Fish oil Omega 3 and heart disease

By , April 7, 2015 1:36 pm

Individuals with high intake of Ω-3 polyunsaturated fatty acids,
usually associated with a high fi sh and low red meat diet, have
low rates of heart disease. Fish oil concentrates reduce triglyceride
levels and increase LDL particle size, a benefi cial effect when
administered in high doses (6–12 g/day).

 

Patients who had
LDL-C levels of less than 70 mg/dL and CRP levels of less than
1 mg/L after statin therapy had the lowest rate of recurrent CV
events.

 

Effect of Plant Sterol–Containing Fats on Blood Lipid Levels

By , April 7, 2015 1:35 pm

Effect of Plant Sterol–Containing Fats on Blood Lipid Levels

Background

In the early 1950s, plant-derived sterols were observed to decrease serum cholesterol levels.1 2 The effective dose in humans was reported to be between 5 and 10 g/d when given in divided doses. The efficacy of plant sterols with regard to lowering blood cholesterol levels was soon confirmed,3 4 5 6 albeit at somewhat lower doses.7 On the basis of these data, plant sterols were briefly used in the reduction of blood cholesterol levels before the introduction of pharmacological agents with higher efficacy and patient acceptance. The resurgence of interest in plant-derived sterols is now coupled with the incorporation of these compounds into fat-containing foods. More recent evidence has shown that esterification of these sterols increases their solubility in fat and their efficacy in lowering low-density lipoprotein (LDL) cholesterol levels.8 9

What Are Plant-Derived Sterols?

Sterols represent a group of compounds that are alcoholic derivatives of cyclopentanoperhydrophenanthrene and are an essential constituent of cell membranes in animals and plants. Cholesterol is the sterol of mammalian cells, whereas multiple sterols, or phytosterols, are produced by plants, with sitosterol, campesterol, and stigmasterol being most common. Plant sterols, although structurally similar to cholesterol, are not synthesized by the human body. They are very poorly absorbed by the human intestine. The specific plant sterols that are currently incorporated into foods intended to lower blood cholesterol levels are extracted from soybean oil or tall (pine tree) oil. Additional sources of plant sterols may be available in the near future. The plant sterols currently incorporated into foods are esterified to unsaturated fatty acids (creating sterol esters) to increase lipid solubility, thus allowing maximal incorporation into a limited amount of fat. Some plant sterols currently available are saturated, to form the stanol derivatives, sitostanol and campestanol, which after esterification form stanol esters.

Effect of Plant Sterol–Containing Fats on Blood Lipid Levels

A clinical study of hypercholesterolemic subjects concluded that esterified β-sitostanol was more efficient than free β-sitosterol, free β-sitostanol, or rapeseed-based margarine alone in lowering serum cholesterol (14). The superiority of β-sitostanol ester has yet to be confirmed because the intakes of the dietary plant sterols were different in the experimental groups of the trial. A comparison of free β-sitostanol with free β-sitosterol, however, showed that the saturated plant sterol increased cholesterol excretion more effectively than the unsaturated plant sterol when infused over several hours in low concentrations (3). Despite the latter finding, a recent comparison of esterified unsaturated sterols from soybeans with the ester of the saturated β-sitostanol indicated that soybean sterol esters had a similar serum cholesterol–lowering effect as the β-sitostanol ester (12). It could therefore be hypothesized that soy sterols and β-sitostanol inhibit cholesterol absorption equally when both fractions are esterified.

In the early 1990s, it was reported that sitostanol ester (3.4 g/d) delivered in the form of rapeseed (canola) oil–based margarine lowered LDL cholesterol levels by ≈10% in modestly hypercholesterolemic subjects and that individuals with apolipoprotein (apo) E4 alleles, previously reported to have the highest efficiency of cholesterol absorption, derived the greatest benefit from treatment.8 9 Subsequent work has established that maximal efficacy with respect to total and LDL cholesterol lowering is achieved at ≈2 g/d and that there is little or no effect on high-density lipoprotein (HDL) cholesterol or triglyceride levels.10 11 12 13 14 15 16 17 18 19 20 21 In addition, these studies demonstrated that the consumption of fats containing plant-derived sterol esters is efficacious in both normolipidemic and dyslipidemic individuals, including those treated with β-hydroxy-β-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors and other lipid-lowering agents. In addition, daily ingestion of 1.8 to 3 g of plant stanol esters in hypercholesterolemic children has been reported to reduce LDL cholesterol levels to an extent similar to that in adults.22 For the most part, the consumption of ≈2 g/d of plant sterol ester has been reported to decrease LDL cholesterol levels 9% to 20%, with considerable variability reported among individuals.10 11 12 13 14 15 16 17 18 19 20 21 There appears to be little difference in efficacy of campestanol ester and sitostanol ester with respect to cholesterol lowering.23

The impact of the sterol/stanol ester–containing fats on LDL cholesterol lowering is relatively consistent regardless of whether the background diet is similar to that currently consumed in Western countries or reduced in total fat, saturated fat, and cholesterol, consistent with current guidelines for hypercholesterolemic individuals, and whether the plant sterol ester–containing fats have been incorporated into regular fat or reduced fat products.8 9 10 11 12 13 14 15 16 17 18 19 20 21

Both unsaturated (sterol ester) and saturated (stanol ester) forms of plant sterols have been used in the above studies. Comparative investigations of the relative efficacy of these 2 preparations in regular-fat margarine have recently been reported.15 21 Superimposed on a background diet high in total and saturated fat, ≈2 to 3 g/d taken in 2 divided doses of both sitostanol ester and sitosterol ester in margarine resulted in 10% to 13% reductions in LDL cholesterol and no significant change in HDL cholesterol levels. An additional study has compared the effect of 2 reduced-fat (40% of fat) margarines containing stanol esters, the sterol esters derived from either tall oil or soybean oil, within the context of diets consistent with the American Heart Association Step 2 diet criteria.24 The efficacy of both preparations was similar, with a decrease of ≈9% in LDL cholesterol levels.

Mechanisms of Action of Plant Stanol/Sterol Ester–Containing Fats

Sterol balance studies have suggested that decreased blood cholesterol levels are attributable, at least in part, to an inhibition of cholesterol absorption.25 This inhibition has been ascribed to a number of mechanisms, including partitioning in the micellar phase of the intestinal lumen, presence in the unstirred water layer or other mucosa barriers that might limit transmembrane transport, and alteration in rates of cholesterol esterification in the intestinal wall.25 26 27 28 29

Plant sterols differ structurally from cholesterol by a methyl or ethyl group in their side chains and are not synthesized in the human body. These structural differences render them minimally absorbable. Serum campesterol levels and stable isotope–labeled cholesterol can be used to estimate the efficiency of intestinal cholesterol absorption in humans.27 28 29 Such data have confirmed the original observations from sterol balance studies that plant-derived sterols decrease the absorption of both dietary and endogenously derived cholesterol in the intestine. It has been speculated that the full magnitude in the decreased rate of cholesterol absorption (33% to 60%) is not realized in decreased LDL cholesterol levels because of compensatory mechanisms that increase the rate of endogenous cholesterol synthesis.8 9 This speculation has recently been confirmed.30 Lipoprotein kinetic studies have associated the significant decreases in LDL cholesterol levels with a decreased production rate of LDL apoB rather than a change in the LDL apoB fractional catabolic rate.12 The general lack of effect of plant-derived sterols on HDL cholesterol levels was reflected in essentially no change in the kinetic parameters of HDL apoA-I.12

Potential Risks Associated With the Use of Plant Stanol/Sterol Ester–Containing Fats

Few adverse effects related to either the short-term or long-term consumption of the plant stanol/sterol ester–containing fats have been reported. However, of concern are some observations of decreased levels of plasma alpha plus beta carotene, α-tocopherol, and/or lycopene as a result of the consumption of foods containing both stanol esters and sterol esters.16 17 23 24 In general, with the exception of beta carotene, these decreases often parallel the decreases in total and LDL cholesterol. Still, at this time it appears prudent to recommend additional monitoring of the effect of foods containing plant-derived sterol/stanol esters on fat-soluble nutrient levels and to recommend that an assessment of the biological significance of the changes observed be determined. The activities of alkaline phosphatase, alanine transaminase, aspartate transaminase, and γ-glutamate transaminase have been reported to be unaffected by plant sterol consumption within the recommended range.17 Other technical data on safety evaluation are now available.31 32 33 34 35 36 37

Plasma levels of plant sterols/stanols have not been or are only minimally elevated after daily ingestion of sterol/stanol ester–containing foods.12 16 23 24 However, there may be some individuals in the population who have abnormally high absorption of plant sterols. For example, individuals homozygous for sitosterolemia absorb substantial amounts of sitosterol, with resultant hypercholesterolemia and development of xanthomas.38 It is not known whether some individuals heterozygous for this condition could absorb higher amounts of plant sterols than the normal population and whether this would lead to adverse effects. In a study of 2 obligate heterozygotes for sitosterolemia,39 increased sitosterol absorption was balanced by enhanced plant sterol elimination. It is not known what percentage of individuals in a given population would have this condition. Still, in the absence of more data on genetic mutations involved in sitosterolemia, it would be prudent to counsel these individuals against the use of these foods at the present time.

Of concern are the potential adverse effects of lowering beta carotene and perhaps other fat-soluble vitamins over long periods of time in children who would be ingesting plant sterol–containing fats. Likewise, data on the effect of these compounds in pregnant women are lacking. Because food products containing plant sterols are likely to be shared during meals by all family members, the potential for intake by nonhypercholesterolemic individuals is significant. Thus, the American Heart Association recommends that further studies and large-scale monitoring be undertaken to determine the long-term safety of plant sterol/stanol ester–containing foods in both normocholesterolemic and hypercholesterolemic adults, as well as in children.

Outcome

The margarine containing sitostanol ester was well tolerated. The mean one-year reduction in serum cholesterol was 10.2 percent in the sitostanol group, as compared with an increase of 0.1 percent in the control group. The difference in the change in serum cholesterol concentration between the two groups was -24 mg per deciliter (95 percent confidence interval, -17 to -32; P<0.001). The respective reductions in low-density lipoprotein (LDL) cholesterol were 14.1 percent in the sitostanol group and 1.1 percent in the control group. The difference in the change in LDL cholesterol concentration between the two groups was -21 mg per deciliter (95 percent confidence interval, -14 to -29; P<0.001). Neither serum triglyceride nor high-density lipoprotein cholesterol concentrations were affected by sitostanol. Serum campesterol, a dietary plant sterol whose levels reflect cholesterol absorption, was decreased by 36 percent in the sitostanol group, and the reduction was directly correlated with the reduction in total cholesterol (r = 0.57, P<0.001).

Modifying Coronary Artery Atherosclerosis

By , April 7, 2015 11:18 am

 

Framingham Heart Study Identifying major CVD risk factors

Over the years, careful monitoring of the Framingham Study population has led to the identification of the major CVD risk factors –
high blood pressure,
high blood cholesterol,
smoking,
obesity,
diabetes, and
physical inactivity

Hypertension
Each 20-mm Hg increase in systolic blood pressure or 10-mm Hg increase in diastolic blood pressure doubles coronary heart disease mortality and stroke mortality. Proposed mechanisms by which hypertension promotes atherosclerosis include damage to endothelial cells, promoting activation and incorporation of lipids into subintima, and stimulation of subintimal smooth muscle cell proliferation.

 

 

 

 

For prevention of CAD, the NCEP has determined that an LDL-C level of less than 100 mg/dL is optimal for CAD prevention, and a level of 70 mg/dL or less is now recommended for persons with existing CAD plus other risk factors. Ideal blood pressure was set at 120/80 mm Hg or less by

 

low-dose aspirin, and fish oil—may be considered, depending on the age and estimated CV risk of the patient.

Each 20–mm Hg increase in systolic blood pressure or 10–mm Hg increase in diastolic blood pressure doubles coronary artery disease mortality and stroke mortality.

It is instructive to note that although human LDL-C concentrations tend to cluster from 120 to 200 mg/dL and atherosclerotic disease is the main cause of death in humans, typical nonhuman mammalian LDL-C levels are 10 to 60 mg/dL, and atherosclerosis does not occur unless animals are fed high-fat food.

 

The risk of a coronary event is thought to increase by 2%for every 1%decrease in plasma HDL

 

 

Framingham Heart Study Identifying major CVD risk factors

Over the years, careful monitoring of the Framingham Study population has led to the identification of the major CVD risk factors –
high blood pressure,
high blood cholesterol,
smoking,
obesity,
diabetes, and
physical inactivity

Hypertension
Each 20-mm Hg increase in systolic blood pressure or 10-mm Hg increase in diastolic blood pressure doubles coronary heart disease mortality and stroke mortality. Proposed mechanisms by which hypertension promotes atherosclerosis include damage to endothelial cells, promoting activation and incorporation of lipids into subintima, and stimulation of subintimal smooth muscle cell proliferation.

 

 

 

 

For prevention of CAD, the NCEP has determined that an LDL-C level of less than 100 mg/dL is optimal for CAD prevention, and a level of 70 mg/dL or less is now recommended for persons with existing CAD plus other risk factors. Ideal blood pressure was set at 120/80 mm Hg or less by

 

low-dose aspirin, and fish oil—may be considered, depending on the age and estimated CV risk of the patient.

Each 20–mm Hg increase in systolic blood pressure or 10–mm Hg increase in diastolic blood pressure doubles coronary artery disease mortality and stroke mortality.

It is instructive to note that although human LDL-C concentrations tend to cluster from 120 to 200 mg/dL and atherosclerotic disease is the main cause of death in humans, typical nonhuman mammalian LDL-C levels are 10 to 60 mg/dL, and atherosclerosis does not occur unless animals are fed high-fat food.

 

The risk of a coronary event is thought to increase by 2%for every 1%decrease in plasma HDL

 

 

Diet and exercise

Certain changes in diet and exercise may have a positive impact on raising HDL levels:[29]

Most saturated fats increase HDL cholesterol to varying degrees and also raise total and LDL cholesterol.[42] A high-fat, adequate-protein, low-carbohydrate ketogenic diet may have similar response to taking niacin (vitamin B3) as described below (lowered LDL and increased HDL) through beta-hydroxybutyrate coupling the Niacin receptor 1.[43]

HDL levels can be increased by smoking cessation,[35] or mild to moderate alcohol intake.[44][45][46][47][48][49]

Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%,[53] making it the most powerful agent to increase HDL-cholesterol.[54][55] A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events.[56] However, niacin products sold as “no-flush”, i.e. not having side-effects such as “niacin flush“, do not contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as “sustained-release” may contain free nicotinic acid, but “some brands are hepatotoxic”; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation.[57]

AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides

As above, but instead of a placebo, patients were given 1,500 to 2,000 mg/day of extended-release niacin.

After two years the niacin group, as expected, had experienced a significant increase in plasma HDL-C (along with some other benefits like a greater reduction in plasma triglycerides).  However, there was no improvement in patient survival.  The trial was futile and the data and safety board halted the trial.  In other words, for patients with cardiac risk and LDL-C levels at goal with medication niacin, despite raising HDL-C and lowering TG, did nothing to improve survival. This was another strike against the HDL hypothesis.

 

CETP. – Dalcetrapib

By 2008, as the AIM-HIGH trial was well under way, another pharma giant, Roche, was well into clinical trials with another drug that blocked CETP.  This drug, a cousin of torcetrapib called dalcetrapib, albeit a weaker CETP-inhibitor, appeared to do all the “right” stuff (i.e., it increased HDL-C) without the “wrong” stuff (i.e., it did not appear to adversely affect blood pressure). It did nothing to LDL-C or apoB.  This study, called dal-OUTCOMES, was similar to the other trials in that patients were randomized to either standard of care plus placebo or standard of care plus escalating doses of dalcetrapib.   A report of smaller safety studies (called dal-Vessel and Dal-Plaque) was published a few months ago in the American Heart Journal, and shortly after Roche halted the phase 3 clinical trial.  Once again, patients on the treatment arm did experience a significant increase in HDL-C, but failed to appreciate any clinical benefit.  Another futile trial.

 

Mendelian randomization

On May 17 of this year a large group in Europe (hence the spelling of randomization) published a paper in The Lancet, titled, “Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.”  Mendelian randomization, as its name sort of suggests, is a method of using known genetic differences in large populations to try to “sort out” large pools of epidemiologic data.

In the case of this study, pooled data from tens of studies where patients were known to have myocardial infarction (heart attacks) were mapped against known genetic alterations called SNPs (single nucleotide polymorphisms, pronounced “snips”).  I’m not going to go into detail about the methodology because it would take 3 more blog posts., But, the reason for doing this analysis was to ferret out if having a high HDL-C was (only) correlated with better cardiovascular outcome, which has been the classic teaching, or if there was any causal relationship.  In other words, does having a high HDL-C cause you to have a lower risk of heart disease or is it a marker for something else?

This study found, consistent with the trials I’ve discussed above, that any genetic polymorphism that seems to raise HDL-C does not seem to protect from heart disease.  That is, patients with higher HDL-C due to a known genetic alteration did not seem to have protection from heart disease as a result of that gene. This suggests that people with high or low HDL-C who get coronary artery disease may well have something else at play.

 

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Dr Thomas Challenger Challenger Mission