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.

Related Topics:

• WebMD Video: Predicting Heart Disease
• Cholesterol Management Message Board with Michael F. Richman, MD, FACS
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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.

Noninvasive Methods to Assess Atherosclerosis: Part 4

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

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

Related Topics:

• WebMD Video: Predicting Heart Disease
• Cholesterol Management Message Board with Michael F. Richman, MD, FACS
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Noninvasive Methods to Assess Atherosclerosis: Part 2

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.

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• CT Scans for Clogged Arteries? Not Yet
• Cholesterol Management Message Board with Michael F. Richman, MD, FACS
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