P < 0-0001) with the primary end point, which was definite coronary heart disease death or non-fatal MI.73 Therefore, in hypercholesterolemic males with angina, statins are able to reduce hard end points. That they have a direct anti-ischemic effect is shown by reduction of ST segment deviations on 48 hour Holter traces in patients with stable angina pectoris, documented coronary artery disease and pre-existing antianginal therapy, the latter not being specified.74 Grade A Statin therapy can improve endothe-lial function, measured in the brachial artery, within 3 days in high-risk patients (elderly patients).75 Formal prospective...

Dietary Cholesterol and Plasma Cholesterol

The effect of dietary cholesterol on plasma cholesterol levels has been an area of considerable debate. In 1972, the American Heart Association recommended that dietary cholesterol intake should average less than 300mgperday as part of a 'heart-healthy,' plasma cholesterol-lowering diet. Since that initial recommendation, a number of other public health dietary recommendations in the United States have endorsed the 300 mg daily limit. Interestingly, few dietary recommendations from other countries contain a dietary cholesterol limitation. The evidence for a relationship between dietary cholesterol and plasma cholesterol indicates that the effect is relatively small, and that on average a change of 100 mg per day in dietary cholesterol intake results in a 0.057 mmoll-1 (2.2mgdl-1) change in plasma cholesterol concentrations. Studies have also shown that the majority of individuals are resistant to the plasma cholesterol-raising effects of dietary cholesterol 'nonresponders' and have...

Dietary Cholesterol

All dietary cholesterol is derived from animal products. The major sources of cholesterol in the diet are egg yolks, products containing milk fat, animal fats, and animal meats. Many studies have shown that high intakes of cholesterol will increase the serum cholesterol concentration. Most of this increase occurs in the LDL cholesterol fraction. When cholesterol is ingested, it is incorporated into chylomicrons and makes its way to the liver with chylomicron remnants. There it raises hepatic cholesterol content and suppresses LDL receptor expression. The result is a rise in serum LDL cholesterol concentrations. Excess cholesterol entering the liver is removed from the liver either by direct secretion into bile or by conversion into bile acids also, dietary cholesterol suppresses hepatic cholesterol synthesis. There is considerable variability in each of these steps in hepatic cholesterol metabolism for this reason the quantitative effects of dietary cholesterol on serum LDL...

Cardiovascular Disease

The risk of heart disease increases with a rise in cholesterol levels especially when other risk factors are present (17-19). Plasma total cholesterol was accepted as a causal factor (among multiple factors) by the World Health Organization (WHO) expert committee in 1982 and by the U.S. National Institute of Health Consensus Development Conference in 1985 (17). Diet and its effects on plasma cholesterol levels are discussed in the next section. Plasma triglyceride levels have also been correlated with increased risk of heart disease (17) and are associated with increased low-density lipoprotein (LDL) cholesterol levels. High blood pressure increases the risk of a stroke, heart attack, kidney failure, and congestive heart failure. When obesity, smoking, high blood cholesterol levels, or diabetes are also present, high blood pressure increases the risk of a heart attack or stroke severalfold. Regular moderate-to-vigorous exercise plays a significant role in preventing heart and blood...

Role Of Diet In Cardiovascular Disease

Improper eating habits accompanied by the lack of exercise increase the risk of gaining excess weight, a major risk factor for heart disease, high blood pressure, and diabetes (14). Diet also affects plasma cholesterol levels. Cholesterol is carried in the blood associated with two major types of lipoproteins LDL and HDL. LDL cholesterol has been High blood cholesterol levels correlated with increased risk of cardiovascular disease. For many years it has been recognized that dietary cholesterol has only a limited effect on plasma cholesterol levels (17). Absorption of ingested cholesterol is poor, and part of the cholesterol in plasma is synthesized in the liver. Total lipid intake, and the type of fat consumed, have more effect in raising plasma cholesterol than does dietary cholesterol (17,20). Saturated fatty acids were found to raise cholesterol, polyunsaturated fatty acids lowered plasma cholesterol, and monounsaturated fatty acids had an intermediate effect. In the classic...

How is the harm of a treatment documented

The most commonly prescribed drugs can be evaluated prior to marketing. In 1997, the FDA approved mibefradil (Posicor) for marketing in the U.S. The product was withdrawn within one year, after multiple serious drug interactions were documented, the most important one with simvastatin (Zocor).

Age and Risk Factor Profile

A few studies have indicated that subjects already at high risk of coronary disease experience a greater beneficial effect of drinking alcohol moderately conversely, only in those with a high risk level is coronary heart disease prevented. Hence, the large Nurses Health Study found that the J-shaped relation was significant only in women older than 50 years of age, whereas younger women who had a light alcohol intake did not differ from abstainers with regard to mortality. Fuchs et al. found that women at high risk for coronary heart disease (due to risk factors such as older age, diabetes, family history of coronary heart disease, high cholesterol, and hypertension) who had a light alcohol intake were at a lower risk of death than women who were at the same risk level but did not drink alcohol. In a study by the American Cancer Society, the finding by Fuchs et al. was confirmed among men,

Therapeutic implications of plaque biology

Angiographic studies have shown that effective lipid lowering with statins reduces the incidence of new lesion formation and produces a significant, but haemodynamically unimportant (0.04-0.07 mm), improvement in established stenoses.15 Importantly, however, they also reduce the rate of progression of preexisting lesions and the number of new vessel occlusions. Both of these beneficial effects are likely to be due to prevention of plaque rupture since, as discussed above, lesions grow by repeated episodes of subclinical rupture and repair, and silent occlusion arises when plaque rupture and thrombosis occur in the context of a well collateralised myocardial circulation such that no significant ischaemia results from the occlusion. Despite the modest effects of statins on size of pre-existing lesions, several outcome studies, both in primary and secondary prevention settings, have shown a substantial (30-40 ) reduction in cardiovascular events in the statin treated groups.16-18 Taking...

The Observational View of Dietary Antioxidants

Cancer and cardiovascular disease (CVD) are the two leading causes of death worldwide, diabetes mellitus is reaching epidemic proportions, and dementia and maculopathy are largely untreatable irreversible disorders that are increasingly common in our aging population. The prevalence and standardized mortality rates of these diseases vary considerably between and within populations. Mortality from CVD varies more than 10-fold amongst different populations, and incidences of specific cancers vary 20-fold or more across the globe. This enormous variation highlights the multiple factors at play in the etiology of chronic age-related diseases. These factors include smoking habit, socioeconomic status, exposure to infectious agents, cholesterol levels, certain genetic factors, and diet. Dietary factors have long been known to play an important role in determining disease risk. Indeed, 30-40 of overall cancer risk is reported to be diet-related, and there is a wealth of compelling...

Other Major Risk Factors

Major risk factors other than LDL cholesterol and diabetes are listed in table 3.1. Age, blood pressure, and high density lipoprotein (HDL) cholesterol, as well as total cholesterol, are used as continuous variables to calculate CHD risk in the current Joint British Societies' guidelines, together with cigarette smoking and diabetes as categorical variables.5 Alternatively age, hypertension, low HDL cholesterol, and family history of premature CHD can all be used as categorical variables to calculate risk.4 A family history of death from CHD in either parent before age 55 conferred a relative risk of 1.3 in their progeny in the Framingham study,6 whereas in the US nurses health study

Prothrombotic factors

Several prospective studies have demonstrated an association between fibrinogen and CHD. Increased concentrations are associated with glucose intolerance, cigarette smoking, and hypercholesterolemia. A fibrinogen concentration of > 3.1 g l is associated with relative risks of CHD of 1.6 in men and 2.9 in women.

Decholesterolized Butter

In the 1980s, there was significant research and market activity in developing decholesterolized milk fat. All this activity was for naught, for the hypothesis of creating a healthier fat (for butter or milk or other dairy product) was not sound. The nutrition community had long recognized that the link between dietary cholesterol and serum cholesterol was weak and that the ratio of total fat-saturated fat had a greater impact on health. In addition, the FDA issued new standards in 1993 (57) that effectively negated the value of decholestering milk fat. The new law

Prevalence Of Risk Factors In Patients With Premature

A large study of the prevalence of modifiable risk factors in US men with angiographically documented coronary artery disease before the age of 60 showed that virtually all had one or more risk factors.11 Compared with controls, the frequency of hypertension was 41 v 19 , of diabetes 12 v 1 , of cigarette smoking 67 v 28 , and of a low HDL cholesterol 63 v 19 . However, the frequency of a raised LDL cholesterol was similar in the two groups, 26 v 26 , reflecting the high prevalence of hypercholesterolaemia in the general population. A subsequent study12 revealed that more than 50 of such patients had a familial dyslipidaemia, the most common being a low HDL cholesterol accompanied by either hypertriglyceri-daemia or mixed dyslipidaemia next came a raised Lp(a), which evinced greater heritability than other familial dyslipi-daemias, apart from FH. Premature CHD is especially common in Asians in whom low HDL cholesterol, raised Lp(a), and hyperinsulinism appear to be more important risk...

Patient selection and cost effectiveness

Drugs and procedures in medicine are applied to different patient groups for different clinical indications. The medical effectiveness of therapies varies considerably according to patient selection. Cholesterol lowering therapy, for instance, will extend the life expectancy of a patient with multiple cardiac risk factors more than it will for a patient with the same cholesterol level and no other cardiac risk factors. Coronary bypass surgery provides greater life extension to a patient with left main coronary artery obstruction than it does to a patient with single vessel disease.18 The cost effectiveness ratio for these therapies will therefore vary among patient subgroups due to the impact of patient characteristics on the clinical effectiveness of therapy, which forms the denominator of the cost effectiveness ratio. Similarly, the cost of a particular therapy may also vary according to patient characteristics, since the therapy itself may be more

Effects on Cardiovascular System

Some studies indicate a positive correlation between caffeine intake and the development of hypercholesterolemia, but many very large efforts to confirm this effect, such as the Framingham study, show no correlation between atherosclerotic cardiovascular disease and coffee intake. Other large studies have shown no correlation between coffee drinking and any form of coronary heart disease (27). The disparate results concerning the effects of caffeine on the cardiovascular system probably relate to the size of the studies, lack of control of unrecognized factors and, very importantly, to the acceptance of cups of coffee as a quantitative measure of caffeine content. Coffee and tea contain many physiologically active compounds other than caffeine. Coffee oils, especially kahweol, have been shown to be cholesterogenic (29).

Practical Recommendations For Screening

Screening individuals with a family history of premature CHD is encouraged by all the current guidelines on CHD prevention, namely the Joint British Societies,5 the Joint European Societies,17 and the US National Cholesterol Education Program (NCEP).4 Each advocates using risk factors to calculate the 10 years absolute risk of a CHD event although they differ in the methodology used and the level of risk above which drug treatment should be commenced. The Joint European Societies guidelines are flawed by omitting HDL cholesterol from the risk calculation, whereas the NCEP's Framing-ham based point scoring system is more laborious than the Joint British Societies', which is also Framingham derived but computerised. Levels of risk above which lipid lowering drugs are advocated range from 15 5 to 20 per 10 years,417 the latter value being the more realistic in current circumstances. The National Service Framework for CHD recommends screening all those under the age of 75 with a family...

Decision analysis in the evaluation of specific products

Cholesterol reduction Several authors have used decision analysis to investigate the cost effectiveness of therapies designed to reduce high blood cholesterol.54 Two recent studies use clinical trial data to assess the cost effectiveness of cholesterol reduction in secondary prevention of coronary artery disease. Johanneson et a 19 developed an analysis based on the Scandinavian Simvastatin Survival Study, which reported that, in patients with pre-existing coronary disease, reduction in blood cholesterol resulted in a 30 reduction in overall mortality based on a median follow-up of 5-4 years. Grade A1a The authors modeled the effects of 5 years of cholesterol-reducing therapy on patients' outcomes, using a model based on data reported from the trial. The costs of therapy were based on the assumption that the use of cholesterol-reducing agents would not entail any additional costs for patients with pre-existing coronary disease other than the cost of medication itself, and then used...

Health Effects of Carbohydrates

Certain NSP (for example fi glycans) have been shown to reduce low-density lipoprotein (LDL) and total cholesterol levels on a short-term basis. Therefore, a protective effect for CVD has been shown with consumption of foods high in NSP. This High-GI diets have been shown to slightly increase hemoglobin A1c, total serum cholesterol and triacylglycerols, and decrease HDL cholesterol and urinary C-peptide in diabetic and hyperlipi-demic individuals. In addition, low-GI diets have been shown to decrease cholesterol and triacylgly-cerol levels in dyslipidemic individuals. There are insufficient studies performed on healthy individuals and further research on the role of GI in lipid profile and CVD risk factors is warranted.

Variations in the transition

There are, however, variations on this theme. Even within Europe, for example, northern Europe and the Mediterranean countries have differences in CVD mortality rates which are better explained by cultural differences in diet than by the level of economic development.21 Japan has so far avoided the CHD epidemic.6 Whether recent changes in diet, with a rise in mean plasma cholesterol levels in the population, combined with high smoking rates, will lead to a major CHD epidemic in the future remains to be seen.

Absorption Transport and Storage Cholesterol Absorption

Cholesterol in the intestinal lumen typically consists of one-third dietary cholesterol and two-thirds biliary cholesterol. The average daily diet contains 300-500 mg of cholesterol obtained from animal Dietary cholesterol intake products. The bile provides an additional 8001200 mg of cholesterol throughout each day as gallbladder contractions provide a flow of bile acids, cholesterol, and phospholipids to facilitate lipid digestion and absorption. Dietary cholesterol is a mixture of free and esterified cholesterol, whereas biliary cholesterol is nonesterified and is introduced into the small intestine as a cholesterol-bile salt-phospholipid water-soluble complex. The only other source of intraluminal cholesterol is mucosal cell cholesterol, derived from either sloughed muco-sal cells or cholesterol secreted by the mucosal cells into the intestinal lumen. Measurements of exogenous and endogenous cholesterol absorption in humans indicate that there is probably very little direct...

Tissue Uptake and Storage

The body pool of cholesterol is approximately 145 g, with one-third of this mass localized in the central nervous system. The remainder of the metabolically active cholesterol pool exists in the plasma compartment (7.5-9 g) and as constituents of body tissues. In humans, tissue cholesterol levels are relatively low, averaging 2 or 3 mg g wet weight. Little information exists regarding changes in hepatic and extrahepatic tissue cholesterol concentrations with changes in dietary cholesterol intake. Animal studies, which are usually carried out using very high levels of dietary cholesterol, have shown that hepatic cholesterol can increase from 2-fold up to 10-fold, depending on the species and other dietary constituents, when dietary cholesterol is increased.

Regulation of Synthesis

Research shows that in most individuals, dietary cholesterol alters endogenous cholesterol synthesis and that this feedback regulation can effectively compensate for increased cholesterol input from dietary sources. The precision of these regulatory responses depends on a number of genetic factors, and data suggest that multiple genetic loci are involved. For example, family studies have shown that in siblings of low cholesterol absorption families, cholesterol absorption percentages are significantly lower and cholesterol and bile acid synthesis, cholesterol turnover, and fecal steroids are significantly higher than in siblings of high absorption families.

Major Dietary Sources

The major sources of cholesterol in the diet are eggs, meat, and dairy products. A large egg contains approximately 215 mg of cholesterol and contributes approximately 30-35 of the total dietary cholesterol intake in the United States. Meat, poultry, and fish contribute 45-50 , dairy products 12-15 , and fats and oils 4-6 . In the United States, the range of dietary cholesterol intake is 300-400 mg per day for men and 200-250 mg per day for women thus, for much of the population the national goal of a dietary cholesterol intake of less than 300 mg per day has been met.

Macronutrient Composition of the Diet

HDL cholesterol The mechanisms whereby saturated fatty acids raise LDL cholesterol levels are not known, although available data suggest that they suppress the expression of LDL receptors. The predominant saturated fatty acid in most diets is palmitic acid (C16 0) it is cholesterol-raising when compared with cis-monounsaturated fatty acids, specifically oleic acid (C18 cis1 n-9), which is considered to be 'neutral' with respect to serum cholesterol concentrations. In other words, oleic acid is considered by most investigators to have no effect on serum cholesterol or lipoproteins. Another saturated fatty acid, myristic acid (C14 0), apparently raises LDL cholesterol concentrations somewhat more than does palmitic acid, whereas other saturates - lauric (C12 0), caproic (C10 0), and caprylic (C8 0) acids - have a somewhat lesser cholesterol-raising effect. On average, for every 1 of total energy consumed as cholesterol-raising saturated fatty acids, compared with oleic acid, the serum...

HIV1 attachment mediated by host cell proteins incorporated into the viral envelope

Although the physical presence of such host constituents on the exterior of virions might be detrimental for the infected individual, the propensity of HIV-1 to acquire numerous host cell surface components could be exploited to control viral load. Indeed, it has been shown in numerous reports that HIV-1 infectivity can be efficiently neutralized, both in vitro and in vivo, with antibodies specific for such host membrane proteins 22, 23, 26, 39, 44, 45, 54, 55 . Interestingly, it was demonstrated that HIV-1 replication is diminished upon treatment with statin compounds (e.g., lovastatin) 56 , the primary drugs used in the treatment of hypercholesterolemia. The antiviral potency of lovas-tatin seems to be linked with its capacity to inhibit interactions between virus-associated host ICAM-1 and cell surface LFA-1. This in vitro work was confirmed by a proof-of-concept small-scale clinical study 57 . In this provocative study, six A1 stage HIV-1 patients not receiving combined therapy...

The 95 per cent confidence interval for the difference between two treatments

Experimental work often concerns comparisons between two differently treated groups of people (or animals or objects). Frequently, we will determine the mean value for some measured end-point in each group and then look at the difference between these. However, our two mean values will almost certainly be based upon samples and each will be subject to the usual random sampling error. If we are estimating the difference between two imperfectly defined values, the calculated difference will also be subject to sampling error. There is an obvious role for the 95 per cent CI for the difference between two means. Figure 5.9 shows a typical case, where we are comparing plasma cholesterol levels in two groups.

Composition Of The

Some elements of the medical profession have emphasized the role of dietary cholesterol in human cardiovascular problems. The negative effect on egg consumption that this emphasis on cholesterol has had led to a number of research attempts to reduce the cholesterol content of eggs. Genetically it has been possible to achieve only slight reductions. Selection of hens for small yolk size has met with some success. A review on altering cholesterol by feeding (5) concluded that dietary modifications resulted in only minor changes in the cholesterol content of egg yolk. Another report (6) states that including 1.5 to 3.0 of menhaden oil in the laying hen's ration results in a temporary reduction of about 50 in the cholesterol concentration in the yolk. The fatty acid composition of the eggs was also modified in that the eicosopentenoic acid and do-cosahexanoic acid (omega-3 fatty acids) content of the yolks was significantly increased when the fish oil was included in the hen's ration....

Serum total and low density lipoprotein cholesterol

Of the average total serum cholesterol in western populations, two thirds is low density lipoprotein (LDL) cholesterol and one quarter is high density lipoprotein (HDL) cholesterol. The atherogenic properties lie in the LDL fraction (sometimes measured as its carrier protein, apolipoprotein B, with which it is highly correlated). Many of the large epidemiological studies and randomized trials measured only total serum cholesterol, and results based on total serum cholesterol have been taken to estimate effects of LDL cholesterol. Fortuitously, the approximation is a good one. The absolute reduction in total serum cholesterol produced by diet and by most drugs (including statins1) is similar to the reduction in LDL cholesterol. Observational differences in total cholesterol between individuals are close to the corresponding differences in LDL cholesterol, because HDL cholesterol is independent of total serum cholesterol.3'4 This arises because the tendency for HDL cholesterol to be...

The two sample ttest an example of a hypothesis test

At first sight, data may seem to suggest that a drug treatment changes people's cholesterol levels or that high salt consumption is associated with high blood pressure, etc. However, we always need to use a statistical test to determine how convincing the evidence actually is. Such tests are known generically as 'hypothesis tests'.

The size of the effect

Table 12.2 Estimates (from 10 cohort studies) of the percentage decrease in risk of ischemic heart disease according to extent of serum cholesterol reduction and age6 Age (years) Estimated percentage decrease in risk for a serum cholesterol reduction (mmol l) of Age (years) Estimated percentage decrease in risk for a serum cholesterol reduction (mmol l) of

Speed of reversal and consistency of observational and trial data

Data have been analyzed from the old generation of 28 randomized trials in which the average serum cholesterol reduction was about 0-6 mmol l (10 ).6 Figure 12.2 shows the reduction in incidence of ischemic heart disease in all trials combined according to time since entry. In the first 2 years there was little reduction in risk. From 2 to 5 years the average reduction in risk was 22 , and after 5 years the reduction was 25 . The ischemic heart disease events in these trials mostly occurred at an average age of about 60, and at this age the estimate of the long-term effect from the cohort studies is 27 (Table 12.2). The similarity of the estimates of effect from the cohort studies and from the trial The six large trials of statins1'7-11 have achieved significantly larger reductions in total and LDL cholesterol. These trials too showed a relatively small reduction in ischemic heart disease events in the first 2 years, but a reduction after 2 years that is close to the maximum indicated...

Potential Mechanisms Indicating a Role in the Etiology of Coronary Heart Disease

The mechanism for risk reduction and the fiber components responsible need resolution. Elevated plasma total and low-density lipoprotein (LDL) cholesterol concentrations are established risk factors for coronary morbidity and mortality. There are abundant human and animal data showing that diets high in soluble fiber lower plasma cholesterol. One population study has shown a significant negative relationship between viscous (soluble) fiber intake and carotid artery atherogensis as measured by intima-media thickness. This association was significant statistically even though average fiber intakes were not particularly high. When dietary fiber intakes have been related to measures of actual disease outcomes, the evidence is less convincing. A protective effect is often observed on univariate analyses, but once confounding variables are added, dietary fiber intake tends not to be a significant independent predictor of risk for developing CHD. However, in one 12-year follow-up study of...

Dietary fat and serum cholesterol

Naturally occurring cis unsaturated fatty acids reduce serum cholesterol by approximately half as much as longer chain saturated fatty acids increase it. Reduction in dietary cholesterol has a small effect on blood cholesterol concentra-tion.5 Substitution of cis unsaturated for saturated fats in the western diet is thus the most appropriate change in lowering the high levels of blood cholesterol in western populations. The reduction in serum total or LDL cholesterol that can easily be attained by individuals trying to alter their diet in isolation from family, friends and workmates is relatively small (about 0-3mmol l, or 5 ). A larger serum cholesterol reduction, about 0-6 mmol l (10 ), is realistic on a community basis, as the availability of palatable low-fat food increases when other family members or the community alter their diet, and the dietary change is perceived more positively. A reduction by about 7 of calories, a realistic target for a high-fat population, would lower...

Dietary Fiber and the Etiology of Hormone Dependent Cancers

Direct binding of sex hormones is possible but is subject to the same concerns as were raised for cholesterol reduction. In addition, it is possible that other components in, or associated with, fiber (phytooestrogens or antioxidants) may be responsible for any observed protective effect. Soy phytooestrogens are believed to play a role in lowering the risk of breast cancer in Asian populations. Lycopenes are antioxidant carotenoids from tomatoes, and their intake has been correlated with a lower risk of prostate cancer.

Complications Of Immunosuppressive Agents

Cyclosporine and FK506 inhibit T-cell proliferation. Nephrotoxicity is a common and usually reversible side effect manifest by elevated serum creatinine levels, hypertension, hyperkalemia, hyperuricemia, and gout. Patients are sensitive to dehydration.12 Other side effects include headache, hirsutism, gingival hyperplasia, hyperglycemia, hypomagnesemia, hypercholesterolemia, hypertriglyceridemia, hepatotoxicity, and hemolytic uremic syndrome. Unlike those of other immunosuppressive agents, blood levels of cyclosporine and FK506 can be monitored along with serum creatinine to avoid serious toxicity however, random levels are rarely helpful and dose is adjusted based on trough levels.3

Peripheral arterial disease

Observational data show the expected association between peripheral arterial disease and serum cholesterol. In a large case-control study the association was equivalent in magnitude to an increase in risk of intermittent claudication of about 24 for a 0-6 mmol l increase in serum cholesterol22 (uncorrected for regression dilution bias), similar in magnitude to the association of serum cholesterol with ischemic heart disease. In the 4S trial (serum cholesterol reduction 1-8 mmol l) the incidence of intermittent claudication was reduced by 38 (95 confidence interval 12 , 56 52 v

Functional Interactions

Reduction in the concentration of bile acids A reduction in the concentration of bile acids will affect the absorption of most fat-soluble compounds. Lower bile-acid concentration may result from increased binding and excretion or from decreased production. For example, the antibiotic neomycin binds to bile acids and increases their faecal excretion, thus reducing their luminal concentration and, in this fashion, decreasing the absorption of fat-soluble vitamins. This interaction, like many others, can be used ther-apeutically to reduce bile-acid turnover in patients with certain liver diseases and to lower cholesterol levels by reducing their reabsorption.

High density lipoprotein cholesterol

There is an inverse association between HDL cholesterol (or apolipoprotein A1) and ischemic heart disease. An absolute increase corresponding to 0-12mmol l (about 10 of the average value) is associated with about a 15 decrease in the risk of ischemic heart disease at age 604'30 or a 20 decrease with adjustment for the regression dilution bias.30 The effect of alcohol in increasing HDL cholesterol is the major mechanism for the lower risk of heart disease in drinkers.31 The effect of smoking in decreasing HDL cholesterol contributes to the excess risk of heart disease in smokers. The statin cholesterol lowering drugs increase HDL cholesterol relatively little. Certain other cholesterol lowering drugs (such as fibrates and niacin) increase HDL cholesterol more, but even in persons with relatively low HDL cholesterol the overall protective effect of these drugs is smaller because they reduce LDL cholesterol less, and so they should not be preferred to statins.

Lipids as screening tests

Serum cholesterol reduction is important in reducing the risk of ischemic heart disease, but cholesterol and other lipids are poor population screening tests for ischemic heart disease. The reason for the apparent discrepancy is that the screening potential of a factor depends not only on the strength of its relationship with disease, but also on its variation in magnitude across individuals in a community. In the case of lipids, the high average values in western societies place everyone at risk, and the variation between individuals is too small for use in population screening. By analogy, if everybody smoked between 15 and 25 cigarettes per day, cases of lung cancer would not cluster in the minority who smoked 25 cigarettes a day to the extent that those who smoked 15 or 20 could be ignored. Moreover, the Gaussian distribution of serum cholesterol means that many people have values around the average and few have relatively high values, so that most ischemic heart disease events...

Fats And Oils Substitutes

At 9 kcal g, fat is the most concentrated source of energy among the macronutrients. According to the Surgeon General's Report on Diet and Health, high intake of dietary fat is associated with increased risk for obesity, some types of cancer, and possibly gallbladder disease. Epidemiologic, clinical and animal studies provide strong and consistent evidence for the relationship between saturated fat intake, high blood cholesterol, and increased risk for coronary heart disease. Excessive saturated fat consumption is the major dietary contributor to total blood cholesterol levels (4). Reflecting national health policy, the Surgeon General, the National Academy of Sciences, the American Dietetic Association, the American Heart Association, the National Cholesterol Education Project, the American Cancer Society, the National Institutes of Health, the USDA, and the U.S. Department of Health and Human Services are among the many health and government authorities that recommend limiting...

Physiologic And Metabolic Effects

Consumption of soluble dietary fibers has been shown to lower blood cholesterol levels in both laboratory animals and humans. Fibers such as oat bran, guar gum, and pectin all have a hypocholesterolemic effect. Several mechanisms of action appear to be responsible for this physiological response. Soluble fibers increase the viscosity of intestinal contents, which alters the mixing and diffusion of nutrients in the intestine and changes rates of nutrient absorption. Impaired bile acid and or cholesterol absorption from the intestine is thought to lead to lowered blood cholesterol

Major Contributors of Dietary Saturated Monounsaturated and Polyunsaturated Fatty Acids and Cholesterol

According to the National Health and Nutrition Examination Survey (NHANES) recall data from 1999-2000, the 10 major dietary sources of saturated fatty acids in US diets are regular cheese (6.0 of the total grams of saturated fatty acids consumed), whole milk (4.6 ), regular ice cream (3.0 ), 2 low-fat milk (2.6 ), pizza with meat (2.5 ), French fries (2.5 ), Mexican dishes with meat (2.3 ), regular processed meat (2.2 ), chocolate candy (2.1 ), and mixed dishes with beef (2.1 ). Hence, the majority of saturated fatty acids are contributed by regular dairy products (16 ), and the top 10 sources contribute 30 of the total saturated fatty acids consumed. The increased prevalence of fat-free and low-fat dairy products provides a viable option with which to encourage a populationwide decrease in saturated fat intake. To put the value of decreasing populationwide intakes of saturated fat into perspective, it has been estimated that the isocaloric replacement of 5 of energy from saturated...

Ldl Hdl and atherosclerosis

Membrane function is compromised if it contains either too much or too little cholesterol. Epidemio-logical studies have classified raised plasma cholesterol levels as a risk factor for atherosclerosis, and it is one of the more important predictors of coronary heart disease (CHD). Elevated plasma cholesterol concentration (hypercholesterolemia) is associated with an increased concentration of LDL, owing to either an increased rate of LDL formation or a decrease in the rate at which they are cleared from plasma, and usually a decreased concentration of HDL. Numerous dietary-intervention studies have aimed both to prevent CHD and to reduce total mortality, but almost all have been ineffective.

Endothelial dysfunction

Relaxing factors, production of an endogenous NO synthase inhibitor, and overproduction of oxygen-derived free radicals including O2. The release of the free radical O2 from smooth muscle cells is believed to be responsible for the oxidation of LDL cholesterol. Raised cholesterol levels and - more importantly - increased levels of oxidatively modified LDL cholesterol (OxLDL) are considered to be among the most powerful inhibitors of normal endothelial function and hence contribute to the process of atherogenesis.

Eicosanoid Metabolism and Biological Effects of n6 and n3 Fatty Acids

Because of the increased amounts of n-6 fatty acids in the Western diet, the eicosanoid metabolic products from AA, specifically prostaglandins, thromboxanes, leukotrienes, hydroxy fatty acids, and lipoxins, are formed in larger quantities than those formed from n-3 fatty acids, specifically EPA. As a result (Figure 5), ingestion of EPA and DHA from fish or fish oil leads to (1) decreased production of prostaglandin E2 metabolites (2) decreased concentrations of thromboxane A2, a potent platelet aggregator and vasoconstrictor (3) decreased formation of leukotriene B4, an inducer of inflammation and a powerful inducer of leukocyte chemotaxis and adherence (4) increased concentrations of thromboxane A3, a weak platelet aggregator and vasoconstrictor (5) increased concentrations of prostacyclin prostaglandin I3 (PGI3), leading to an overall increase in total prostacyclin by increasing PGI3 without decreasing PGI2 (both PGI2 and PGI3 are active vasodilators and inhibitors of platelet...

Total Saturated Fat Content of Diets

Using statistical techniques, results from independent experiments have been combined to develop equations that estimate the mean change in serum lipoprotein levels for a group of subjects when carbohydrates are replaced by an isoenergetic amount of a mixture of saturated fatty acids. The predicted changes for total LDL and HDL cholesterol and triacylglycerols are shown in Figure 1. Each bar represents the predicted change in the concentration of that particular lipid or lipoprotein when a particular fatty acid class replaces 10 of the daily energy intake from carbohydrates. For a group of adults with an energy intake of 10 MJ daily, 10 of energy is provided by about 60 g of carbohydrates or 27 g of fatty acids. A mixture of saturated fatty acids strongly elevates serum total cholesterol levels. It was predicted that when 10 of dietary energy provided by carbohydrates was exchanged for a mixture of saturated fatty acids, serum total cholesterol concentrations would increase by...

Effect of trans Fatty Acids on Plasma Lipoproteins

Raised plasma concentrations of low-density lipoprotein (LDL) are considered to be a risk factor for coronary heart disease (CHD) in contrast, reduced concentrations of high-density lipoprotein (HDL) are considered to increase risk. It therefore follows that to help protect against CHD, diets should ideally help to maintain plasma concentrations of HDL cholesterol and to lower those of LDL cholesterol. Dietary factors that raise LDL and lower HDL concentrations would be considered to be undesirable in this context. C18 monounsaturated trans fatty acids decrease HDL cholesterol concentration this is in contrast to saturated fatty acids which produce a small rise in HDL levels. In comparison with the effects of oleic and lino-leic fatty acids, C18 monounsaturated trans fatty acids raise LDL cholesterol and lower HDL cholesterol levels.

Public Patient Outcomes

Significantly advancing the care of patients (e.g., statins in hypercholesterolemia in the 1990s). More untreatable diseases are finding amelioration or improvement through product innovation over the past 20 years (e.g., HIV infections with new classes of antiviral drugs, anemia of kidney disease and cancer with epoietin alfa, and enzyme deficiency diseases such as Gaucher disease with enzyme replacement). A novel product choice has been created because of its unique mechanism of action different from existing products, altering a key newly identified pathophysiologic process for a disease (e.g., aromatase inhibitor Arimidex or oncogene inhibitor Herceptin for breast cancer), or a better side effect profile has been achieved (e.g., Nonsteroidal anti-inflammatory drugs for arthritis versus aspirin). The new product achieves patient care improvement with higher efficacy over prior therapy, becoming a clinically superior or even best-in-class product (e.g., Crestor as a statin for high...

Guide for Separating Food Folklore Facts from Fiction in Clinical Situations and A Practical Example

For example, when the patient's prescription drug is one that is metabolized by cytochrome 3A (CYP 3A), a dramatic effect can occur if grapefruit juice or other forms of the fruit are consumed. Grapefruit juice enhances the effects of these drugs over time by decreasing their oral clearance. However, the effects of the interaction depend on the nature of the drug (for some drugs there is little or no effect) and the size of the interaction. Interaction occurs only if the drug is metabolized by CYP 3A, if it normally undergoes pre-systemic extraction with CYP 3A, and if it is given orally. The interactions vary. For example, with the statins - drugs commonly used to lower serum cholesterol -they are strong for simvastatin and lovastatin, moderate for atorvastatin and cervastatin, and low for fuvastatin and pravastatin. Similarly, sedatives, hypnotics, and other drugs vary as to whether they induce interactions or not.

Pathology and dysfunction

One of the more common causes of stasis and thus infection in the United States is gallstone disease. Bile salts, cholesterol, and calcium salts usually are found in perfect solution in bile however, when an imbalance occurs, the bile salts come out of solution and precipitate into sludge or stones. Hemolytic states, such as due to sickle cell disease, results in the formation of pigmented stones, whereas high cholesterol states result in cholesterol stones, the most common form of gallstones. Mostly, these stones are formed where natural stasis of bile occurs in the gallbladder. Stones are, however, rarely formed in the bile ducts or intrahepatically. Stones are generally asymptomatic until they cause obstruction. Biliary pain can be caused by contraction of the gallbladder, but severe disease typically does not appear until a stone occludes the bladder or a duct. A gallbladder with stones is called cholelithiasis. Obstruction of the outflow of the gallbladder by a stone, results in...

Natural Occurrence Of Microbial Polysaccharides In Foods

Bacteria (Streptococcus, Lactobacillus and Lactococcus spp.), and a number of structural studies have recently elucidated the nature of some of these polysaccharides. These and other reports can be found in the reviews of De Vuyst and Degeest (1) and Laws et al. (2). Less is yet known about the relationship between structure and physical properties than is the case for Gram-negative bacterial products such as xanthan and gellan (3). As well as the deliberate addition of microbial polysaccharides to food products to obtain specific properties, there are a number of bacterial fermentations in which polysaccharide is produced and is needed to yield a specific type of product. An example of this can be found in certain types of fermented milk product such as yogurts. In some of these, the production of polysaccharide during bacterial growth is claimed to enhance the product, particularly in respect of the body and texture of the product and in its smoothness and mouth feel. This is...

Pathophysiology of Stone Formation

Among lipid-lowering drugs, Clofibrate seems to have the greatest association with increased gall stone formation. The role of statins in gall bladder disease remains to be elucidated. Approximately one-third of patients treated with octreotide, a somatostatin analog, develop new gall stones. Cef-triaxone (Rocephin) has been shown to cause sludge formation in children. A large fraction of ceftriax-one is secreted in bile (40 ) and forms complexes with calcium, resulting in an insoluble salt. The sludge disappears when ceftriaxone is discontinued. Diet and lipid profile The ingestion of refined sugars has been shown to be associated with gall stone disease. However, no such association has been shown for alcohol or tobacco. It is not clear if high serum cholesterol predisposes to gall stone formation. In fact, the contrary has been shown in some studies. This is also the case for dietary cholesterol ingestion, which was shown to be a protective factor for gall stone formation in one...

Benefits of Low Glycemic Index Carbohydrates on Cardiovascular Disease Risk Factors

High glycemic index foods induce postprandial hyperinsulinemia, which is a powerful predictor for metabolic risk factors and CVD in epidemiological studies. Both cross-sectional and prospective population studies have shown favorable lipid profiles in association with high carbohydrate diets. Initially, these benefits were attributed to a high fiber content. However, when the glycemic index is controlled for, it is the low glycemic index diets rather than high fiber content that have the greatest influence on high-density lipoprotein (HDL) cholesterol, insulin sensitivity, and fibrinolytic parameters. In a cross-sectional study on more than 2000 middle-aged subjects, the glycemic index was a stronger determinant of HDL cholesterol than any other dietary factor, be it carbohydrate or fat. In this study, the HDL cholesterol of the women whose habitual diet was within the lowest quintile for glycemic index was 0.25 mmol l higher than that for women whose dietary carbohydrate was within...

Our Nutritious Past and Todays Health

Nutritional anthropologists have developed biocul-tural evolutionary models that offer holistic explanations for the interaction of genes and culture in an evolutionary context. They have described what our prehistoric ancestors may have eaten based on archeological skeletal remains and through cross-cultural comparison of what currently living hunter-gatherer populations eat. For example, diet and activity patterns of Kung San modern-day hunter-gatherers who live in the Kalahari Desert in southern Africa have been studied. They consume mostly plants (approximately 70 -80 of the food by weight), have high levels of physical fitness, low blood-cholesterol levels, and adequate and well-balanced nutrition. Stone age diets have been estimated to have consisted of wild game meat and wild plants. Compared with modern diets in industrialized societies they probably included more protein and dietary fiber and less fat (Eaton & Konner, 1985 Eaton, Shostak, & Konner, 1998).

Contemporary Low Calorie Carbohydrate Restricted Diet

In view of the well-recognized link between insulin resistance syndrome, hyperuricemia, and gout, a diet emphasizing reduced calorie intake with moderate restriction of carbohydrates and liberalization of protein and unsaturated fat consumption has been espoused for patients with gout. Low-purine foods are often high in both carbohydrate and saturated fats these foods tend to further decrease insulin sensitivity, thereby contributing to even higher levels of insulin, glucose, triglycerides, and low-density lipo-protein cholesterol and lower high-density lipoprotein cholesterol levels, all of which result in increased risk of coronary heart disease among these patients. Conversely, a calorie-restricted, weight-reduction diet that is low in carbohydrates (40 of total calories) and relatively high in protein (approximately 120 g per-day compared to 80-90 g in the typical Western diet) and unsaturated fat content, with no limitation of purine content, has been studied and found to result...

Clinical applications

It is possible to use immunoadsorbents as artificial organs in clinical applications. For example, patients with homozygous familial hypercholesterolemia have extreme elevations of plasma low density lipoprotein (LDL) which can be removed extracorporeal by pumping plasma or even whole blood over sterile columns of anti-LDL agarose. This process is termed LDL-apheresis. Although the antigen-antibody complexes formed in the sorbent column activate complement, this can be suppressed by the use of citrate, a calcium complexing agent, as the anticoagulant.

Homocysteine and Vascular Disease

In the mid-1970s, David and Bridget Wilcken rein-vigorated McCully's hypothesis with their observation that a subset of patients with premature coronary artery disease had reduced ability to metabolize homocysteine. Notably, this association was observed in individuals who did not have any of the severe genetic defects that underly homocystinuria, suggesting that less severe or modest impairment of homocysteine metabolism may contribute to vascular disease risk. Subsequently, the advent of reliable, high-throughput assays for total plasma or serum homocysteine in the 1980s (see below) allowed for large-scale epidemiological assessment of associations between homocysteine and vascular diseases, both cross-sectionally and longitudinally. Through the 1990s, an explosion of population and case-control studies established that hyperhomocysteinemia is, indeed, a risk factor for heart attack, stroke, thrombosis, and peripheral atherosclerotic disease. Moreover, the risk associated with...

Other Dietary Approaches for the Prevention and Management of CVD

When considering diets very low in fat and high in carbohydrates ('very low-fat' diets), it is important to separate the effects of the composition of the diet from confounding factors associated with intentional weight loss. For the purposes of this discussion, a very low-fat diet will be defined as less than 15 of energy as fat. Consumption of a very low-fat diet without a decrease in energy intake frequently decreases blood total, LDL, and HDL cholesterol levels and increases the total cholesterol HDL cholesterol ratio (less favorable) and triglyceride levels. A mitigating factor may be the type of carbohydrate providing the bulk of the dietary energy complex (whole grains, fruits, and vegetables) or simple (fat-free cookies and ice cream). The reason for this later observation has yet to be investigated. Notwithstanding these considerations, for this reason moderate fat intakes, ranging from < 30 to 25 to 35 of energy Current interest in the area of weight loss is centered on...

Possible Implications Of Observations In Rat In Human Behavior

In classical lipid nutrition for the prevention of atherosclerosis and related diseases, hypercholesterolemia and animal fat were considered to be the major risk factors and high-LA vegetable oils were recommended. Although this recommendation was found to be ineffective (Multiple Risk Factor Intervention Trial Research Group, 1982) and even to be risky for atherosclerosis-related diseases, an increase in the incidence of violent death was observed to be associated with it (Strandberg, 1991 Muldoon, 1990 ). The plasma cholesterol level does not decrease significantly after prolonged dietary recommendations to raise the vegetable oil animal fat ratio (or P S ratio) of food the hypocholesterolemic effect of dietary LA was found to be only transient (Okuyama, 1997, 2000). Therefore, it is not cholesterol that is associated with the increase in the incidence of violent death rather, the increased intake of LA and the elevated n-6 n-3 ratio are likely to be the cause, in view of the...

Dietary Factors with Limited or Uncertain Effect on Blood Pressure

Numerous studies, including both observational studies and clinical trials, have examined the effects of fat intake on blood pressure. Overall, there is no apparent effect of saturated fat and n-6 polyunsatu-rated fat intake on blood pressure. Although a few trials suggest that an increased intake of monounsa-turated fat may lower blood pressure, evidence is insufficient to make recommendations. Likewise, few studies have examined the effect of dietary cholesterol intake on blood pressure. Hence, although modification of dietary fat and cholesterol intake can be recommended as a means to prevent and treat hyperlipidemia and dyslipidemia, evidence is insufficient to recommend these changes alone as a means to lower blood pressure.

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).

Alteration of a Major Fatty Acid Level

An example of oil modification by this technique is the development of high-oleic-acid soybean oil by DuPont through antisense suppressing and or cosuppression of oleate desaturase. The new oil has an oleic acid content of 80 or higher, compared with 24 in normal soybean oil (Liu, 1999). The crop looks so promising that about 50,000 acres were planted in 1998. Because it is more stable, this oil does not require hydrogenation for use in frying or spraying, which reduces processing costs and also avoids the formation of trans fatty acids, which are associated with high cholesterol levels. In addition, this new oil has a longer useful life, which is desirable in the fastfood industry (Riley and Hoffman, 1999). In the case of sunflower, the modified crop is known as mid-oleic sunflower, which has a modified fatty acid profile. It was grown on 100,000 acres in the U.S. in 1998. The seed produces low saturated fat oils with 60 to 75 oleic acid, compared with 16 to 20 in normal oil. This...

Inflammation and cardiovascular disease

Higher serum CRP concentrations may identify patients more likely to respond to aspirin or statin therapy. Among 543 cases and matched controls in the Physicians', Health Study, aspirin reduced myocardial infarction by 56 among those with the highest quarter of baseline CRP level, versus a 14 reduction in those in the lowest quarter.60 In the CARE61 and AFCAPS Texas CAPS62 studies, patients with high CRP levels benefitted from statin therapy even in the presence of low to normal LDL cholesterol. Statins lower CRP concentrations,63 and may have anti-inflammatory properties. The ongoing Pravastatin Inflammation CRP Evaluation (PRINCE) study is testing the effectiveness of statin therapy among patients with high CRP levels.64 ACE inhibitors may also decrease inflammation. However, CRP levels did not predict response to ramipril in the HOPE study (Smieja etal., 2002, personal communication).

Inflammation conclusions and recommendations

Whether high CRP levels require treatment, and whether other inflammatory risk markers should be measured routinely, is not clear from the available evidence. Whether these inflammatory molecules play a causal role in atheroma formation also remains unknown. The beneficial effects of aspirin and of statins in CV prevention may be mediated in part by their anti-inflammatory actions. Grade B

R Common to both approaches

Many groups have found it useful to work backwards through the development and approval process from proposed optimal and minimal package inserts, in an effort to better define the studies that may be needed to support early clinical trials and possible regulatory questions (Fig. 4.21). The major label claims involve five areas noted in the slide and drive at least the five noted aspects of development. As an example, consider the development of a new drug for a cancer indication. What cancers could be treated How will the drug be used clinically (standalone or adjunctive therapy, first-line treatment or salvage treatment, etc.) Are there patient subsets that may respond differently Are there certain toxicities of existing drugs to avoid or not exacerbate How will the drug be administered (oral, intravenous, subcutaneous, etc.), and for how long (a few minutes, days, months, years) How large do phase III trials need to be and what is the approvable end point Answers to these questions...

Can net benefit be determined

Pioglitazone (Actos) on cardiovascular events.3 The primary composite outcome included incidence of mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, revascularizations and amputations. Notably absent was congestive heart failure, a known adverse effect of the glitazones, especially when given in combination with insulin. PROactive failed to show a statistically significant reduction of the primary outcome, but there was a strong favorable trend (RR 0.90, 95 CI 0.80-1.02). The difference for one of the secondary composite outcomes (incidence of mortality, nonfatal myocardial infarction and stroke) reached nominal statistical significance (RR 0.84, 95 CI 0.72-0.98). The numerical reduction for the primary outcome was fifty-eight events and for the secondary outcome fifty-seven events. The authors concluded that pioglitazone improves the cardiovascular outcome in patients with Type-2 diabetes. In the main publication,3 however, they failed to point out that the...

Effects of Dietary Fats and Cholesterol on Lipoprotein Metabolism

The cholesterolemic effects of dietary fatty acids have been extensively studied. The saturated fatty acids Ci2 o, C14.0, and Ci6 0 have a hypercholester-olemic effect, whereas Cig 0 has been shown to have a neutral effect. Monounsaturated and polyunsatu-rated fatty acids in their most common cis configuration are hypocholesterolemic in comparison with saturated fatty acids. The effects of trans fatty acids on lipid levels are under active investigation. Our current knowledge shows that their effect is intermediate between saturated and unsaturated fats. The effect of dietary cholesterol on lipoprotein levels is highly controversial. This may be due in part to

Chemical Composition

Table 1 shows the chemical composition of whole krill body taken in the period December through February. It can be seen that the chemical composition of krill is well balanced in foodstuff. The lipids of krill have a high iodine value of 110-190. About 70 of the whole lipids of krill is unsaturated fatty acid. Concentration of oleic acid, eicosapentae-noic acid, and docosahexaenoic acid are high. Krill lipids are, however, not easily oxidized, which may be due to their high concentration of vitamin E in the oil as antioxidant. Cholesterol levels of shellfish are higher than that of fish krill is not an exception. Krill tissue contains 62.4-71.6 mg 100 g cholesterol. Krill contains large amounts of vitamin A, D, and the B group complex. Most of the vitamin A is astaxanthin in the whole body, which is highly concentrated in the eyes.

Effects of Diet on LDL Metabolism

The effects of dietary fat and cholesterol on LDL metabolism have been extensively studied. However, the effects of dietary cholesterol are still highly controversial. Whereas some studies have demonstrated increased LDL production and decreased catabolism associated with high cholesterol intakes, others have failed to find such associations.

Familial Combined Hyperlipidemia

Familial combined hyperlipidemia (FCH) was initially described as the combination of hypercholester-olemia and hypertriglyceridemia within the same kindred, and with kindred members having one of these abnormalities or both. Moreover, most subjects with FCH have HDL cholesterol levels below the i0th percentile. Affected subjects have elevation in VLDL, LDL, or both. This disorder has a frequency of approximately 10 in survivors of

Familial Lipoprotein a Excess

Lp(a) concentrations are highly variable among individuals however, they tend to remain constant during a person's lifetime. Between 80 and 90 of the variability appears to be of genetic origin, owing, for the most part, to variations at the structural apo(a) gene locus. Lp(a) concentrations are inversely associated with a size polymorphism of apo(a). This polymorphism is due to differences in the number of a multiple repeat of a protein domain highly homologous to the kringle 4 domain of plas-minogen. Diets and medications used to lower LDL cholesterol levels do not appear to have a significant effect on Lp(a) concentrations however, niacin has been reported to decrease Lp(a) levels. There have been reports suggesting that diets high in trans fatty acids have some raising effects on Lp(a) levels, whereas estrogen replacement lowers Lp(a) in post-menopausal women.

General Guidelines for the Treatment of Lipoprotein Abnormalities for CHD Prevention

There is a clear benefit from lowering LDL cholesterol with diet or drug therapy in patients with hyperlipidemia or CHD or both. Dietary therapy includes using diets that are restricted in total fat (< 30 of calories), saturated fat (< 7 of calories), and cholesterol (< 200 mg day-1). Pharmacological therapies include anion exchange resins, niacin, and HMG CoA reductase inhibitors. The latter agents have been demonstrated to also lower CHD mortality. It should be noted that dramatic interindividual variations have been demonstrated in response to diet and drug therapies. Consequently the efficacy of hypolipidemic therapies will vary from individual to individual. More information is needed about the benefits of HDL cholesterol raising in patients with low HDL cholesterol levels as well as the benefits of lowering triacylglycerol plasma concentrations, and more specifically the triacylgly-cerol carried in lipoprotein remnants. This is also true regarding the benefits of Lp(a)...

Coronary artery disease

Assessed coronary artery disease associated with an increase in waist circumference, that reached an odds ratio of over 12 in patients with familial hypercholesterolemia.73 Weight gain has also been associated with a significant increase in coronary risk.30 Thus, a weight gain of 15 kg after age 21 was associated with an increased coronary risk of 83 in women and 46 in men. Weight reduction has been consistently shown to lower blood pressure, lower plasma glucose and insulin levels, prevent the development of type 2 diabetes, lower plasma triglycerides and raise low levels of HDL cholesterol, and improve other risk factors for coronary artery disease.5,15 It is therefore very likely that weight reduction will substantially lower coronary risk in obese patients. However, there are currently no hard end-point data from randomized controlled trials of weight loss on morbidity and mortality in patients with coronary artery disease.

Drug interactions affecting absorption

Adsorption is the process of ion binding or hydrogen binding and may occur between anti-infectives such as penicillin G, cephalexin, sulfamethoxazole, or tetracycline and adsorbents such as cholestyramine. Because this process can significantly decrease antibiotic exposure (33,34), the concomitant administration of adsorbents and antibiotics should be avoided.

The role of plant sterols and stanols in functional dairy products in reduction of cholesterol

Plant sterols and stanols appear to be as effective in dairy products as in spreads with lowering of LDL cholesterol of 5-10 . No significant changes in HDL cholesterol or triglyceride occur with either food carrier. Volpe (2001) was the first to show an effect of low fat yoghurt containing 1 g day of soybean derived sterols (whether free or esterified was not specified) in 30 men and women with elevated LDL cholesterol. LDL cholesterol was lowered by 6.2 after four weeks compared with placebo. Eleven of the volunteers continued for another four weeks on 2 g day of sterols and achieved an LDL cholesterol-lowering of 15.6 but there was no placebo period to compare it with. Given that during the placebo period in the first part of the study LDL cholesterol fell by 4.9 it would appear that 2 g day of sterol in yoghurt lowers LDL cholesterol by about 10 . A 40 butter fat based spread containing 2.4 g day of esterified soybean sterols lowered median LDL cholesterol by 18.7 in a small study...

Do surrogate markers predict benefit in individuals

It has been generally assumed that only patients with hypercholesterolemia or hypertension benefit from lipid-lowering or antihypertensive treatment. Recent trial reports, however, have raised questions about these assumptions. The Heart Protection Study1 investigated simvastatin (Zocor) vs. placebo taken over 5 years in 20,500 subjects. The fairly unselected study population included those with normal and abnormal serum lipids, as well as those with and without a history of vascular disease. Convincing subgroup analyses demonstrated that subjects with normal lipids and no vascular history (i.e., those with no indication for statin treatment) benefited the same as those in other subgroups, in terms of relative event reduction. The authors raised the logical question -- Is elevated total or LDL cholesterol in serum a reliable indicator for initiation of lipid-lowering (statin) treatment Should treatment guidelines and treatment decisions be based only on these measures Clearly, drugs...

Saturated Fatty Acids

The Seven Countries Study (7) was a landmark epidemiologic investigation that played a seminal role in establishing a relationship between diet and the incidence of coronary heart disease (CHD). Moreover, this study also provided evidence that diet affected serum cholesterol levels and that an elevation in cholesterol increased risk of coronary disease. This marked the beginning of the dietheart hypothesis era, a time during which numerous studies were conducted to examine the effects of different dietary factors on risk factors for coronary disease. Many of these studies evaluated the relationship between the type of fat in the diet and serum cholesterol levels. An important finding of the Seven Countries Study was that saturated fat intake (as a percentage of calories) was significantly correlated with serum cholesterol levels 80 of the variability was due to differences in dietary SFA among the populations. Moreover, SFA intake was also correlated with five-year incidence of CHD....

Unsaturated Fatty Acids

MUFAs are a unique class of fatty acids that provides great flexibility in diet planning. They can be used to replace SFAs or carbohydrate calories or both. Depending on the substitution made, there can be a variable change in the total fat content of the diet, varying from essentially no or little change to an approximate twofold increase. The impact of these scenarios has already been discussed. In brief, however, diets high in MUFA (that are low in SFA and cholesterol) will lower total and LDL cholesterol and plasma triglycerides and minimize any potential decrease in HDL cholesterol levels (14). In individuals with diabetes, MUFAs improve the glycemic profile (plasma glucose and insulin levels) (15). There is some evidence that MUFAs may decrease susceptibility of LDL particles to oxidative modification (which is an important initiating event in the development of atherosclerosis), thereby reducing their atherogenic potential (16).

Polyunsaturated Fatty Acids Omega6 Fatty Acids

Evidence that certain SFAs raise blood cholesterol levels whereas PUFAs lower them was a justification for several major diet trials designed to lower CHD risk by feeding a high-fat diet (about 40 of calories) that was low in SFA and very high in PUFA (16 to 20 of calories Oslo Diet Heart Study, 19 VA Diet Heart Study, 20 Finnish Mental Hospital Study, 21). These studies all showed that this diet lowered CHD risk by 24 to 53 concomitant with a reduction in serum cholesterol of 13 to 15 . Because of the perception that these diets might be associated with a higher incidence of cancer and also because this diet is not consumed by population groups worldwide to meaningfully assess its safety, it has not widely been recommended for the prevention and treatment of CHD. Recent studies have reported that while PUFA has a greater total and LDL cholesterol-lowering effect versus MUFA, the differences are not as great as once believed. Thus, for practical purposes, MUFA or PUFA will elicit...

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 comm

Functional Properties and Tissue Health

In certain circumstances, lycopene can reduce LDL-cholesterol levels, possibly by inhibiting hydroxymethylglutaryl CoA reductase (HMGCoA reductase), the rate-limiting enzyme for cholesterol synthesis (see below). Lycopene was shown to have modest hypocholesterolemic properties in one small clinical trial.

Lycopene and Cardiovascular Disease

The European Multicentre Euramic Study, which reported that risk of developing myocardial infarct was inversely related to lycopene intake, after appropriate adjustment for other cardiovascular risk factors. Some Scandinavian studies have subsequently supported this claim moreover, lycopene is capable of reducing LDL-cholesterol levels, possibly by inhibiting hydroxymethylglutaryl CoA reductase (HMGCoA reductase), the rate-limiting enzyme for cholesterol synthesis.

Effect of drugs on long term arrhythmia mortality

One consequence of CAST was a general consensus, on the part of clinical investigators and regulatory authorities, that licensing new antiarrhythmic drugs might well require demonstration that those drugs did not increase mortality. Two large mortality trials have been conducted with pure I . blocking compounds SWORD tested the dextro-rotary (non-P blocking) isomer of sotalol, and DIAMOND tested dofetilide. In SWORD, d-sotalol increased mor-tality,12 whereas in DIAMOND, dofetilide produced no eVect on mortality.13 These diVerences likely arose from diVerences in trial design, and in particular eVorts to minimise the possibility of torsades de pointes during long term treatment in DIAMOND. Amiodarone has been tested in a CAST-like population and been found to exert a modest effect to decrease mortality,14 an effect that may be potentiated by co-administration of P blockers.15 Despite numerous attempts, calcium channel blockers have not been shown to exert a major effect to reduce...

Gender and cardiovascular disease

The sex differential in the age of onset of CHD is also one of the reasons why estrogen is of interest as a potential preventive treatment for CHD. Lipid levels in children of both sexes are similar until puberty, when high density lipopro-tein (HDL) cholesterol levels fall by about 10mg dl in boys only, while low density lipoprotein (LDL) cholesterol levels decrease by about 5mg dl in girls.2 These changes may be attributable to rising androgen and estrogen levels in boys and girls respectively. The sex differential for HDL cholesterol persists through adult life, but is less marked in older persons. LDL cholesterol levels rise during adulthood, and in older women LDL cholesterol levels eventually catch up with those in men. Estrogen levels in women gradually decline, starting some years before the menopause, during which time LDL cholesterol levels rise and HDL cholesterol levels decrease.3 These lipid changes may underlie the lower CHD risk in premenopausal women, and the gradual...

Coronary heart disease

Thus, there is a plethora of potential mechanisms by which estrogen may reduce the risk of CHD.16 Unfortunately, the existence of mechanisms does not necessarily translate into clinical benefit. A treatment that has a favorable effect on an intermediate mechanism may decrease the incidence of target clinical events, or may turn out to have no effect, or may actually increase the event rates. The treatment may also have unanticipated adverse effects on other clinical events.17 For example, a number of early lipid lowering drugs, such as thy-roxin and estrogen, were abandoned after it was found that, although these drugs decrease cholesterol levels, they also increase the cardiovascular morbidity and mortality in men.18

Should changes in a surrogate marker be extrapolated within a drug class

Favorable changes in a surrogate marker are sometimes insufficient to recommend full approval and widespread use of the first drug of a particular class. Clinicians and regulatory agencies prefer to see trial evidence of event reductions. When simvastatin (Zocor) was shown to reduce total and LDL-cholesterol, the FDA approved the drug, but asked for outcome trials. When the first large simvastatin trial, 4S,6 showed a convincing reduction in all-cause mortality in coronary patients, use of the drug increased markedly. It is appropriate that the clinical criteria for accepting the first drug of a class are the Cerivastatin (Baycol) was introduced as a potent lipid-lowering agent, and promoted as another statin. Many were led to believe that it was interchangeable with the other approved statins, which had very positive event and safety data. By lowering the cost of the drug compared to the other brandname statins, the manufacturer of cerivastatin succeeded in gaining modest market...

Availability and Transport of Circulating Cholesterol

Free cholesterol is the precursor for all steroid hormones, but free cholesterol is typically not found within ste-roidogenic cells. Cholesterol transport involves protein protein interactions and is critical for steroid biosynthesis. Most of the cholesterol is provided by low-density lipoproteins (LDL) or high-density lipoproteins (HDL), although small amounts of cholesterol are produced by de novo synthesis. The LDL HDL cholesterol complexes bind to specific membrane receptors and are subsequently

STSegment Elevation Myocardial Infarction

-Isosorbide mononitrate (Imdur) 30-60 mg PO qd. Aldosterone Receptor Blocker if EF < 40 -Eplerenone (Inspra) 24 mg PO qd -Spironolactone (Aldactone) 25 mg PO qd Statins -Rosuvastatin (Crestor) 10 mg PO qhs OR -Atorvastatin (Lipitor) 10 mg PO qhs OR -Pravastatin (Pravachol) 40 mg PO qhs OR -Simvastatin (Zocor) 40 mg PO qhs OR -Lovastatin (Mevacor) 20 mg PO qhs OR -Fluvastatin (Lescol)10-20 mg PO qhs.

Effect of Meal Frequency on Absorption

Meal frequency not only affects insulin and glucose levels but also influences an individual's circulating lipids. An inverse relationship exists between meal frequency and lipid levels, suggesting that infrequent feeding leads to an increased risk of cardiovascular disease due to large fluctuations in circulating lipids. Increased meal frequency, on the other hand, is associated with several benefits, such as decreased serum cholesterol levels, decreased total high-density lipoprotein cholesterol ratio, decreased esterified fatty acids, and decreased enzyme levels in adipose tissue associated with fatty acid storage. Paradoxically, individuals who report that they eat more frequently not only have lower total and low-density lipoprotein cholesterol (LDL-C) but also have a greater intake of energy, total fat, and saturated fatty acids. Considering that some of these results were found in a free-living

Mechanisms Underlying the Metabolic Effect of Meal Frequency

The mechanisms underlying beneficial responses to frequent feeding as opposed to an infrequent meal pattern are not fully understood. Frequent feeding has been shown to elicit lower plasma glucose fluctuations than does a more infrequent eating pattern. The absolute amount of carbohydrate eaten at each episode of ingestion in a frequent feeding pattern is simply not great enough to elevate glucose to the same extent as more infrequent eating. Small elevations in plasma insulin seen with frequent feeding are most likely in response to minimal fluctuations in glucose. The mechanisms responsible for the effect of an increased frequency of meal eating on lipid metabolism are not as clear-cut. The lower serum cholesterol levels observed during frequent feeding may be related to lower serum insulin levels. Insulin appears to have a key role in enhancing the hepatic synthesis of cholesterol through its ability to stimulate hydroxymethylglutaryl-coenzyme A reduc-tase (HMG-CoA), the...

Venous thromboembolism

Persisted over the duration of the study. These findings on an adverse event from a clinical trial are very similar to those from the observational studies. In exploratory analyses, other risk factors for venous thromboembolism included older age at menopause, lower extremity fractures, cancer, being within 90 days of inpatient surgery, or non-surgical hospitalization. After non-fatal MI the risk was increased for 90 days. Use of statins or aspirin appeared to decrease risk it should be noted, however, that these were non-randomized comparisons and that the large number of comparisons performed may have led to chance findings. The WEST study investigators stated that there were no differences in venous thromboembolism between treatment groups.53 As noted above, healthy women in the WHI have been informed of an excess risk during the first few years of the study.35 Some trials with intermediate or surrogate outcomes (for example, the Postmenopausal Estrogen-Progestin Interventions and...

Treatment recommendations

However, until these clinical trial data are known, it may be wise to consider alternatives to hormone therapy even for proven indications such as prevention of osteoporosis.65 For osteoporosis prevention, exercise, diet, calcium, and vitamin D may be recommended, and for treatment the bis-phosphonates and raloxifene have been shown to prevent fractures. Lifestyle measures and medical management of risk factors such as high blood cholesterol and high blood pressure will prevent many cases of CHD and stroke, and for secondary prevention of CHD aspirin, statins, (3 blockers, and ACE inhibitors have all been found to be effective.64 The AHA statement acknowledges that the current recommendations are based mainly on data from trials using standard doses of conjugated equine estrogens and medrox-yprogesterone, and that evidence is insufficient for different preparations, routes of delivery, and doses that may have a more favorable or more adverse effect on cardiovascular outcomes.

Potential Effects Requiring Further Clinical Work

Cholesterol control The cholesterol-lowering effects of probiotics have been the subject of two recent reviews with contradictory results. The first, which focused on short-term intervention studies with one yogurt type, reported a 4 decrease in total cholesterol and a 5 decrease in LDL. Contrary to this, the second review concluded that no proven effects could be found. In this context, it is clear that long-term studies are required before the establishment of any conclusion.

TABLE 2075 Clinical Presentation of Myxedema Coma

Laboratory evaluation of patients with suspected myxedema coma may reveal anemia hyponatremia hypoglycemia elevated transaminases, creatine phosphokinase, and lactate dehydrogenase levels hypercholesterolemia and arterial blood-gas abnormalities (decreased P o2 and increased Pco2). The electrocardiogram may demonstrate sinus bradycardia, prolongation of the QT interval, and low voltage with flattening or inversion of T waves. A chest radiograph may demonstrate an enlarged cardiac contour caused by a pericardial effusion. 910

Aboriginal populations

The common CHD risk factors among Aboriginal people include obesity, abdominal obesity, diabetes, elevated blood pressure, low HDL cholesterol, and tobacco use. The prevalence of cigarette smoking is generally high and increasing among Aboriginal people the prevalence varies greatly between reserves.98'102 The prevalence of diabetes in the Strong Heart Study was an astounding 48 in the 45-64 year age group compared to approximately 5-5 in the US general population, and the prevalence of obesity was between 26 and 41 , with an average BMI of 31 and waist-hip ratio of 0-96 in men.103 Interestingly, the prevalence of hypertension and elevated serum cholesterol among Aboriginal people appears to be lower when compared to the general US population. In Canada, however, the prevalence of hypertension requiring drug treatment, and elevated cholesterol requiring medication, was significantly increased among Aboriginal people compared to a similar sample of non-Aboriginal people.98 In addition,...

Blacks of African origin

In most urban and virtually all rural regions of SSA the prevalence of traditional CVD risk factors among blacks is low. However, with urbanization, an increase in conventional cardiovascular risk factors and CVD rates is expected.111 An example of this is found in South Africa, as the rapid migration of blacks to urban centers has led to increased poverty, obesity, hypertension, LDL cholesterol, and a decrease in HDL cholesterol.112-115

High Risk Hypertensive Patients

Some patient groups have such high CVD risk and chance of benefit that they require antihypertensive treatment even for mild hypertension (> 140 90 mm Hg) without formal calculation of absolute risk. Patients with any form of symptomatic atherosclerotic vascular disease, including previous myocardial infarction, bypass graft surgery, angina, stroke or transient ischaemic attack, peripheral vascular disease or atherosclerotic renovascular disease need treatment of even very mild hypertension (> 140 90 mm Hg) for secondary prevention. Indeed there is mounting evidence that secondary prevention patients with normal blood pressure (< 140 90 mm Hg) benefit from blood pressure reduction. This is similar in principle to reducing normal or even low cholesterol with statins. Patients with target organ damage such as LVH, heart failure, proteinuria or renal impairment also have high CVD risk and need treatment of even very mild hypertension. Older patients (> 60 years) have high CHD...

Problems With Targeting Absolute Risk

The principle of targeting treatment at high absolute CHD risk rather than high cholesterol is now accepted for statin treatment, but the similar policy for antihypertensive treatment is less widely known and practised. Antihypertensive treatment was targeted at defined blood pressure thresholds for decades, and the idea that treatment to lower blood pressure should not be targeted at blood pressure but at CHD risk is difficult for some to grasp. This difficulty is compounded by the intense interest in more precise measurement of blood pressure using ABPM, and ever more detailed analyses of ABPM patterns.

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Lower Your Cholesterol In Just 33 Days

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