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Understanding Risk Factors for Heart Disease

Part I: Lipids and C-Reactive Protein

August 2009

By Dr. William Davis

A return-to-basics discussion about the tests that predict risk for heart disease—and what nutritional supplements help correct them

Well before coronary heart disease itself gets underway, so-called risk factors for heart disease declare themselves. Atherosclerotic plaque initiates and grows for good reason. Risk factors identify some of those reasons. 

This is the role of risk factors: To provide an indication that potential for atherosclerosis is present.

If you’ve become a bit confused about this conversation over the past few years, you are not alone. Controversy over the importance of risk factors, the overselling of cholesterol drugs, and the emergence of newly identified risk factors for heart disease has made this a rapidly changing, and often difficult to follow, discussion.   

The understanding of risk factors for heart disease has come a long way since the 1940s, when it was not at all clear just what aspects of diet, lifestyle, or genetics lay behind the disease. Even cigarette smoking was still being advertised as a healthy habit: “Camels: Smoked by more doctors than any other brand!”   

But, even after nearly 60 years of research and heated debate, there is not uniform agreement on what causes heart disease. We’ve zigzagged around the role of diet, cholesterol, and fats, while newly appreciated phenomena like inflammation, genetic factors, and vitamin D deficiency emerge and even further transform the discussion.  

We might regard it as 60 years of confusion—or 60 years of wisdom gained. Despite the controversies and persistent uncertainties, surely there are some nuggets of wisdom to be learned. 

The ASTEROID Trial: Good-bye to heart attack?

Glowing pronouncements about reversal of heart disease followed in the wake of the AstraZeneca-sponsored clinical trial of the statin drug, rosuvastatin, that showed modest reductions in the volume of coronary plaque after participants took two years of rosuvastatin, 40 mg per day.1   

Is it true? If coronary atherosclerotic plaque is reduced by this drug, does this single trial signal the end to all heart attacks and coronary heart disease?

The cure for coronary heart disease, according to this line of thinking, has already been discovered and its name is rosuvastatin.

But before you indulge in an evening at the local fast food restaurant, park yourself in front of the TV with a quart of Ben and Jerry’s Chunky Monkey® ice cream, and throw your fish oil and niacin in the trash, let’s reconsider this argument.

How is heart disease caused? What role do cholesterol and other risk factors for heart disease play? Is it conceivable that a strategy as simple as a single drug (rosuvastatin) can essentially halt heart disease for good?

In the ASTEROID Trial, 346 participants completed a two-year course of treatment with the cholesterol drug, rosuvastatin (Crestor®), 40 mg (the maximum FDA-approved dose). The volume of coronary atherosclerotic plaque was assessed using intracoronary ultrasound (IVUS), both at the start and after 24-months of treatment. (IVUS is an invasive procedure performed during heart catheterization.) Dr. Steven Nissen of the Cleveland Clinic, lead investigator of ASTEROID, reported that, on rosuvastatin, LDL cholesterol was reduced from 130 mg to 60.8 mg/dl, HDL increased from 43 mg/dl to 49 mg/dl plaque. In addition, plaque volume was reduced by an average of 6.9% in the (10 mm) segments studied in each participant.

More recently, the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin, or JUPITER, Trial, of rosuvastatin, 20 mg per day, in 15,000 participants was prematurely halted because of a clear statistical benefit in reducing cardiovascular events in those taking the drug vs. placebo. (Publication of the results is pending.)

The trial results are, undoubtedly, good news for prevention of heart disease. It sure beats three stents and bypass surgery, or a fatal or debilitating heart attack. It also adds to the national conversation on prevention of heart disease and subtracts from the notion that heart disease should be addressed only with major heart procedures like stents and bypass surgery.

But there are several major reasons to view the ASTEROID results with skepticism:

  • The ASTEROID study was industry sponsored. (The financial disclosures of the lead investigators also read like a Who’s Who of the drug industry.) This is, unfortunately, true of much of the data behind statin drug trials: Paid for and thereby potentially influenced by the people most likely to benefit from positive results.  
  • Contrary to the results of the trial, in real-life, the dose of drug used in the study is generally an intolerable dose that, in my experience, results inevitably in incapacitating muscle aches and weakness. (Though I used this strategy initially, I do not have a single patient who has been able to tolerate more than a few months of this drug at the ASTEROID dose.) Taking it for a lifetime (since it can only work as long as you take it) seems inconceivable. 
  • Though not reflected in the ASTEROID trial, it is highly unlikely that a single drug can correct and eliminate the ill-effects of many other sources of heart disease risk, and the results are therefore not able to be applied generally to a broader population. For instance, the genetic pattern, lipoprotein(a), present in 17-20% of people with coronary disease, is not corrected with the drug.       

To reverse all coronary atherosclerotic plaque, an agent(s) would have to address inflammatory processes, genetic factors like lipoprotein(a), phospholipase A2, small LDL, low HDL (including genetic variants), the effects of obesity, deficiency of vitamin D, etc. Sure, rosuvastatin reduces LDL, raises HDL modestly, and reduces C-reactive protein (a measure of inflammation). That still leaves many other crucial factors uncorrected.   

Is this another tool and another choice for the prevention of heart disease? Yes, it is. Is it a cure for heart disease? Hardly.

Risk factors: One at a time

Let’s begin with the four common values present on the standard lipid panel.

LDL cholesterol

LDL cholesterol has become a frequent fixture in the modern lexicon, a topic as common as money and the weather. It has also proven to be the number one most profitable entity—ever—for the drug industry. While this flood of revenue has driven enormous research (and marketing) efforts, it has also served to muddy the waters of truth, since much research behind LDL cholesterol is drug industry-driven and paid-for.

LDL cholesterol is one of the four values provided on any standard cholesterol panel. It is meant to reflect the amount of cholesterol present in the low-density fraction of lipoprotein blood particles (as opposed to those in the high-density fraction, or HDL). It is the basis for most conventional predictions of heart disease risk, since it has been statistically connected to occurrence of heart attack and is recoverable from atherosclerotic plaque when examined.

It is often called "bad" cholesterol, since the higher the LDL, the greater the likelihood of cardiovascular events like heart attack, an observation documented repeatedly from the Framingham Study to other populations.2-4 Despite the controversies the drug industry has created by its overenthusiastic marketing of the LDL-reducing statin drugs, reduction of LDL cholesterol, whether with statin drugs, diet, fibers like oat bran or ground flaxseed, or other strategies (see below) has been confidently tied to reduction in heart attack.5

But there are some limitations.

While LDL is a predictor of heart disease, it is far from a perfect predictor. High LDL cholesterol doesn’t always mean risk for heart disease; low LDL cholesterol doesn’t necessarily mean low risk for heart disease. Most people are unaware that LDL cholesterol is a calculated value, not measured. It is obtained by subtracting measured HDL and triglycerides from total cholesterol, based on an equation developed in the 1960s by Dr. William Friedewald at the National Institute of Health. Because it is calculated, LDL is frequently inaccurate, not uncommonly under- or over-estimating the true value by 50% or more when compared to more accurate measures (like apoprotein B or LDL particle number obtained through lipoprotein testing).6 Nonetheless, calculated LDL is, at least, a reasonable starting place to gauge risk, meaning, the lower the LDL, the better.

Several foods and supplements can be used to reduce LDL cholesterol:

  • Raw nuts—1/4-1/2 cup or more per day of raw almonds, walnuts, and pecans can reduce LDL cholesterol 20-30 mg/dl. Because of their very low carbohydrate content and relatively inefficient absorption of this high-fiber food, I advocate plenty of raw nuts, virtually unrestricted quantities. (But not processed nuts like mixed nuts roasted in hydrogenated oils, “honey-roasted,” or roasted and salted; these are the variety that do indeed make you fat and cause increased LDL cholesterol.)
  • Pectin—found in apples, the rinds of citrus fruits, as well as in supplement form.
  • Oat bran—3 tbsp per day as a hot cereal or in other foods like yogurt, fruit or protein smoothies, granolas.
  • Ground flaxseed—2 tbsp per day, also as a hot cereal or added to yogurt or other foods. This is a first choice for fiber in people with high blood sugars, since it contains no digestible carbohydrates. 
  • Psyllium seed—Known better as Metamucil®, this soluble fiber preparation, like oat bran and flaxseed, reduces LDL cholesterol when two tablespoons per day are taken (usually in water or juice).
  • Beans— Starchy varieties like black, pinto, Spanish, red, and kidney; ½ cup per day.
  • Phytosterols—A soybean oil derivative available as butter substitutes, Take Control® and Benecol®, as well as other products.
  • Green tea—In a recent randomized, controlled trial, participants taking green tea extract capsules (375 mg per day) reduced LDL by 16%.7
  • Cocoa—As cocoa powder or dark chocolates, cocoa flavonoids are proving to exert cholesterol-reducing effects, in addition to blocking LDL oxidation and raising HDL.8
  • Red yeast extract—A nutritional supplement that showed more promise initially, while it still contained the statin agent, lovastatin. Since the FDA forced manufacturers to remove the lovastatin, leaving the mixed mevinolins, its effects have become rather erratic, ranging from moderate LDL-reducing power to none. If you come across a preparation that yields genuine effect, stick with it.
  • Soy protein powder—Three tablespoons a day in fruit smoothies, protein shakes, or blended in yogurt or other foods lowers LDL around 12%. Also consider other soy protein sources like soy nuts, soy cheese, soy milk, soy butter, and low-carb pasta (if made with soy protein).    

All of these strategies reduce the entire range of LDL cholesterol particles, big and small. However, there are also strategies that reduce the most dangerous small LDL preferentially. That will be a topic for future discussion.

Total cholesterol

Total cholesterol is a source of great confusion, but one that seemingly has cast an indelible impression on the minds of most Americans.

That’s because the conversation on the dangers of high cholesterol—in both the blood as well as in diet—was the focus of early conversations dating back to the 1950s and 1960s. Back then, you had high cholesterol or you didn’t; the discussion did not include the various sub-fractions of cholesterol like LDL and HDL. It was just total cholesterol.

But total cholesterol is (and always has been) a composite value, a combination of undesirable fractions (LDL and triglycerides), as well as desirable (HDL). Does high total cholesterol therefore represent high LDL cholesterol (bad) or high HDL cholesterol (good), or some combination? Does low total cholesterol signify low LDL cholesterol or low HDL cholesterol? Total cholesterol is a flawed value that often clouds the significance of cholesterol issues, rather than clarifying it.

There is no doubt that total cholesterol does, in a broad population, correlate with heart attack and other cardiovascular events.9 Total cholesterol >240 mg/dl, for instance, carries a three-fold increased risk of cardiovascular events compared to people with total cholesterol <210 mg/dl.2 However, total cholesterol is a miserably inaccurate value when applied to a specific individual, whose total cholesterol can mean a number of different things. We’ve all known someone with high cholesterol who has never suffered any evidence of heart disease, or someone with low cholesterol who has. Cholesterol is a flawed measure of hidden heart disease in any specific individual at any one point in time. This flawed measure is also the value often cited by critics of the lipid hypothesis—and they’re right. 

Clouding the issue further is the early concern that cholesterol in foods will increase blood cholesterol—makes sense, doesn’t it? However, this phenomenon has since been shown to exert only modest blood cholesterol-increasing potential.10 Dietary cholesterol, because of inefficient absorption, does not appreciably impact on blood cholesterol.

While it proved modestly useful in the past, the time for total cholesterol has come and gone. It is now the model-T of cholesterol testing, which means it’s time to advance. 

High-density lipoproteins (HDL)

Subtract the cholesterol contained in LDL, along with the cholesterol in the very low-density lipoprotein fraction (VLDL, represented by triglycerides) and you’re left with HDL cholesterol. But the cholesterol from HDL is different.

Greater levels of HDL are protective because this particle removes cholesterol from vessel walls and carries it to the liver for disposal, a processed called “reverse cholesterol transport,” sort of like traffic flowing in the opposite lane. For this reason, HDL is often called "good" cholesterol.

Plenty of studies have demonstrated, beyond any doubt, that the higher the HDL, the less the risk for heart attack and other cardiovascular events. While we need more clinical data on the benefits of increasing HDL (or, perhaps, its reverse cholesterol transport capacity, or some fraction of HDL), studies like the VA-HIT show that cardiovascular events are reduced 11% for every 5 mg/dl increase in HDL (with the drug gemfibrozil, in this study).11

More than high LDL, low HDL values are common in people with heart attacks and heart disease. In fact, even the Framingham Study has determined that, more than LDL, low HDL is a better predictor of future heart attack.12 Unfortunately, due to the dominance of statin cholesterol drugs to reduce LDL, HDL is often neglected in clinical practice.   

The most important fraction of the HDL family is large HDL, sometimes called “HDL 2b,” the most active in removing cholesterol (“reverse cholesterol transport”). The large fraction is commonly deficient when total HDL is less than or equal to 60 mg/dl. Treatments that increase total HDL tend to shift particles towards the large fraction, as well.

Both total and large (HDL2b) HDL can be increased with:

  • Niacin—Doses of 500–1500 mg are a very effective method of raising HDL and shifting HDL towards the healthiest large particles. Niacin also reduces triglycerides, undesirable small LDL particles, and reduces LDL. When used in combination with statin agents, there is a profound reduction in heart attack risk.13 Doses exceeding 500 mg per day should be taken under medical supervision, since there is a small risk of liver toxicity at higher doses. Generous hydration helps minimize the “hot flush” side-effect that is common with niacin. We usually begin with 250-500 mg per day at dinner, with increases of 250-500 mg every four weeks until the desired dose is reached. 
  • Omega-3 fatty acids (EPA, DHA) from fish oil, through its effects on reducing triglycerides and VLDL, increases HDL modestly, since triglycerides modify HDL structure and accelerate degradation. Total daily EPA + DHA of 1200 mg per day is a confident starting dose; higher doses should be discussed with your physician. We commonly use 1800-3,000 mg per day, occasionally up to 5000 mg or more, without ill-effect.
  • Vitamin D is proving to be among the most exciting ways to raise HDL. Rises in HDL of 5, 10, sometimes 20 or more mg/dl are common.
  • The fibrate class of prescription drugs (fenofibrate, gemfibrozil) increases HDL between 2-4 mg/dl.
  • Nutritional strategies that increase HDL include dramatic reduction or elimination of high-glycemic index (rapid sugar release) foods like sweets, soft drinks, and wheat (even whole wheat and whole grain) and cornstarch products. Foods that increase HDL include lean proteins like lean red meats, chicken, fish, eggs, almonds, walnuts, sunflower and pumpkin seeds; fibers like oat bran and ground flaxseed (but not wheat bran or wheat products); monounsaturated oils like olive and canola.
  • Alcoholic beverages—Red wine may be the best source, since it is richest in healthy flavonoids, as well. Increases in both total HDL, as well as large HDL, are seen.
  • Exercise—The effects can vary, but increases of up to 5-10 mg/dl are common with high levels of exercise.
  • Weight loss—This can be a very significant effect, depending on how overweight a person is when they start. However, be aware that, with substantial weight loss, there is an initial drop in HDL in the first few weeks, followed by a long-term rise.
  • Flavonoids—such as dark chocolates and green tea have the power to raise HDL, generally by a few milligrams.7,8