Cholesterol Management 101

Herbal Medicines & Cholesterol: Part 1

2010-02-09T09:29:00.000-08:00

Are They Safe? Do They Really Lower Cholesterol?

I originally posted on this topic in 2007 because I wanted to talk about the possible dangers associated with some "herbal" medicines, also know as nutraceuticals, and the research done on their possible cholesterol lowering effects. In the February 9th edition of the Journal of the American College of Cardiology, there is a paper about the hidden dangers of these "herbal" medicines. They reviewed nearly 90 papers that have addressed herbal and complementary therapies and cardiovascular effects. They listed 15 common herbal medicines that are known to adverse interact with conventional cardiovascular medicines. Many patients, however, think that since these medicines are "natural" their dangers should not be considered in the same way as medications. The author found data from the 1990s suggesting that more patients consult complementary and alternative medicine providers than regular physicians. I have included other medicines and functional foods that are thought to have a cholesterol lowering effect in this review.

Grapefruit juice, for example, has a negative effect on an enzyme called CYP3A4 in the intestine, which can cause substantial elevations of the statin drugs lovastatin, simvistatin, and atorvastatin when taken simultaneously. An 8 ounce glass of grapefruit juice in the morning followed by an evening dose of statin produces only a modest increase in the amount of the drug in the body while a larger glass does produce a substantially larger effect.

At least 3 well-designed studies failed to document any influence of garlic on serum lipoproteins (the particles that carry the cholesterol). Garlic is one of several herbal remedies with specific cardiovascular effects in it's own right. Garlic inhibits platelet clumping in the blood and thus lead to increased bleeding risks when taken with clopidogrel (Plavix), warfarin (Coumadin), and aspirin.

Guggulipids are found in the arid regions of India and Pakistan, and believed to be the active ingredients in the resin of the Commiphora Mukul "Guggul" tree. This substance is marketed in the US under the name "Guggulipids" as a dietary supplement and is promoted to control cholesterol. The gum resin of the Guggul tree has been used in Ayurveda for more than 2,000 years and is believed to have many health benefits including treating obesity.

Though there have been numerous studies evaluating the impact of guggul on lipids, these studies have concentrated on the Eastern Indian population. Of the two placebo controlled trials, the study performed in the Indian population found that guggulipids lowered LDL cholesterol by 12%. On the strength of this study, guggul was approved for use in India. A single study reported in the US was a carefully designed 8-week, double blind randomized, placebo-controlled trial using a parallel design. During this carefully controlled clinical trial, the Guggulipids did not lower LDL cholesterol and in fact actually increased LDL cholesterol in the majority of treated patients. Of some concern was the high rate of hypersensitivity rashes (9% of the participants). Interestingly, in both Indian and Western studies, there does appear to be some patients who did respond to Guggulipids. The percentage of people responding favorably in the Indian trials suggests that perhaps the Indian population may differ in some basic ways (genetically or environmentally) from the primarily Caucasian population.

Policosanol is a mixture of long-chain primary aliphatic alcohols isolated from sugarcane wax. Policosanol products can also be derived from wheat germ, rice bran and beeswax. The most widely available policosanol product comes from Cuba and is sold as a lipid-lowering product in over 40 countries. Until recently, a single Cuban research group performed nearly all studies conducted on policosanol. These Cuban studies show promise. However, with the recent publication of a number of negative studies outside of Cuba, the beneficial effects of policosanol have been called into question. Overall, recent placebo-controlled trials examining the lipid altering effects of sugarcane-derived policosanol failed to find any significant lipid-altering effects. At the present time, policosanol cannot be recommended for the treatment of hyperlipidemia.

Is cinnamon safe? In 2003 an in-vivo study was concluded on 60 diabetic candidates in Pakistan. The results of this study were released to the Western media and a frenzy of cinnamon capsules were sold in the US and other countries promoting Cinnamon's lipid lowering effects. Since that time, numerous studies in Germany and in the Netherlands have been published. The result of these studies differs significantly from the original Pakistani study. Based on the data from these studies, it would appear that the early enthusiasm for cinnamon supplementation might have been premature.

Last year I wrote a blog posting about the dangers of red yeast rice and I strongly encourage everyone to read it. I stated that there is a new compound from China that has been found called XYZ which has not been adequately studied and may pose a health risk. The official position of the National Lipid Association is to stay away from red yeast rice at the present time and I support their position. Red yeast rice is the fermented product of rice on which red yeast has been grown .The active ingredient in red yeast rice is believed to be Monacolin K, an agent reported to be identical to lovastatin (a commonly prescribed statin). Like statins, red yeast has been found to directly reduce lipids. There is little doubt that the proprietary preparation of red yeast rice, known as Cholestin favorably alters lipids.

However, due to legal issues, this preparation is no longer commercially available in the US. In 1998, the FDA determined that red yeast rice did not conform to the definition of a dietary supplement under the 1994 Diet Supplement and Health Education Act (DSHEA). This act states that marketed dietary supplements cannot contain a compound already approved as a drug (in this case, lovastatin) unless the substance was available commercially before the drug's approval. At present, Cholestin is still available in Canada, Europe and Asia - however, great caution should be exercised because Cholestin has been reformulated and no longer contains the important red yeast rice extract, but rather polymethoxylated flavones extracted from citrus fruits, geraniol and marine fish oils. It is unclear if this or other proprietary preparations of" red yeast extract will provide the same lipid effects. The FDA has issued a warning to consumers regarding three brands of red yeast rice. For more information go to www.fda.gov and type "red yeast rice" in the search box.

The FDA recommends that consumption of 1.5 ounces of nuts per day MAY reduce cardiovascular risk. Aside from the fatty acid composition of nuts, other components such as arginine, plant sterols, and phenolic components may play a favorable role in the lowering of lipid levels for those who eat nuts as a regular part of their diet. Walnuts and almonds have been most comprehensively studied. Most clinical trials evaluating the impact of nuts on lipid profiles have been small scale (10-49 participants). LDL-C (the bad cholesterol) reduction has been consistently shown in these small scale studies, typically in the range of 12-13%. Though less consistent, triglyceride reduction was shown. However, HDL-C (the good cholesterol) generally remained unchanged. One must always remember that these studies are far too small to establish any guidelines and there certainly is not one ounce of outcome data regarding the effect on cardiovascular morbidity and mortality.

The American Dietetics Association evidence library concludes that "consumption of 50-113 grams (1/2 cup to 1 cup) of nuts daily with a diet low in saturated fat and cholesterol decreased total cholesterol by 4-21% and LDL-C by 6-29% when weight was not gained." However, we have to remember that a diet rich in nuts is a heavy caloric load and may lead to weight gain. I recommend somewhat smaller portions of nuts as part of a healthful diet.

There are two kinds of fiber or nondigestible carbohydrates. The first, which is insoluble, aids in bowel function. An example is wheat bran. The second is soluble fiber, now referred to as viscous fiber, which has an additional cholesterol lowering effect. Examples include dried beans, grains, certain fruits and vegetables. Psyllium is a source of soluble fiber and has been shown to augment the lipid lowering response when combined with other lipid lowering medications. Oat products have the most soluble fiber of any grain. Several recent studies have looked specifically at the effects of oats or oat bran on LDL-C. Both oats and oat bran demonstrated favorable results in the lowering of LDL-C. Robitaille's study on overweight pre-menopausal women provided 28 grams of oat bran daily over 4 weeks and not only obtained LDL-C reductions, but also demonstrated an 11.2% increase in HDL-C. In moderately hypercholesterolemic men and women, a study found significant positive results from the consumption of barley. A reduction of 20% in total cholesterol and 24% in LDL-C was obtained in 1 study.

The ATP III (Adult Treatment Panel) recommends a minimum of 5-10 grams a day of total dietary fiber for people with even mildly elevated LDL-C levels, but higher intakes of 10-12 grams of fiber per day can be more beneficial in those with more severe hyperlipidemia.

In large prospective epidemiological studies, total dietary fiber has been shown to protect against coronary heart disease. These studies examined the relationship between whole grain consumption and CHD. Researchers found 20-40% reduction in CHD risk for those who habitually consumed whole grains as compared to those who rarely ate whole grains. There are several mechanisms by which it is believed dietary fiber may protect against CHD. They include lowering serum cholesterol and LDL-C, attenuating blood triglyceride levels, and decreasing hypertension. Fiber consumption also predicts insulin levels and weight gain more strongly than a low total fat and saturated fat diet. High fiber diets may protect against obesity and cardiovascular disease (CVD) by lowering insulin levels. It has been shown that the intake of dietary fiber is inversely correlated with cardiovascular disease risk factors in both sexes.

However, most of the evidence shows that a mixture of both soluble and insoluble forms of fiber is an important part of a diet that promotes general good cardiovascular health. Based upon this conclusion, the National Academy of Science recommends 25 grams per day of fiber for women 19-50 years of age and 21 grams per day for women over 50. For men 19-50 years of age, 38 grams per day is recommended and 30 grams for men over 50. This is set from an established 14 grams of fiber per 1,000 calories.

In the last 12 years, soy has been believed to lower LDL-C. However, recent data has not shown soy to be a practical means to lower LDL-C. In order to achieve any meaningful LDL-C reduction, large amounts of soy are required. Even when individuals consume half their daily protein with soy protein only a very small reduction (3%) in LDL-C is achieved. Soy seems to be a more efficacious lipid-lowering agent in persons with marked hyperlipidemia. It should be noted that reduction in lipids may be due to replacing high-fat animal protein with soy rich foods that may indirectly result in lipid reduction via a reduction in saturated fat intake.

Lecithin is another widely promoted lipid-lowering functional food that is derived from soy beans and sold as a "fat emulsifier". Many people believe that this "emulsifier" actually breaks down fat and cholesterol in the bloodstream. These claims are totally unsubstantiated by any medical literature.

Another promoted cholesterol lowering remedy is daily a dose of apple cider vinegar. To date, I have yet to see substantial evidence in the form of any clinical trial evidence that supports these claims.

I have tried to shed some light on the most common nutraceuticals that are promoted to lower lipid levels. I have used solid, evidence-based studies to provide the latest, most accurate information. Perhaps you have found studies on the Internet to support the claims that many of these functional foods will lower cholesterol levels. I would like to bring three important points to your attention.

First, it is important to remember that most of consumer-based literature published has no or little scientific components and are purely retrospective data gathered via questionnaires. Remember, any one can write a paper on any topic and get in published in some type of journal but I can guarantee that none of these journals are "peer review" journals.

Second, the nutraceutical industry is unregulated. Although Congress is once again calling on this industry to be regulated, nothing will probably be done. It is possible for companies promoting functional foods to fund a study that is designed to show the favorable results they had planned on prior to construction of the study.

Finally, what is most important is outcome data. This simply means, as a result of the drug or supplement's effect on lipid levels, did that substance affect change that resulted in fewer cardiovascular events and death?

As a cholesterol expert, I fully believe it is important to lower cholesterol by any means necessary. My greatest concern for patients and consumers regards the safety of many of the supplements we have discussed. Simply stated, they have not been well studied. Be an informed patient! When taking any substance, caution should always be exercised. There are many drug interactions with over-the-counter supplements, vitamins and other nutraceuticals and a medical professional well-versed in lipid management should be consulted before considering any drug or non-drug protocol. A medical professional well-versed in lipid management should be consulted before considering using any type of medicine to lower cholesterol.

- Michael Richman, MD, FACS

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"Designer Steroids" and Cholesterol Levels

2010-01-11T19:29:00.005-08:00

The Association Between Over-the-Counter Androgen Supplements and Abnormal Cholesterol Levels...

In prior postings, I have talked about the fact that the supplement industry is not regulated. Androgenic Anabolic Steroids(AAS) have been associated with a wide range of adverse effects on the lipid levels. This group of nutraceuticals are marketed as "dietary supplements" and available on the internet, yet most of the public is unaware of the hidden dangers. There are two products in particular that have caused problems in previously healthy individuals. The first is known as Superdrol(methasteron) and the second is Orastan-E (prostanozol). While both of these products are on the prohibited list of the 2008 World Doping Agency, their legal status is not clear. According to the Anabolic Steroid Control Act of 2004, the sale of these "designer" steroids as nutritional supplements is prohibited in the US; however, these products are not on the list of banned steroids.

Many side effects have been reported with the use of AAS. The HDL cholesterol (the good cholesterol) has been shown to decrease by 40-70% while they increased the LDL cholesterol (the bad cholesterol) by an average of 36%. In one study of male weight lifters, oral administration of stanozolol led to a LDL cholesterol increase of 29% and a 35% increase in apolipoprotein B levels. In my posting titled Advanced Lipoprotein Testing, I discussed LDL particles being the most numerous type of atherogenic particle of all the ApoB particles. The higher the level of apoB particles, the greater the risk of cardiovascular morbidity and mortality. ApoB particles are the transport vehicles that drive the cholesterol into the artery wall leading to atherosclerosis. It has been suggested that the magnitude of AAS induced lipid changes are dose dependent. Recovery from the negative effects on the lipid profile is more dependent on duration rather than the dosage of AAS.

Chronic cholestatic liver disease is often associated with the use of these "designer" steroids. The best way to describe what cholestasis refers to is that it is a "slugging" of the bile. It then gets clogged in the liver resulting in an elevation in the liver enzymes and the bilirubin levels and causes liver damage. This type of liver disease is associated with an increased LDL cholesterol levels. Superdrol has been shown to cause cholestatic jaundice.

In about 60% of AAS users, a decrease in libido occurs which is typically reversible. He exact time for complete recovery is not known and is dependent on dose and duration of AAS use although full recovery has been shown to take up to a year once the drugs are stopped.

As these types of "designer" drugs become more readily available via the internet, their dangerous side effects need to be clearly stated. I have previously discussed the dangers of Red Yeast Rice and the fact that this type of nutraceutical is not regulated either. It is important for the public to know that sham studies and articles in non-peer review journals are widely available touting the benefits of all these unregulated drugs. It is also important to remember that one can get anything published in some magazine for the right amount of money. I would proceed with caution and talk to a physician before proceeding with the use of these "designer" steroids.

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C-Reactive Protein - What's All The Hype About?

2009-12-08T05:29:00.001-08:00

During the last ten years, compelling experimental and clinical evidence has demonstrated that both systemic and local inflammation might play a prominent role in the cause of atherosclerosis (clogging of arteries) and its clinical complications. Because these processes accompany all stages of atherogenesis, measurement of plasma concentrations of these inflammatory markers might aid in identifying those individuals at high risk for coronary artery disease. In particular, they may add to the predictive value to improve the assessment of future global cardiovascular risk.

Among the numerous circulating biomarkers of inflammation, C-reactive protein (CRP), is an acute phase reactant with a short half life of approximately 19 hours. More than 25 studies published during the last 10 years have provided strong evidence that C-reactive protein predicts cardiovascular risk in various scenarios, not only in initially healthy subjects, but in those who manifest atherosclerosis. This blood protein, which only a short time ago was thought to be by many more important than cholesterol, is now regarded as just a risk factor for cardiovascular disease. This substance, C-reactive protein, is unquestionably associated with heart disease in that the more C-reactive protein in a person's blood, the greater the likelihood of heart disease.

In early July 2009, a study published in The Journal of the American Medical Association analyzed data from approximately 100,000 people and concluded that their study argues against the notion that the protein causes heart disease. The idea that if indeed an elevated C-reactive protein causes heart disease, wouldn't lowering it protect people? Well, this is not the case. Lowering C-reactive protein does not protect people from the development of cardiovascular disease. There was much confusion last year after the findings of the Jupiter Study were released because many people believe that C-reactive protein caused heart disease and those patients who had low cholesterol but high C-reactive protein had fewer heart attacks if they took the statin Crestor. Statins also have the effect of lower C-reactive protein. Could this mean that lowering C-reactive protein could prevent heart disease? It may; however, what has been proven time and time again is that cholesterol-lowering was protective.

Despite multiple attempts to develop drugs to lower C-reactive protein, many experts now feel that it is time to abandon that search. One of the proponents of using C-reactive protein happens to be Dr. Paul Ridker of Brigham and Women's Hospital. He was the author of the Jupiter Study and said the findings of the study did not change anything for him. It is pretty ironic that he invented the laboratory test for highly specific C-reactive protein and who profits from its use. There was a study also done in London with 35 co-authors who developed a technique that allows one to get answers quickly about causality. In other words, it is their thought that white blood cells invade artery walls releasing damaging chemicals leading to plaque formation. The study showed that in a population, there are people who just happen to produce more C-reactive protein throughout their lives and others who just happen to produce less. If indeed C-reactive protein causes heart disease, those who make more would have more heart disease. The study did not find this. There was absolutely no association between CRP and heart disease rate. So, in other words, the association between C-reactive protein and heart disease must reflect something else. C-reactive protein is thus just a marker of inflammation.

While I do have multiple patients who come in asking for C-reactive protein to be drawn, I explain with gentle reassurance that with the exception of being performed in select populations, I feel it should not be done routinely as there are many other markers of increased risk. Indeed, C-reactive protein can be elevated due to other causes of inflammation, leading to falsely elevated results.

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Advanced Lipoprotein Testing

2009-11-03T02:33:00.004-08:00

I originally posted on this topic 16 months ago after the untimely death of Tim Russert. Since that time, thousands of people have died from cardiovascular disease. It is the number one killer in the USA and approximately over 2600 people die each die from it each day.

Last week, the book that I co-authored with Tom Dayspring M.D. and William Cromwell M.D., two noted lipidologists, was published. It is titled Lipid and Lipoprotein Disorders: Current Clinical Solutions. I thought it was apropos to try and draw attention again to this most important topic.

Hyperlipidemia is the most modifiable risk factor leading to atherosclerosis, yet traditional lipid testing may miss up to 50% of people who have abnormal lipids. Prevention includes identifying people at risk and providing the best treatment individualized to their specific problem. Atherosclerosis results from a buildup of cholesterol-laden macrophages in the arterial intima. This occurs when atherogenic lipoprotein particles (principally low-density lipoprotein [LDL]) enter the arterial wall, become oxidized, and are subsequently ingested by macrophages.

It is with this background that I will discuss advanced lipoprotein testing and its role in identifying all patients at lipid related risk and as a tool for management of abnormal lipid levels. I often ask myself how is it that healthcare providers do not understand this type of testing? I honestly believe that if all people are identified as being at risk, and then if treated appropriately, we would significantly change the face of cardiovascular morbidity and mortality. As physicians, we are taught in medical school that it is all about total cholesterol, HDL-C, LDL-C, and triglycerides, yet few really understand the limitations of traditional lipid testing. I hear everyday physicians say that if it is so important how come everyone is not doing it? I believe the answer is that one does not want to change from old patterns of thinking, and according to other physicians, it is too much trouble to learn and understand.

Recently, the ADA/ACC released a Joint Concession Statement on lipoprotein management in patients with cardiometabolic risk (CMR). The full text is available on my website www.lipidcenter.com. I believe it is mandatory reading. It states that patients with CMR in the moderately high, high, and very high risk groups, it is now the standard of care to quantitate lipoproteins by performing ApoB or LDL-P on all patients to ascertain risk and as a goal of therapy.

As many of us in healthcare know, since sterols are insoluble in the blood, they need to be driven around the body in lipoproteins. These include HDL-P, VLDL-P, and LDL-P among others. HDL particles are also known as ApoA and all the particles that cause atherosclerosis are known as ApoB. Although NCEP (National Cholesterol Education Panel) recommends calculating the non-HDL cholesterol, this value only can alert the physician that there may too many lipoprotein particles despite having a normal LDL-C. Approximately 90-95% of the circulating ApoB particles are LDL-P, which have a half-life of around 3 days. As varying amounts of triglycerides and cholesterol are driven around the body, in what I tell my patients are "cars", the ApoB particles enter the arterial wall if there are too many of the "cars" circulating in the bloodstream. By simple diffusion, all the bad particles flow from inside the artery and move into its wall and are "eaten" by macrophages, which become foam cells and are the hallmark of atherosclerosis.

In eight published studies of over 11,000 subjects, using LDL-P and other lipoprotein concentrations remained the most significant and independent predictor of cardiovascular morbidity and mortality over any other lipid parameter including the usual ratio that all physicians and patients talk about. In a nutshell, it is the number of LDL particles that matter most... it is the number of cars that cause a traffic jam not the people in the cars[TM]. For example, what if a person with moderate risk has met NCEP guidelines and has a LDL-C of 110mg/dl. How do I know that there are not 100 cars with one person driving or two big buses with 55 people? The answer is that I do not unless I measure LDL-P directly by using NMR or as a second option measuring ApoB with Gel Electrophoresis. Traditional testing measures the passengers and lipoprotein testing measures the cars, and it is the number of cars (LDL-P) measured by NMR (Nuclear Magnetic Resonance) that are the most numerous ApoB particles in the body and matter most in the development of atherosclerosis.

Although a comprehensive review of each of the methodologies to perform lipoprotein testing is beyond the scope of this blog post, I feel that measuring LDL particles directly using NMR is the best way to ascertain someone's true risk and then use that number as a guide to management. As I said in my posting about Alex Trebeck, the CDC states that 50% of people who have heart attacks have "normal" cholesterol. I hope you now understand why this can happen, having a normal LDL-C but high LDL-P, and be proactive and demand that your physician performs advanced lipoprotein testing.

[TM]-US Trademark No. 77/693074, The Center For Cholesterol Management

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Heart Disease in Women - Where Do We Stand?

2009-10-05T12:51:00.010-07:00

I wanted to interrupt our series on "Markers of Cardiovascular Risk" to write about heart disease in women. I have a large number of female patients who still do not know the extent of heart disease in women. They are often told by their primary care physician that if they take estrogen replacement therapy then they are protected from heart disease. Nothing could not be further from the truth.

Atherothrombotic disease is the number one cause of morbidity and mortality in American women. Real progress in both our understanding and making therapeutic progress in women began in the mid 1990s, as randomized clinical trial data started to emerge. Many of our previous beliefs and paradigms based on men's data or observational trials of women have had to undergo radical rethinking.

Prior to 1998, estrogen was a standard part of prevention regimens. However, current guidelines from the American Heart Association, American College of Cardiology and the National Cholesterol Education Program have refocused our efforts on how to accurately assess risk and to prevent and treat atherosclerosis with evidence based therapies. All of the organizations have removed estrogen from the list of therapeutic modalities which should be used for cardioprotection.

There is now data available from multiple large and small randomized controlled trials looking at cardiovascular (CV) outcomes and plaque prevention or stabilization and estrogen (unopposed) has been successful in only one carotid plaque study. These trials included both secondary and primary prevention settings. Data from the giant Women's Health Initiative, looking at over 27,000 postmenopausal women has failed to detect any cardioprotection and has identified a small trend towards adversity in the EPT group. In contrast, other therapies such as statins, fibric acids, ace inhibitors, anti-platelet drugs have all demonstrated an ability to improve CV outcomes and/or plaque in women.

It is now recognized that atherothrombosis is a chronic inflammatory disease of the arteries that begins very early in life and causes clinical events in adulthood. It is rupture of nonocclusive plaques, which generates an arterial thrombus [a blood clot that forms within an artery] that causes most of the morbidity and mortality of cardiovascular disease. Therapies that stabilize the plaque have been successful in improving outcomes. There are many abnormalities that lead to endothelial dysfunction or inflammation, including lipoprotein, coagulation, renin-angiotensin, homocysteine as well as other disorders. The high sensitivity C-reactive protein (CRP) has emerged as the most readily available and reproducible diagnostic tool to indicate the presence of endothelial inflammation and to help assess CV risk is present. We will discuss C-reactive protein in my next posting. There is no data to show that lowering the C-reactive protein reduces one's risk. If elevated, then it serves as a marker for increased CV risk. Researchers have identified therapies that reduce C-reactive protein and also identified oral estrogen as an agent capable of aggravating CRP levels.

New insights into lipid biology have identified lipoproteins, which transport the lipids (cholesterol and TG) as the major players in plaque etiology and inflammation. The concentrations and sizes of VLDL, IDL, LDL and HDL are culprits in initiating and worsening arterial plaque. Removing atherogenic lipoproteins or modifying them into non-atherogenic particles is emerging as a very effective strategy. Triglycerides and HDL-C, through their influence on lipoprotein concentrations, particle composition, particle size, and relationship to insulin resistance have emerged as significant predictors of risk in women.

Understanding coagulation, inflammation, genetics, and lipoprotein biology also is providing insights into both the efficacy of combination standard lipid drug therapies as well as the complexities of estrogens' or selective estrogen receptor modulators (SERMs) effect on the vasculature. Such insights also provide plausible mechanisms as to why different estrogens, progestogens and SERMs and their routes of administration may have widely varying CV effects and safety. The timing of estrogen therapy with respect to earlier versus later in menopause is emerging as critical to vascular response.

If we are to begin to make real progress in the battle against CVD in women, we must identify risk using our new diagnostic tools much earlier in life and become extremely aggressive in our therapies including lifestyle and pharmacologic strategies. We also need to fine tune who estrogen will or will not benefit.

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Elevated Homocysteine: Cardiovascular Risk Factor or Hype?

2009-09-14T13:27:00.003-07:00

Homocysteine is an amino acid that cannot be synthesized by the human body. It is synthesized from the essential amino acid called methionine in the body. An essential amino acid means that it is indispensable for life. Methionine must be supplied in the diet. High levels of methionine can be found in sesame seeds, brazil nuts, fish, meats and some other plant seeds. Most fruits and vegetables contain very little of it. Most legumes are also low in methionine.

Although at first not generally accepted, epidemiologic trials conducted over the past 25 years have provided ample support for the association of mild hyperhomocysteinemia (high levels of homocysteine) with an elevated risk of cardiovascular disease. The independent risk of cardiovascular events conferred by mild elevated serum homocysteine levels and the association of elevated levels with a deficiency of folic acid and vitamin B12 was thought to be a unique target for a preventative approach. In the Women's Antioxidant and Folic Acid Cardiovascular study, it was shown that supplemental folic acid and B vitamins do not lower the risk for important vascular events even though they lower homocysteine levels. The Vitamin Intervention for Stroke Prevention Trial showed that although there was a dose dependent reduction in homocysteine levels, there was no reduction in vascular events. In the Norwegian Vitamin Trial (NORVIT) showed that there was no significant effect of folic acid and B12 on the risk of recurrent heart attacks or sudden death from coronary artery disease. There was, however, a trend toward more heart attacks. The HOPE-2 was a prevention trial that showed that treatment consisting of vitamin B12, vitamin B6, and folic acid for 5 years was associated with a reduction in homocysteine levels. Once again, there was no reduction in heart attack, stroke, or death from cardiovascular causes.

Maybe the answer lies in why patients with elevated homocysteine are at risk for CVD. There has never been a definite, accepted reason explaining the CVD risk seen in patients with high homocysteine. Is homocysteine the atherogenic culprit or is it simply a marker of some other pathological process? It has been proposed that homocysteine is simply indicative of impaired renal function, a major CVD risk factor, and perhaps treatment should be directed at the kidney and not the homocysteine per se.

The truth is we really are not as smart as we think we are about most cardiovascular risk factors and so far have failed to discover others. It is speculative at best to predict what therapeutic manipulation of a given risk factor will do until it is subjected to properly designed, prospective, blinded outcome trials. It took many years before homocysteine was accepted as a risk factor and it took a decade of excellent clinical trials to prove that treating it with B-vitamin and folic acid is no longer justified. As usual, most of the previous data was from studies of men, but now we also have the answer in women. Therefore, if B-vitamin and folic acid therapy is null, screening patients with expensive homocysteine assays and following the levels over time is no longer justified. Likewise, the monies spent on vitamin therapy can be directed at better-proven therapies, including balanced diets to provide these supplements.

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Markers of Cardiovascular Risk - PLAC Test

2009-08-12T05:39:00.002-07:00

Lp-PLA2(PLAC TEST)

I have received several calls over the past several months asking if I did the PLAC test. In thinking what I would write about, I decided that I would begin a series devoted to explaining the newest risk factors that can be used as markers of increased cardiovascular risk.

The first marker I want to discuss is Lipoprotein-associated Phospholipase A2( Lp-PLA2). Lp-PLA2 can be measured using a widely available laboratory test called the PLAC test. It is an enzyme that, in humans, is bound to the lipoprotein particles. Liporotein particles are the vehicles that drive cholesterol around the body and also into the walls of an artery causing atherosclerosis. The most abundant lipoprotein particle that is responsible for clogging ones' arteries is the LDL particle (LDL-P). Lp-PLA2 is involved in the production of proinflammatory products. There has been some controversy regarding the exact biological role of Lp-PLA2 activity on atherosclerosis. Studies do suggest that Lp-PLA2 is closely aligned with the key stages of atherosclerosis. In addition to being associated with LDL particles, it is secreted by the cells responsible for inflammation within a plaque inside of an artery wall. In numerous epidemiological studies, an independent association between Lp-PLA2 concentrations and an increased risk of cardiovascular events has been observed in individuals with varying degrees of baseline risk. If one looks at histological sections of the arterial plaques that have increased risk for rupture, there is increased staining for Lp-PLA2. Simply put, an increased level of Lp-PLA2 is associated with an increased risk of cardiovascular events, namely ischemic strokes.

Lp-PLA2 testing is not yet formally endorsed by a CDC/American Heart Association panel. A recent expert committee was convened to establish an algorithm to most appropriately interpret Lp-PLA2 testing. The expert panel said that the PLAC test is not appropriate to further stratify risk in patients who did not require treatment for high cholesterol. They did state that an Lp-PLA2 level >200ng/ml would warrant reclassifying the patient to the next highest risk category which would require more more aggressive treatment of the high cholesterol levels. Lp-PLA2 may play an important role in the progression of atherosclerosis and overall plaque stability. In the future, Lp-PLA2 may be a viable target to further reduce global cardiovascular risk.

Noninvasive Methods to Assess Atherosclerosis: Part 4

2009-07-07T08:42:00.001-07:00

We are going to finish up our series discussing two modalities which most people are not familiar with as way to assess for atherosclerosis.

Cardiac Magnetic Resonance Imaging

MRI uses radio waves and magnets to create images of your organs and tissues. Unlike computed tomography scans (also called CT scans) or conventional x-rays, MRI imaging doesn't use ionizing radiation or carry any risk of causing cancer.

Cardiac MRI is a sophisticated powerful imaging system tool that provides superb anatomic, functional, and tissue images. Since MRI is done for nearly everything, many centers now perform cardiovascular MRI and it is thought to be a cardiac "all-in-one" tool. We will be limiting our discussion to the use of MRI in evaluating atherosclerosis.

Based on the current level of technology available, MR-based evaluation of coronary anatomy remains challenging. The sensitivity, specificity, and accuracy for diagnosing any coronary disease is 100, 85, and 87%, respectively, in patients with either left main coronary artery disease or three vessel disease. Sensitivity refers to the actual positive studies that are correctly identified and specificity refers to the actual negatives that were correctly identified. Atherosclerotic plaque has been studied using cardiac MRI in both the heart and peripheral arteries. In 2002, one study suggested that cardiac MRI might be useful in detecting subclinical atherosclerotic vascular disease. While this technology is very exciting and promising as a screening tool to detect atherosclerosis, it cannot be recommended routinely at this time.

Ankle-Brachial Index

ABI was initially used to identify the presence and extent of peripheral vascular disease (PVD). In my residency, every patient with symptoms of PVD underwent an ABI. While some think this is difficult to do, every medical student learns to do this on their surgery rotation. The only requirements are a blood pressure cuff and a hand held Doppler probe. ABI is measured as the ratio of the systolic blood pressure in the foot/ankle arteries (posterior tibial or dorsalis pedis arteries) over the systolic blood pressure in the arm artery (brachial artery). Both the arm pressures are measured and both the arteries in each leg. The higher leg pressure in each leg is then divided by the higher pressure recorded in the arm. If 1 is a normal value, then incremental reductions indicate worsening vascular disease. In a definitive paper, after adjustments were made for age, LDL cholesterol, and carotid intimal medial thickness (CIMT), an ABI <0.9 was shown to be an independent predictor of cardiovascular events. An ABI <0.9 yielded a 90% sensitivity and 98% specificity for moderate-to-severe obstructive peripheral artery disease as determined by a confirmatory conventional angiogram. While ABI alone is not ideal to screen for mild disease, it is estimated that 40% of patients with positive ABI were asymptomatic, which would mean that it is an effective way to identify vascular disease before it is clinically apparent. A patient with symptoms and an abnormal ABI should then undergo an angiogram to identify the correct anatomic location of vascular disease.

Part 1: CIMT
Part 2: CT Angiogram of the Heart
Part 3: Coronary Artery Calcium Scoring

Noninvasive Methods to Assess Atherosclerosis: Part 3

2009-06-09T02:04:00.001-07:00

Coronary Artery Calcium Using CT Tomography

I want to continue with our series of ways to help identify atherosclerosis in the body in order to better classify one's risk of a cardiovascular event or death. We already talked about using duplex ultrasound to measure carotid intima-media thickness and CT angiogram of the heart arteries. Now we are going to talk about using CT scan to identify the amount of calcium in the heart arteries (CAC scoring).

First of all, I want to make a general comment. As a heart surgeon think I have a unique perspective on coronary artery disease as I have seen and felt literally thousands of heart arteries. A cardiologist never sees the heart other than by an x-ray. The difference between a heart surgeon (cardiothoracic surgeon) and a cardiologist is often confusing to many people. Basically, a cardiac surgeon cuts and feels the heart in order to do a procedure and a cardiologist relies on x-rays only.

I also think it is important to say one thing about coronary artery atherosclerotic disease. Contrary to popular beliefs, when narrowing of the artery occurs, it occurs from inside the artery wall and pushes the inner layer called the intima outwards narrowing the artery. In other words, the cholesterol plaques do not start on the surface of the artery where the blood flows. Early plaques, which are most prone to rupture, contain little or no calcium. As the plaque matures, it may acquire calcium. Think of how bone develops. A young child has soft bones that are more pliable and less prone to fractures as compared to adult bones that are most rigid and are calcified. Instead, the cholesterol must be driven into the artery walls in what are called lipoproteins. To understand this whole concept, you can go to my website, Center for Cholesterol Management.

Now with these facts out of the way, we can talk about using CT scan to assess the amount of calcium in the atherosclerotic plaques in the artery. This is not a way to identify blockages in the artery. It is only a way to assess if there is coronary atherosclerosis. Like I said earlier, many plaques have little or no calcium. In 2007, the American College of Cardiology and American Heart Association published "Clinical Consensus Document on Coronary Artery Calcium Scoring Using Computerized Tomography". This paper was extremely thorough and gave final recommendations about when this method should be used. It is certainly overused by physicians and in fact will not be paid for by any private insurance or Medicare. When patients are evaluated as to risk of future cardiovascular events, they are classified as low risk, moderate risk, and high risk. Low risk is a 0-10% chance over a 10 year period, moderate risk 10-20% and high risk being 20% or greater. According to the expert committee, the only group may be considered for CAC scoring is the intermediate risk group. Here is the exact quote:

"The Committee judged that it may be reasonable to consider use of CAC measurement in such patients based on available evidence that demonstrates incremental risk prediction information in this selected (intermediate risk) patient group. This conclusion is based on the possibility that such patient might be reclassified to a higher risk status based on high CAC score, and subsequent patient management may be modified".

In addition, "CAC data are strongest for Caucasian, non-Hispanic men. The Committee recommends caution in extrapolating CAC data derived from studies in white men to women and to ethnic minorities."

The other problem is that not all centers have the same equipment and when they are being read by the doctor, there is tremendous observer variability. Ideally, if patients are going to get CAC scoring, they should be performed at the same place and looked at by the same person as the prior study. The clinical role of CAC scoring is not defined yet: however, it does offer promise as a screening tool or as a precursor to invasive angiography. At this point, further trials need to be done before it can be recommended for everyone.

Part 1: CIMT
Part 2: CT Angiogram of the Heart

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Noninvasive Methods to Assess Atherosclerosis: Part 2

2009-05-11T14:00:00.001-07:00

CT Angiogram of the Heart

We talked about the use of Carotid Intimal Medial Thickness (CIMT) measurements as a way to assess if there is diffuse atherosclerosis in the arteries of the body in Part 1 of this series. Now let's talk about imaging the coronary arteries of the heart using a CT scan. About 10 months ago, there was a five-page article in the New York Times (Sunday edition) about this very topic. The article talked about the fact that this newer technology was being overused for financial gain while there was little evidence showing it was any better than the older technology, and it exposes the patients to the equivalent of several hundred chest x-rays and the resulting increased cancer risk.

Personally, I was delighted to see this article expose the truth about this overused method. Oprah and Time Magazine had raved about this type of angiogram prior to this article being written, but obviously they had not done their homework and explored the true factual data.

The role of CT angiogram of the coronary arteries in clinical practice is not defined yet and is absolutely not a screening tool for detecting blockages in the heart arteries in patients with no symptoms. Conventional coronary angiography is still the gold standard and is required by every cardiac surgeon in order to accurately assess the coronary arteries prior to heart bypass surgery. The American Heart Association does not endorse CT angiogram as a screening tool or as a precursor to standard coronary angiograms either.

In November 2008, an article in the New England Journal of Medicine stated that "Cardiac CT angiography misclassifies diagnosis of coronary stenosis in too many patients to replace conventional invasive imaging". This group from Johns Hopkins University found that it misclassifies approximately 13% of the areas of narrowing and also noted that, without evidence of outcome benefit, "a high resolution cardiac CT angiographic image of the heart is just another pretty picture." I couldn't agree more.

I would like to share a story about a patient I recently saw at my office in Los Angeles and his experience with the CT angiogram of the heart arteries. This Hollywood producer had gone to his cardiologist for routine stress testing. His doctor suggested that he have a CT angiogram of his heart instead. Since this is not a procedure covered by insurance companies, he spent several hundred dollars out of his own pocket to get the test done. The test came back and he was told that he had a 90% blockage of his LAD (Left Anterior Descending Artery) of his heart, a so-called "widow-maker" lesion. His cardiologist told him that he should not exercise until the doctor got back from a trip to Eastern Europe in three weeks, at which time some further testing would be done.

The patient came to see me during this time period and was frantic. I recommended to him that he should get some type of stress testing - which should have been done first before any thing else was done. His thallium stress test came back normal and did not show any area of his heart supplied by this artery as having limited blood flow.

It was at this time that his cardiologist came back from his trip. The patient called him and asked what he should do now. His cardiologist said that he would perform a standard coronary angiogram - which was normal.

The reason I am telling this story is to show what could have potentially happen and what did happen to this nice man. First of all, he had three tests when he could have had just one. The conventional angiogram has many risks, which I touched on in Part 1, and also may have led to him having an unnecessary angioplasty and stent placement. He also was exposed to the equivalent of nearly 1500 chest x-rays.

Stay tuned for Part 3; we will discuss CT Calcium Scoring of the heart arteries.

Related Topics:

Noninvasive Methods to Assess Atherosclerosis

2009-04-22T12:02:00.009-07:00

Part 1: CIMT

Cardiovascular disease remains the number one killer of both men and women. Does knowing this fact make it obligatory for health care providers to provide some type of warning system to possibly prevent a cardiovascular event or death? Let's look at the various techniques that are currently in use to potentially identify early atherosclerosis which would then permit early aggressive treatment. I do understand that many people who read my blog have different levels of understanding of these difficult medical issues. While I will try to keep it simple, I believe it is important to do it in such a way as to not trivialize such an important topic.

Invasive coronary angiography (angiogram or cardiac catheterization) is still the gold standard to identify clinically significant coronary artery disease. Like all invasive procedures, there are inherent risks associated with the procedure - risks that include heart attack, stroke, death, damage to the artery in the arm or groin used as the puncture site, and kidney failure to name a few.

I believe that many cardiologists indiscriminately perform angiograms of the heart arteries for reasons that are clearly not supported by the literature. With this said, I prefer to perform noninvasive testing in order to identify patients at risk. If after following a treatment algorithm, it is felt that coronary angiogram becomes necessary; it then can be done in accordance with well-accepted indications.

Noninvasive Methods
Let's first look at carotid intima-media thickness, also know as CIMT. This involves measuring the thickness of two concentric (circular) layers of the neck arteries using duplex ultrasound. To be more precise, it measures the thickness of the first two layers of the mid-portion of the common carotid artery. CIMT was first reported as a surrogate or substitute marker for atherosclerosis in 1986. This was a comparison between autopsy studies and what was found in B-mode ultrasound studies. There was a measurement error of less than 20% in 77% of the subjects studied. In a follow up study, they found that patients with high cholesterol had increased CIMT augmented by including traditional risk factors. Fourteen years later, the American Heart Association deemed CIMT the only acceptable noninvasive method for assessment of cardiovascular risk. It is thought that any increase in CIMT is a reactive process secondary to shear stress and pressure within the artery from hypertension and plaque formation.

The ARIC trial is the largest CIMT observational cardiac endpoint trial to date. In 13,870 middle-aged adults, CIMT measurements were increased in those patients with coronary artery disease. Quantification studies showed that a .2mm increase in CIMT yielded a 33% relative risk increase in heart attack and 28% for stroke. Similarly, in both the CHS study and Rotterdam study, increased CIMT correlated with subclinical atherosclerosis. Since CIMT is a recognized marked of cardiovascular risk, it is used as a primary endpoint in clinical trials. The beneficial effects of cholesterol lowering on CIMT progression have been demonstrated in ARBITER, ASAP, and ACAPS. In the ENHANCE study, the results were not accurately portrayed by the media and I have previously written about the actual results on my blog. Additional studies using different blood pressure medicines are ongoing in order to see their effect on CIMT.

The main problem with measuring CIMT is that there has been significant inter-observer variability. Technical advancements in B-mode ultrasonography have reduced this problem.

To be continued...

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Red Yeast Rice - Buyer Beware!

2009-03-16T07:12:00.003-07:00

I have had an increasing number of patients come to see me who are taking Red Yeast Rice (RYR) as the only means to treat their high cholesterol. Many people make the assumption that this is a "natural medicine" and that it is completely safe to use and actually works.

Unfortunately, RYR is not the wonder drug that many folks think that it is and may actually be harmful. First, one must remember that in 2008, there were many products manufactured in China that were found to be tainted with lead and melamine, to name a few of the contaminants.

Red Yeast Rice extract is the fermented product of rice on which red yeast has been grown . The active ingredient in red yeast rice is believed to be Monacolin K, an agent reported to be identical to lovastatin (a commonly prescribed statin). Like satins, red yeast has been found to directly reduce lipids. There is little doubt that the proprietary preparation of red yeast rice, known as Cholestin favorably alters lipids. However, due to legal issues, this preparation is no longer commercially available in the US. In 1998, the FDA determined that red yeast rice did not conform to the definition of a dietary supplement under the 1994 Diet supplement and Health Education Act (DSHEA). This act states that marketed dietary supplements cannot contain a compound already approved as a drug (in this case, lovastatin) unless the substance was available commercially before the drug's approval.

At present, Cholestin is still available in Canada, Europe and Asia - however, great caution should be exercised because Cholestin has been reformulated and no longer contains the important Red Yeast Rice extract, but rather polymethoxylated flavones extracted from citrus fruits, geraniol and marine fish oils. It is unclear if this or other proprietary preparations of red yeast extract will provide the same lipid effects. The FDA has issued a warning to consumers regarding three brands of red yeast rice. For more information, visit the FDA website and type in red yeast rice in the search box.

As a result of a study published in the June 15, 2008 issue of the American Journal of Cardiology, the National Lipid Association (NLA) felt compelled to write an official statement on this RYR study. This study suggested that a new ingredient of RYR, called Xuezhikang (XZK), may have significant benefits. The published study was a randomized, double-blind, placebo study conducted in Chinese hospitals on 4,870 patients who had a previous heart attack within the past 5 years. The primary endpoint was the occurrence of a major coronary event or death from coronary or cardiac causes. The striking findings of this study are the 45% reduction of the relative risk of major coronary events and the statistically significant reductions in CV and total mortality The NLA recommended that physicians and patients should beware that the composition of this product is not yet known and any future use will depend on the results of ongoing studies.

XZK is produced by the Beijing WBL Peking University Biotech Co. Ltd and is the purified extract of Chinese RYR with multiple components. This product is not sold in the USA, lacks FDA approval, and is not identical to other products sold in the USA as "red yeast rice". This does not mean that this particular brand is not brought into this country illegally. Like the product known as Cholestin, XZK contains lovastatin, plants sterols, and isoflavones. At the present time, it is not known to what extent, if any, lipid- lowering accounts for treatment benefit.

To summarize the current thought on this preparation and all other types of RYR,

Physicians should not advise patients to take any RYR supplement as efficacy has not been proven for any indication.

If you are taking a medicine for cholesterol management, continue to take your prescription. Do NOT add any RYR to your current medications as adverse effects may be more likely.

RYR should not be substituted for statins. The active ingredients of any of the preparations currently sold in the USA are unknown.

Omega-6 Polyunsaturated Fatty Acids & Your Heart

2009-02-17T06:24:00.001-08:00

There is a large body of literature suggests that higher intakes of omega 6 polyunsaturated fatty acids (PUFAs) reduce risk for coronary heart disease (CHD). The American Heart Association just published a science advisory in Circulation on January 27, 2009, titled Omega-6 Fatty Acids and Risk for Cardiovascular Disease. There are some noted physicians and medical groups that have recommended substantial reductions in the intake of PUFAs due to this possible association.

Linoleic acid (LA) is the primary dietary O-6 PUFA and cannot be synthesized by human beings. Therefore it has to come from food sources. While there are no firm requirements for the amount of daily intake, it is felt that .5-2% of the total energy is sufficient. The LA can be converted into something called linolenic acid. This can be converted into the metabolically active O-6 PUFA called arachidonic acid (AA). This is very important as I will explain a little later. LA comes primarily from vegetable oils like corn, sunflower, safflower, and soy. According to the National Health and Nutrition Survey data indicates that usual intake of LA in adults greater than or equal to 19 years of age is 6.7% of energy.

The arguments for the reductions in the intake are based on the assumption that because there is an inflammatory component to coronary artery disease (CAD) and AA is the substrate for the production of a variety of pro-inflammatory mediators, reduction in the intake of LA should reduce the inflammatory potential and therefore lower the risk for CAD. Despite this fact, O-6 PUFAs also have anti-inflammatory properties. In one study, when healthy volunteers were given 7 times the usual intake of AA in a 7-week controlled feeding study, no negative inflammatory response was observed. Other studies also support this finding. At present, there is little direct evidence of a net pro-inflammatory, pro-atherogenic effect of LA in humans.

The cholesterol lowering effect of LA is well established. Epidemiologically, the replacement of 10% of calories from saturated fatty acids with O-6 PUFAs is associated with an 18 mg/dl decrease in LDL cholesterol which is greater than that observed with similar replacement with carbohydrate. These findings confirm a beneficial effect on cholesterol lowering of O-6 PUFAs beyond that produced by the removal of saturated fatty acids. Favorable effects of higher LA intake on cholesterol levels are thus well documented and would predict significant reductions in CAD risk. Nevertheless, not all studies support a beneficial effect of LA of coronary heart disease risk markers. For example, an angiographic study published in 2004 reported a direct association between PUFA intakes and artery narrowing in women with CAD. Like many studies, this particular study did not evaluate outcomes so indeed it is possible that this association did not result in increased morbidity and mortality.

In summary, AHA advisory was undertaken to summarize the current evidence on the consumption of PUFAs and CAD risk. Data from randomized trials, case-control and cohort studies, and long term animal feeding experiments indicate that eating at least 5-10% of energy from O-6 PUFAs reduces the risk in relation to lower intakes. The data also suggest that higher intake seems to be safe and even more beneficial. To reduce PUFA levels from their current levels would be more likely to increase, than to decrease, risk for CAD.

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Sterols and Stanols (Part 2)

2009-01-27T11:40:00.006-08:00

In the last post, I gave a brief overview of sterols and stanols and how they are absorbed in the intestine. I want to start this post by talking about what happens when the sterols (cholesterol and noncholesterol sterols) are absorbed at the intestinal epithelium (the tissue that covers the small and large intestine).

There is no doubt that the noncholesterol sterols are effective in reducing cholesterol levels by blocking absorption from the intestine. Evolution has gone to great lengths to keep noncholesterol sterols out of the human body, so almost immediately after absorption, some of the cholesterol and virtually all of the noncholesterol sterols are pumped back into the intestinal lumen (cavity) via something called ATP binding cassette transporters - ABCG5/G8.

As I previously stated, only about 50-55% of ingested cholesterol makes it into chylomicrons in order to be transported to the liver for processing. These ATP binding cassette half-transporters G5 and G8, facilitate transport of sterols out of cells of both the intestine and liver into the intestinal lumen and into the bile. Any sterols that are not pumped back into the intestine become part of the contents of the intestinally produced chylomicron particle that transports lipids to the liver. 70% of the cholesterol in the body is transported as an ester, not as free cholesterol, and this is called cholesterol ester.

Any noncholesterol sterols that were not sent back to the intestine via ABCG5/G8 also become part of the chylomicron and thus gain entry into the bloodstream. Noncholesterol sterols are not esterified as humans do not have the enzymes necessary for that. When these unesterified sterols get into an arterial wall, they are more atherogenic than cholesterol (an esterified sterol). This means they have a greater artery clogging potential than does cholesterol.

If one lacks these transporters (homozygote), all sterols are absorbed and none are pumped back out: this is a very rare homozygous condition leading to the disease called sitosterolemia or phytosterolemia. It is associated with severe atherosclerosis, as noncholesterol sterols (which cannot be esterified) are more atherogenic than cholesterol. Heterozygotes, people who have some transporter function, eliminate some but not all of these phytosterols. Stanols do not require these transporters to get back into these intestines. This is the reason that they are safe and effective to reduce cholesterol. Stanols are commercially available in the supermarket in a product called Benecol.

We are now beginning to understand that not everyone has perfect functioning G5/G8 transporters and noncholesterol sterols get into some people, especially those with family history of CAD (coronary artery disease) and postmenopausal women. These sterols may contribute to their atherosclerosis. Such patients have slightly elevated sitosterol and campesterol levels (no where near what the homozygous patients have). Clinicians have no way of knowing which of our patients may be over absorbing sterols without measuring sitosterol levels. This is not routinely done in clinical practice.

Although sterols are artificially added to many foods and baby aspirin, it should be clear that in some people they may do more damage than does cholesterol. Prior to the introduction of eztemibe (Zetia), there was no way to effectively block the absorption of cholesterol and noncholesterol sterols. I have posted previously on this blog about ezetimbe (Zetia). Zetia typically reduces the absorption of all sterols by 50%. It is FDA approved to lower cholesterol and noncholesterol sterols (sitosterolemia). Since the majority of cholesterol is produced in the liver, Zetia does not have a great effect in lowering ingested cholesterol. Statins are the first line therapy in treating high cholesterol. In was shown in a trial called the 4S trial that as a statin lowers cholesterol levels and block it's production, intestinal absorption of cholesterol and noncholesterol sterols increases. Using Zetia would eliminate this problem.

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Sterols and Stanols (Part 1)

2009-01-07T05:09:00.008-08:00

I hope everyone had a nice New Year's celebration! I have wanted to write on this topic for several months, but every time I started, there was a new question on my message board that I felt had to be addressed more in depth. I will do this in two or three different parts. My goal is to not only educate you about these substances, but also make people aware that in some situations sterols other than cholesterol can cause atherosclerosis. I know that most of the public has no idea about phytosterols, but you may have seen the term on some brands of baby aspirin. I am also perplexed that the majority of physicians that I have encountered do not know the difference between a sterol and a stanol.

Let's start with some definitions.

Cholesterol is a sterol. A sterol is a steroid with an alcohol group attached to it.

Stanols are saturated or reduced sterols that are similar to cholesterol but have a methyl or an ethyl group attached to it. This difference minimizes stanol absorption in the intestines.

Cholestanol is a stanol. Cholesterol can be broken down by the liver into cholestanol - cholestanol is a by-product of cholesterol metabolism.

We consume many sterols from plant sources (sitosterol, campesterol, and stigmasterol), shellfish (desmosterol and fucosterol) and animal sources (cholesterol). If sterols or stanols are esterified (combined with fatty acids), then they can be incorporated into margarine. All of these sterols - with the exception of cholesterol - are collectively referred to as noncholesterol sterols. Collectively, these sterols can be called phytosterols. Sitosterol represents about 80% of all noncholesterol sterols in the diet and is the most well known noncholesterol sterol in the diet.

When fats (triglycerides) enter the intestine in our food, they are broken down into their basic building blocks. The main breakdown products are called fatty acids. These fatty acids and sterols from dietary sources are packaged into what is called a micelle. These micelles "ferry" these fatty acids and sterols to the intestinal lining (epithelium) and then they are absorbed by passive diffusion into the intestinal cells. Passive diffusion is a biological principle that substances flow through a semi-permeable membrane from an area of higher concentration to an area of lesser concentration. There is no pump required to get them out of the intestine and ultimately into the bloodstream. Most humans absorb about 50% of sterols in the intestines; but some people are what is termed "hyperabsorbers" (they absorb 60-80%) and some are "hypoabsorbers" (they absorb less than 50%).

Next: While the food and pharmaceutical industries are pushing sterols in the diet, they may be in fact causing CAD. Why and how can phytosterols do this? Let's look at the data showing that this occurs. I will also talk about the fact that atherosclerosis does not occur with stanol ingestion.

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Vitamin D and Cardiovascular Disease - Part 2

2008-12-05T10:32:00.004-08:00

In my last posting, we discussed the importance of vitamin D in cardiovascular disease. I want to now talk about treatment of vitamin D deficiency. I had previously stated that serum 25(OH)D is the best functional measure of vitamin D status. Most experts agree that a serum level less than 20 ng/ml indicates deficiency and 21-29 ng/ml is considered insufficiency. The optimal range is still debated but most experts consider a level between 32-50 ng/ml to be normal.

The current recommended daily allowance for vitamin D in US is 200 IU/day for children and adults up to 50 years, 400 IU/day for age 51-70, and 600 IU/day over age 70. New research on the non-skeletal benefits of vitamin D has made these guidelines obsolete. Various studies have shown that the greatest physiologic effects have occurred in daily doses of 2000 IU or higher. Doses between 1000-2000 IU daily for adults are likely needed in absence of sun exposure to maintain levels of 30-50 ng/ml 25(OH)D. Vitamin D3 (cholecalciferol) is the form photosynthesized in mammals. Skin exposure without sunscreen can provide adequate amounts of vitamin D3. Vitamin D does not naturally exist in significant amounts in the human food chain. Milk is fortified with 400IU/quart. It is extremely difficult to consume adequate amounts of vitamin D from the diet unless one consumes oily fish frequently such as sockeye salmon. Cod liver oil and O3FA do not provide adequate amounts.

Vitamin D2 (ergocalciferol) is the plant-based form and is added to certain foods and multiple vitamins and is the only form available by prescription in the US. Toxicity and overdose have been related to vitamin D2 intake but not D3 intake. Doses of more than 50,000 IU daily of vitamin D2 were associated with high calcium and low phosphorous levels in the blood whereas doses up to 10,000 IU daily of D3 for 5 months do not cause toxicity. Symptoms of toxicity include weakness, loss of appetite, itching, thirst, excessive urination, and weakness.

In my own practice I treat patients only after drawing a 25(OH)D level. If the patient is deficient, I have managed them with over-the-counter vitamin D3, 5000 IU daily for 8 weeks and continue an additional 8 weeks if levels do not rise above 30 ng/ml. Once this is achieved, 1000-2000 IU each day is used for maintenance therapy. Doses are adjusted for obese patients and those with darker skin pigmentation. Ideally, levels should stay between 35-90 ng/dl. As levels normalize, many patients have a reduction in fatigue and also less muscle pain and cramping.

Vitamin D and Cardiovascular Disease - Part 1

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Vitamin D and Cardiovascular Disease - Part 1

2008-11-04T13:02:00.002-08:00

Vitamin D is a topic that is rarely discussed but has been the subject of new and exciting research regarding its role in cardiovascular disease.

Vitamin D deficiency is now recognized as a pandemic. One billon people worldwide have deficiency or insufficiency. You may ask yourself why is this important and how does it relate to cardiovascular disease? The simple reason is that the evidence of the association between low levels of 25 hydroxyvitamin D [25(OH)D] and higher risk of cardiovascular disease is growing. 25(OH)D levels in the blood is the best functional measure of vitamin D status.

In a recent prospective case-controlled study, 18,225 men free of cardiovascular disease were followed for 10 years. It was shown that blood levels of [25(OH)D], vitamin D, less than 30 ng/ml are associated with an increase risk of heart attack. Men who had a level greater than or equal to 30 ng/ml had half the risk of a heart attack independent of other cardiovascular risk factors. Another recently published study from Austria and Germany looked at 3,258 patients who were going to have a coronary angiogram and followed them for 7.7 years.

Low vitamin D levels were associated with cardiovascular death. The American Heart Association has published findings online based on NHANES data which indicated a strong graded association between low vitamin D levels and peripheral vascular disease (PAD) with the incidence rising by 35% for each 10 ng/ml decline in vitamin D levels even after statistically adjusting for CVD risk factors.

Vitamin D deficiency is associated with obesity, hypertension, glucose intolerance, and metabolic syndrome (insulin resistance). It has also been associated with other chronic illnesses including colon, prostate, and breast cancer, autoimmune disorders, and polycystic ovarian disease to name a few.

We have long known the effects of vitamin D on the musculoskeletal system. Deficiencies affect muscle performance and may contribute to myalgias (muscle pain), proximal muscle weakness, loss of muscle mass, and increased risk of falling.

One study showed that 93% of persons 10-65 years of age who came to a hospital emergency room complaining of muscle aches and bone pain were deficient in vitamin D. I bring this up because some patients on statins complain of muscle and joint pain and many physicians blame the medication and stop it. Statins can reduce cardiovascular morbidity and mortality by up to 40%. Many patients, therefore, would not be on necessary drugs (statins) to reduce their cardiometabolic risk because of a presumed side effect of the medication when the person may be vitamin D deficient.

The major source of vitamin D is from the sun, diet, and dietary supplements. 25(OH)D level is the most accurate way to test for a deficiency. It should be noted that the blood concentrations varies by season so levels may need to be done again to accurately reflect one's true level.

While the optimal level of 25(OH)D is the subject of debate, most experts consider 32-50 ng/ml (or 50-80 nmol/L) to be normal. A level less than 20 ng/dl indicates deficiency and 21-29 ng/dl is considered insufficiency. Since sunlight is a major source of vitamin D, sunscreen reduces synthesis of D3 by 93-99% depending on the SPF. Synthesis also decreases with age and obesity decreases the amount available for use in the body.

Little or no D3 is produced from November to February for those residing above 35 degrees north latitude. The darker one's skin pigmentation, the more exposure to sunlight necessary to achieve the same levels as a lighter skinned person. There are numerous drugs that lower absorption or increase the destruction of vitamin D in the body. Some stains, however, have been found to increase the levels of vitamin D.

In the next part, I'll discuss treatments for Vitamin D deficiency.

Vitamin D and Cardiovascular Disease - Part 2

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Niacin

2008-10-08T08:59:00.008-07:00

I want to get back to discussing lipid modulating drugs. I have been getting many questions regarding niacin on my message board and what it exactly does. I know there is a lot of information out there that it is some kind of wonder drug that raises your HDL-C (good cholesterol) and keeps you from having heart attacks. This is only partly true. As I have said many times before, there is no way to measure how well HDL-C functions. We only measure a number. In other words there is no qualitative test to measure how well the HDL-C works in our bodies, but only a quantitative test. There has never been a prospective randomized study done to correlate an HDL-C level with an outcome. I am not sure that following the HDL-C in patients on niacin tells us anything. Let's talk about what niacin really does.

First of all, niacin is a member of the B-vitamin family and is sometimes referred to as vitamin B3. It is a soluble B vitamin that impacts all lipid subfractions but is not widely used because of the associated side effects. Niacin-induced flushing, which is the result of vasodilatation of the blood vessels, is the most common side effect and usually occurs within 20 minutes following ingestion and may last for up to 60 minutes.

The way niacin works is rather complicated, but in addition to its antiatherogenic activity, the primary use of niacin is to lower triglyceride levels. Niacin reduces the mobilization of free fatty acids from fatty tissue resulting in reduced secretion of VLDL-P from the liver which is a precursor of LDL-P. While it does lower LDL-C, LDL-P, and apoB, this occurs through its triglyceride lowering abilities. Niacin also increases HDL-C. Although niacin does lower Lp(a), in my previous posting I stated that the goal is to lower LDL-P and statins are the primary to drug to perform this function.

Niacin has been associated with abnormal liver tests and causes significant liver toxicity. It should be discontinued if the liver enzymes (ALT/AST) exceed 3X the upper limit of normal. The use of over-the-counter niacin should be discouraged. Many of these preparations are not labeled as sustained release and when combined with a fiber (an example would be oat bran) can become sustained release and adversely affect the liver enzymes. Food maximizes the availability of niacin. It can raise uric acid levels and should be used cautiously in patients with gout.

As I stated earlier, the most common complaint is flushing and this occurs in all patients treated with therapeutic doses of niacin. This is also the most common reason patients stop using the medication. This can be minimized by pretreatment with aspirin or Motrin. Flushing is increased when taken with hot beverages. Gastritis and peptic ulcer disease are also some of the most common reasons for inability to tolerate niacin. Hyperglycemia occurs in patients taking niacin. Patients who are borderline diabetics can become overtly diabetic although data from the ADMIT trial indicate that it can be used safely in diabetics.

Although we still await serious outcome data with niacin, there is good data from very small trials that adding niacin to a statin lessens the thickness of the carotid arteries (CIMT), improves findings on angiograms, and reduces clinical events (the FATS and HATS trials). We await confirmation of this in the much larger AIM HIGH trial which is currently underway. They are not seeing the 90% reduction in clinical events in the AIM HIGH trial that occurred in HATS or the trial would have been stopped for ethical reasons.

In conclusion, while niacin is a drug that should be kept in the armamentarium of a physician that practices lipidology, it should not be used as a first line drug to lower LDL-C or LDL-P. I primarily use it in patients with high triglycerides with known coronary artery disease - in addition to a statin. As I write about in every posting, the name of the game to ensure cardioprotection is to lower LDL-P or apoB and this is now recommended by the American Diabetic Association and American College of Cardiology as a standard of care in patients with moderately high, high, or very high cardiometabolic risk. The full text can be found on my website at www.lipidcenter.com.

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Lipoprotein (a)

2008-09-08T16:24:00.001-07:00

Before we continue our series discussing more lipid-modulating drugs, I want to talk about another topic that I have been asked about frequently on my message board: What is Lp(a) and what can one do for it?

Lipoprotein (a), which is pronounced "little a", is simply an LDL particle to which a protein called apolipoprotein (a) is attached. As I have discussed before in a previous posting about advanced lipoprotein testing, LDL particles are the vehicles that transport cholesterol through the body.

They "drive" the cholesterol into the arterial wall and then the LDL particle becomes a foam cell which is the hallmark of atherosclerosis. Apolipoprotein (a) can also be attached to triglyceride enriched VLDL particles which can also can accelerate plaque formation. Since 90-95% of all the circulating "bad" particles are LDL-P, they become the most important target to modify in order decrease the number of "cars" that move the cholesterol into the arterial wall. So the question remains: If one has an elevated Lp(a), are they at increased risk of a cardiovascular event?

In most epidemiologic studies, the risk of elevated apolipoprotein (a) depends on the LDL cholesterol level. In the large Physicians Health Study, Lp(a) conveyed no risk unless the LDL-C is > 160mg/dl. In the Women's Health Study, Lp(a) was of no risk unless it was very high (>90th percentile) and the LDL cholesterol was also elevated. Thus, elevated Lp(a) in the face of normal cholesterol is not a risk factor.

The proper treatment of elevated Lp(a) is to lower one's bad cholesterol. That means lowering LDL-P or ApoB (or its surrogates - LDL cholesterol and non HDL cholesterol). Although a statin is the primary drug used to treat high cholesterol, they have not been shown to lower Lp(a).

The reason relates to one of the ways a statin works to lower cholesterol. Statins increase the number of receptors made by the liver to bind to the LDL particles. It seems that when apolipoprotein(a) is attached to an LDL particle, it is "camouflaged" from the LDL receptor. Those particles that do not have the apoliporotein (a) attached are cleared in the usual fashion by binding to the LDL receptors. So statins will lower the LDL cholesterol, ApoB, and LDL particle levels but have little to no effect on Lp(a) levels. Despite this, the lowering of the cholesterol carrying particles would greatly lower the clinical risk of a cardiovascular event.

The best way to increase the number of receptors to remove the particles is with a statin, statin/zetia combination, or a bile acid sequestrant( I have had a prior posting on both zetia and bile acid sequestrants).

There are drugs they inhibit the synthesis of apolipoprotein (a) by the liver. These include fibrates, estrogen, evista, and niacin. It is most important to remember that there are no clinical outcome studies relating event reduction to what a drug does to Lp(a). As we have talked about previously, there are numerous studies that have conclusively shown that lowering LDL-C or LDL-P saves lives.

Some people advocate niacin to lower Lp(a) levels, but there is not one ounce of clinical trial data that outcomes would be affected by using niacin to lower Lp(a). As I have said over and over, the name of the game is to lower the LDL-P or ApoB and is still the best way to reduce risk if one has dyslipidemia and high Lp(a).

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Fibrates - Part 2

2008-08-18T15:13:00.005-07:00

In my last posting, we began talking about Fibrate therapy and their role in lipid modulation. I want to start out by talking about fibrates and interactions with the kidneys. When the National Lipid Association's Safety Task Force published their recommendations to healthcare professionals in the March 2007 edition of The American Journal of Cardiology, they began by stating that before the initiation of fibrate therapy, the status of one's kidney function should be known.

If significantly impaired renal function is present, the patient should be prescribed Lopid (gemfibrozil), unless taking a statin, or a lower starting dose of Tricor (fenofibrate-48 mg is the most common available dose) should be considered. With impaired kidney function, the periodic monitoring of kidney function is recommended.

Here's why shouldn't you take gemfibrozil while taking a statin. Gemfibrozil increases the likelihood of myopathy (see my posting titled Statins and Muscle) when combined with a statin. Due to pharmacokinetic interactions, gemfibrozil can increase the concentrations of simvistatin, lovastatin, pravastatin, atorvastatin, and rosuvastatin. It has the least effect on the statin called fluvastatin, which is sold under the brand name Lescol.

The evidence shows that if gemfibrozil is necessary, fluvastatin is the appropriate statin option to consider. It baffles me that on a daily basis I see many patients on gemfibrozil combined with all the statins except fluvastatin. Many physicians do not know this fact.

Most insurance company and medicare drug plans are also uninformed because each time I write a prescription for fenofibrate with a statin, it gets denied and it is recommended that I use gemfibrozil. It seems like I spend an hour a couple of days each week writing authorization letters to get my patients on the appropriate drugs. It should be noted that in patients with diabetes, fenofibrate is the safest and most appropriate choice. After the WHO and HHS trials, there was a concern about a possible increase in cancer-related deaths. Ultimately after significant observation, it was deemed to have occurred by chance.

In 2000, a joint ACC/AHA/NHLBI advisory committee on the use and safety of statins reviewed 8 controlled clinical trials of statin-fibrate therapy involving almost 600 patients. This review found that 1% of patients experienced CK levels >3 times the upper limit of normal without muscle symptoms, and 1% withdrew from therapy because of muscle discomfort. No cases rhabdomyolysis were reported. The task force concluded that the combination of a moderately dosed statin with a fibrate "appears to have a relatively low incidence of myopathy, especially when used in persons without multiple-system disease or multiple medications." In conclusion they said that fenofibrate is the preferred option when combined with a statin.

I want to say something about the studies done to support the use of fibrates in lipid management and the reduction of cardiovascular disease and death. One in particular, called the VA-HIT, gemfibrozil was associated with a 22% reduction in death from CAD and a 11% reduction in overall mortality. As I stated in my previous fibrate post, fibrates are recommended and are optimal therapy for patients with high triglycerides and low HDL and the VA-HIT remains the sole trial among other larger fibrate outcome trials to actually study this population group.

In conclusion, the use of gemfibrozil and fenofibrate in patients with abnormal lipids characterized by high triglycerides and low HDL cholesterol in clinical trials demonstrates an improved cardiovascular benefit. In my next posting, we will look at the effect of Niacin on lipid modulation.

Fibrates - Part 1

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Fibrates - Part 1

2008-07-24T09:41:00.003-07:00

Fibrates have an important role in treating hypertriglyceridemia, in raising HDL (good cholesterol levels), and in treating patients with diabetes and metabolic syndrome. The two most widely used fibrates are Fenofibrate (Triglide, Tricor, Lofibra, Antara) and Gemfibrozil (Lopid), and Clofibrate (Atromid-S).

The mechanism of action is somewhat complicated. In summary, the main physiologic effect is to reduce VLDL (very low density lipoproteins) which are the main transport vehicle for triglycerides. Triglycerides typically fall 20-70%. They do also lower LDL cholesterol a modest 10% or less but this is not a primary use for the fibrates.

Surprisingly, in patients with very high triglyceride levels, this class of drugs can actually cause LDL cholesterol to rise. HDL cholesterol levels do typically rise. Fenofibrate may be useful for the purpose of LDL reduction with low triglyceride levels when statins, Niaspan, and bile sequestrants cannot be tolerated.

The major side effects of the fibric acid drugs are gallstone disease and abdominal discomfort. In rare cases, myopathy, which I discussed at great length in my posting about statins and the effect on muscles, can occur but usually when it is taken with a statin. While some medical professionals, have reported renal (kidney) dysfunction while on fibrates, this has never been shown to be true.

Although there does exist a case report of fenofibrate associated reversible acute kidney dysfunction in 3 kidney transplant patients, one must remember that transplant patients are on a multitude of drugs which affect kidney function.

Fibrates are, however, infrequently associated with an increase in serum creatinine. Serum creatinine is measured in the blood and is used to measure renal function. Some investigators have found that the source of the creatinine probably reflects and induced elevation of the metabolic production rate of creatinine.

In my next posting, we will talk about the use of fibrates in patients with actual kidney dysfunction or on dialysis prior to their use and also the major studies which have proven their effectiveness and safety as a mainstay of lipid management.

Fibrates - Part 2

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Advanced Cholesterol Testing

2008-06-26T14:39:00.001-07:00

I was originally planning on starting to talk about medicines used to lower Triglycerides but due to the untimely death of Tim Russert, I wanted to discuss Advanced Cholesterol Testing. Last week I had the great pleasure of being interviewed on a nationally syndicated radio show. I was asked what I believed could be done to bring more awareness to physicians and the public about the epidemic of Cardiovascular morbidity and mortality? The entire podcast is available on my website and the feedback that I have received from my patients was that I took a difficult topic and made it so easy to understand for the average person. I hope that after listening and reading this posting you will see the need to perform this special type of cholesterol testing.

Over three years ago, I opened The Center for Cholesterol Management as the only free standing lipid clinic in the Los Angeles area dedicated to Advanced Lipoprotein Particle Testing. As a board certified Cardiothoracic surgeon, I feel I have a unique perspective about coronary artery disease in that I am able to clinically correlate angiographic findings with actual operative findings which in so many incidences are discordant. Coronary artery disease is a largely misunderstood entity.

Hyperlipidemia is the most modifiable risk factor leading to Atherosclerosis, yet traditional lipid testing may miss up to 50% of people who have abnormal lipids. Prevention includes identifying people at risk and providing the best treatment individualized to their specific problem.

It is with this background that I will discuss Advanced Lipid Testing and its role in identifying all patients at lipid related risk and as a tool for management of abnormal lipid levels. I often ask myself how come health care providers do not understand this type of testing? I honestly believe that if all people are identified as being at risk, and then if treated appropriately, we would significantly change the face of Cardiovascular morbidity and mortality.

As physicians, we are taught in medical school that it is all about Total Cholesterol, HDL-C, LDL-C, and Triglycerides, yet few really understand the limitations of traditional lipid testing. I hear everyday physicians say that if it is so important why isn't everyone doing it? I believe the answer is that one does not want to change from old patterns of thinking, and according to other physicians, it is too much trouble to learn and understand. Recently, the ADA/ACC released a Joint Concession Statement on Lipoprotein Management in patients with Cardiometabolic Risk(CMR). The full text is available on my website. I believe it is mandatory reading and states that patients with CMR in the moderately high, high, and very high risk groups, it is now the standard of of care to quantify lipoproteins by performing ApoB or LDL-P on all patients to ascertain risk and as a goal of therapy.

As we all know that since sterols are insoluble in the blood, they need to be driven around the body in Lipoproteins. These include HDL-P, VLDL-P, and LDL-P among others. HDL particles are also known as ApoA and all the particles that cause atherosclerosis are known as ApoB. Although NCEP( National Cholesterol Education Panel) recommends calculating the non-HDL cholesterol, this value only can alert the physician that there may too many lipoprotein particles despite having a normal LDL-C. Approximately 90-95% pf the circulating ApoB particles are LDL-P which have a half-life of around 3 days. As varying amounts of Triglycerides and Cholesterol are driven around the body, in what I tell my patients are "cars", the ApoB particles enter the arterial wall if there are too many of the "cars" circulating in the bloodstream.

By simple diffusion, all the bad particles flow from inside the artery and move into its wall and are "eaten" by macrophages which become foam cells and are the hallmark of Atherosclerosis. In eight published studies of over 11,000 subjects using LDL-P and other Lipoprotein concentrations remained the most significant and independent predictor of cardiovascular morbidity and mortality over any other lipid parameter including the usual ratio that all physicians and patients talk about. . In a nutshell, it is the number of LDL particles that matter most... it is the number of cars that cause a traffic jam, not the people in the cars. For example, what if a person with moderate risk has met NCEP guidelines and has a LDL-C of 110mg/dl.

How do I know that there are not 100 cars with one person driving or two big buses with 55 people? The answer is that I do not unless I measure LDL-P directly by using NMR or as a second option measuring ApoB with Gel Electrophoresis. Traditional testing measures the passengers and lipoprotein testing measures the cars, and it is the number of cars(LDL-P) measured by NMR (Nuclear Magnetic Resonance) that are the most numerous ApoB particles in the body and matter most in the development of Atherosclerosis.

Although a comprehensive review of each of the methodologies to perform Lipoprotein Testing is beyond the scope of this post, I feel that measuring LDL particles directly using NMR is the best way to ascertain someone's true risk and then use that number as a guide to management. As I said in my posting about Alex Trebek, the CDC states that 50% of people who have heart attacks have "normal" cholesterol. I hope you now understand why this can happens, having a normal LDL-C but high LDL-P, and be proactive and ask that your physician performs Advanced Cholesterol Testing.

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Technorati Tags: cholesterol, testing, lipids, LDL, HDL, LDL-C, LDL-P

Lowering LDL Cholesterol: Bile Acid Sequestrants

2008-06-09T10:46:00.001-07:00

The next group of Gastrointestinally Active Lipid Lowering Drugs I will talk about are the Bile Acid Sequestrants (BASs). Like Zetia, this class of drugs works in the intestines. They have been used since the 1960s. Since they are not absorbed into the body they are inherently safe and also safe during pregnancy.

They are a good class of drugs for young adults contemplating a potential lifetime of exposure to a medication and are the only class of drugs recommended by NCEP for use in children. The three most common adverse events that have been reported are constipation, rarely leading to obstruction, increase in plasma triglyceride levels, and decrease absorption of some medicines and certain vitamins. The newest agent, Colesevelam (Welchol)-available as a tablet, has greater affinity for bile acids compared with the older medicines such as Cholestyramine(Questran)-available as a powder, so it has fewer drug interactions and is less likely to cause constipation.

The main problem with this class of drugs for patients with hypercholesterolemia can be the taste, the amount that needs to be taken, and the bloating and constipation. I tell my patients to take a stool softener while on this class of drugs or to drink prune juice. Since the development of Welchol and the improved gastrointestinal tolerance, more patients are willing to take BASs. In an analysis of 3 randomized, placebo-controlled trials of Welchol added to statin therapy, constipation was only reported in less than 10% of patients and less than 5% withdrew secondary to side effects.

These classes of drugs are anion-exchangers and cause increased clearance of LDL-C from the blood. As I said previously, they work in the intestines by binding bile acids, and thus, interrupt the circulation of bile acids back to the liver. Since there is less bile acid available, cholesterol is converted to bile acid and the concentration of cholesterol within the liver falls. As this happens, LDL receptor activity of the liver cell increases which then increases LDL clearance from the blood.

The largest set of data on Bile Acid Sequestrants comes from the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). Reduction in coronary risk corresponded to LDL-C reduction. When the maximum dose of 24 grams/day of Cholestyramine was used, there was 28% reduction in LDL-C and a 39% reduction in CHD risk. The BASs have been used alone or in combination with other lipid lowering medications in one major trial with a clinical endpoint and in five with angiographic endpoints.

BASs should be avoided in patients with TGs greater than 400mg/dl because they tend to raise TG levels. If it is be used in combination with medicines to lower TGs, this is not a major concern but if used alone should only be used if one's TG level is less than 200mg/dl.

Finally, due to potential drug interactions, coumadin, thiazide diuretics, propanolol, tetracycline, penicillin G, phenobarbital, thyroid preparations, estrogens, progestins, and digoxin should be administered one hour before or four hours after taking the older BAS agents. The current evidence has shown that Welchol can be taken concurrently with these medicines. The next class of drugs we will explore in the coming weeks will be fibrates.

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Lipid Control with Zetia (Ezetimibe)

2008-05-20T13:15:00.005-07:00

The next drug used in lipid modulation we will talk about is Zetia (ezetimibe). I will not go into the ENHANCE study again as I have had two previous postings on it. The only thing I will say is that the official stance of the National Lipid Association is that on the basis of that study, Zetia achieved the expected response in regard to LDL-C lowering and there were absolutely no safety issues.

Zetia is a new class of drugs known as cholesterol absorption inhibitors. It inhibits the absorption of dietary and biliary cholesterol without affecting the absorption of triglycerides or fat soluble vitamins. It works in the small intestine and inhibits cholesterol uptake and absorption. It has a half-life of 22 hours and this allows once daily dosing and it is not affected by food intake.

Zetia has been shown to reduce LDL-C in patients with hypercholesterolemia. Although some physicians use it as monotherapy, most lipidologists use it as an add on drug when cholesterol goals are not met on statin therapy. There is a low potential for drug interactions and Zetia does not interact with statins.

Several randomized clinical trials with Zetia 10 mg have demonstrated decreases of LDL-C of 17-18.2%, decreases in total cholesterol of 12%, and increases of HDL of 1.3%. Zetia combined with statins has been studied in 4 randomized clinical trials and the efficacy of the combination in lowering LDL-C was superior to the statin alone. For example, in one study, Zetia 10mg/Lipitor 10mg was as effective as Lipitor 80mg. One must remember that as the statin dose is increased the side effects are also increased so it is much better to use a lower statin dose combined with Zetia.

In terms of safety, Zetia is a very safe drug. The incidence of elevations in liver enzymes greater than three times normal ranges from 0-0.8% with statin monotherapy compared with 0-2.2% with Zetia plus statin co-administration.

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Technorati Tags: cholesterol, Zetia, ENHANCE, statins, LDL, HDL, health and wellness

Omega-3 Supplements, Environmental Toxins and Fish

2008-04-30T17:14:00.000-07:00

I wanted to start out the second part of the O₃FA (Omega-3) postings by talking about environmental toxins and fish because I have to confess that I was always confused about the true facts about toxins and fish consumption. There is no doubt that high fish oil intake through the consumption of large amounts of fish may present a risk for increased environmental toxin exposure.

Let's begin by talking about mercury. Mercury may come from coal-fired power plants, waste incinerators, and mining operations as well as other sources. Once airborne, the pollutants fall to the ground in rain or snow and get into the water supply and are converted by bacteria to methylmercury which is toxic to humans. Large and older fish have accumulated more mercury than younger small fish. Also, predatory fish near the top of the food chain tend to accumulate more mercury.

Mercury poisoning by fish consumption has resulted in in neuropsychiatric signs and symptoms including numbness in the mouth and extremities, ataxia, auditory impairments, and most importantly, severe neurologic damage to children born to mothers with toxic mercury exposure. Despite this information, the totality of the evidence supports that the benefits of fish oil exceeds the potential risks, including intake in women of childbearing age with the exception of a few. It needs to be clear that these recommendations only apply to fish oil intake through the consumption of fish.

With regard to fish oil intake though select fish oil supplements, testing has shown that the level of mercury and other environmental toxins is very low or negligible. This occurs for two reasons. First, oxidized mercury is only water soluble and insoluble in oil and thus would not be expected to represent a significant toxicity risk with the intake of fish oils. Second, selected fish oil supplements undergo extensive purification processes to remove toxins and with the prescription fish oil preparations undergoing even more rigorous regulatory processes.

PCBs, Organocholorine pesticides , the most common one being DDT, and dioxin has also found their way into the water supply and ultimately fish consumption has been associated with toxicities from these agents. Dioxin is the primary component of Agent Orange which was used as a defoliant in the Vietnam War and is considered a carcinogen. Manufacturers of selected fish oil supplements have implemented purifications and quality controls designed to reduce the risk of exposure to these toxins. Thus, O₃FA supplements may be preferable to fish consumption as a therapeutic source of O₃FA.

The caveat to all this is that the Nutriceutical industry is largely unregulated. Although the FDA designates O₃FA supplements as "generally regarded as safe", they are not subject to premarket review and approval requirements like prescription medicines. Some fish oil manufacturers elect to pursue "USP-Verified" marks on their label which indicates compliance with standards set by the US Pharmacopeia (USP) which is a independent, not-for-profit, organization established in 1820 that has set the legally recognized standards for identity, strength, quality, packaging, purity, and labeling.

Many physicians are unaware of USP monographs. The USP is also involved with the verification of products through the voluntary Dietary Supplement Verification Program. The presence indicates that the USP has rigorously tested and verified the supplement. The O₃FAs that I take and give to my patients are USP certified. Some manufacturers make the false claim the their O₃FA is "pharmaceutical grade" when they have not gone through the rigorous processes and oversight required to receive approval as a prescription pharmaceutical so beware of this misleading statement.

When I am asked if a particular brand of O₃FA contains excessive vitamins or toxins to pose a health risk, I answer by saying that it depends on the operating and purification processes each company uses. The only way to know is if it is "USP-Verified". The only thing that one must know is that this labeling does not address the efficacy of a supplement. For efficacy information a label needs to state the amount of EPA and DHA within the O₃FA and then the proper dose can be determined.

In my office, I show patients five of the most common brands and although they same 1000mg per tablet, if one looks on the back of the label, there is usually about 300mg of EPA and DHA. So when I tell patients to take 4000mg, they would need to take about 12 pills although the front says 1000mg. One would think they only need to take 4 pills. This is misleading. I generally encourage patients to take highly concentrated liquid which contains 3200mg per teaspoon if they are treating high Triglycerides or 2-3 500mg concentrated fish oil tablets if they are using fish oil for only Cardiovascular clinical benefits.. Please beware of this problem especially if the O₃FAs are being used to treat Hypertriglyceridemia.

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