Herbal Medicines & Cholesterol: Part 1

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

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?

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

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?

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?

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

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.