Understanding Risk Factors for Heart Disease

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. 

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

Triglycerides and Very low-density lipoproteins (VLDL)

After LDL cholesterol and HDL cholesterol, very low-density lipoproteins (VLDL) are a third class of blood particles that contain cholesterol. On a standard cholesterol panel, VLDL cholesterol is estimated by measuring triglycerides (since triglycerides ¸ 5 yields VLDL cholesterol levels.) 

VLDL particles are formed in the liver by combining cholesterol, triglycerides, and the protein, apoprotein B, in addition to other “ingredients.” VLDL production is very sensitive to the availability of triglycerides, and any increase in triglyceride availability also increases VLDL production in the liver. This is a very common situation with excess carbohydrates in the diet, diabetes, metabolic syndrome and insulin resistance.

After release from the liver, VLDL particles encounter enzymes that transform them into LDL particles. Increased VLDL can therefore lead to increased LDL. In addition, when triglycerides and VLDL particles are plentiful, they also interact directly with LDL particles, which cause the excess triglycerides to be deposited in LDL particles. This triggers a chain of events that leads to the most undesirable small LDL particles (discussed in Part II). Excess triglycerides and VLDL also interact with HDL particles, which also causes a reduction in HDL, as well as a shift in HDL to the less beneficial smaller varieties of HDL particles.14

Both triglycerides and VLDL can be effectively managed with:

• Fish oil—Omega-3 fatty acids from fish oil are an extremely effective means of reducing both triglycerides and VLDL. Benefits begin at 1000 mg per day of total omega-3 fatty acids (EPA + DHA); the dose of fish oil depends on the concentration of EPA and DHA in the fish oil brand you choose. Higher doses of EPA and DHA, e.g., 3000 mg, 5000 mg, even 8500 mg per day, can be considered for very high triglycerides or VLDL (though this should be managed with the assistance of your health care practitioner). The FDA has approved a prescription form of fish oil for treatment of a genetically-determined form of high triglycerides, familial hypertriglyceridemia. Having used both prescription and non-prescription forms for this genetic disease, as well as for lesser degrees of elevated triglycerides, I can confidently say that, beyond the concentration of EPA and DHA per capsule, there is virtually no difference in my experience (beyond the exorbitant cost for the prescription form).
• Niacin—Niacin (vitamin B3) reduces triglycerides up to 60-70% and is an effective strategy to reduce excess VLDL at doses of 500–2000 mg. Any niacin dose >500 mg per day should be prescribed and monitored by your health care practitioner.
• The fibrates (gemofibrozil, fenofibrate) are two prescription agents that substantially lower VLDL and triglycerides. Statin drugs like LipitorÒ and CrestorÒ, while principally prescribed for LDL cholesterol reduction, can also reduce triglycerides by up to 30%.

Nutritional strategies can be enormously effective for reduction of triglycerides and VLDL. In past, low-fat diets were used to reduce triglycerides but proved miserable failures that eventually made triglycerides worse. Instead, reduction in carbohydrates, especially refined carbohydrates, can reduce triglycerides and VLDL.15 Low-glycemic index foods like proteins and healthy oils; exercise; weight loss, when appropriate; and adequate sleep can all contribute to reducing triglycerides and VLDL. One unique strategy we have used with enormous success is to eliminate all wheat products (refined and whole grain), along with elimination of any food made with cornstarch, as well as other high-glycemic index foods (e.g., fruit drinks, candies, snacks, etc.). This has yielded drops in triglycerides of hundreds of milligrams.

It is important to minimize exposure to fructose, particularly processed foods made with high fructose corn syrup, since this common sweetener boosts triglycerides significantly, as well as possibly increasing risk for diabetes and increasing appetite.16

National guidelines (ATP-III) recommend that triglycerides be kept at 150 mg/dl or lower. However, in our experience in reversal of heart disease, we aim for triglyceride levels of 60 mg/dl or lower. At this triglyceride level, VLDL is also minimized.  

C-reactive protein (CRP)

While inflammation can serve a protective function at the site of an injury, it has another face: a silent process that erodes health and lies at the source of multiple conditions, including diabetes, cancer, and heart disease.17 

CRP is a blood protein produced by the liver whenever any inflammatory process is active in the body, whether or not you’re aware of it. Obvious sources of inflammation, like pneumonia and knee arthritis, will raise CRP to high levels. Although its exact function in the body is unknown, the blood concentration of CRP does seem to parallel the degree of inflammation.

CRP is therefore a commonly available blood test that can serve as a gauge of inflammation. While very high C-reactive protein levels >10 mg/l nearly always represent inflammation outside of the heart and do not necessarily indicate increased coronary risk, lower levels (<10 mg/l) can be used to gauge low-grade inflammation that stimulates coronary plaque activity. Levels >3 mg/dl increase risk for heart attack three-fold, even when LDL cholesterol is low.17 When elevated CRP occurs in the company of other risks for heart disease (increased LDL, small LDL, etc.), there is as much as a 6 to 7-fold greater risk of heart attack.19  

“We have to think of heart disease as an inflammatory disease, just as we think of rheumatoid arthritis as an inflammatory disease.”

Paul Ridker, MD
Harvard University

Why another blood test?

Though cholesterol and the values from the standard lipid panel are helpful, they all too often fail to reliably predict future heart attack. As inflammation that lurks beneath the surface is proving to be a potent cause of heart disease, increased CRP has also proved to improve the predictive power of lipids, perhaps yielding a clearer glimpse into the future.  

Predictably, drug manufacturers have tried to persuade us that the only effective way to reduce CRP is with statin drugs, which reduce CRP from 20–50%.20 This is simply not true: there are many ways to reduce CRP as well as, or even more effectively, than the statin drugs.

Here are approaches to consider that reduce CRP and thereby help remove inflammation as a contributor to your risk for heart disease:

Nutritional supplements that reduce inflammation:

•  Vitamin D—Vitamin D can be among the most potent anti-inflammatory strategies available, reducing CRP dramatically.21 In our clinic, we start at daily doses of 1000–2000 units and frequently increase to 4000–6000 units per day, particularly when there’s little sun exposure. Some people require much higher doses, especially in winter; dose is best judged by obtaining a blood level of 25-OH-vitamin D to gauge the degree of deficiency. (We aim to achieve 25(OH) vitamin D levels of 50-60 ng/ml.)  
•  Omega-3 fatty acids—Omega-3 fatty acids from fish oil are the foundation for any heart disease prevention program. CRP reduction is just one of the many beneficial effects. Cardiovascular benefits begin at a dose of 1000 mg of omega-3 fatty acids, EPA + DHA, including CRP reductions of approximately 30%.
•  Niacin—At doses of 1000 mg per higher (which should be used with medical supervision) reduces CRP 15-20%.22
•  Flavonoids suppress inflammation. Resveratrol or red wine (southern French and Italian wines are the most plentiful sources); green tea; cocoa (dark chocolate); and flavonoid-rich foods, such as deeply-colored fruits (citrus, blueberries, raspberries, plums, pomegranates, etc.) and vegetables (spinach, dark lettuces, green peppers, red peppers, etc.) have all been demonstrated to reduce inflammatory responses.23-25
•  Fibers—Healthy fibers, particularly raw almonds, walnuts, oat bran, wheat germ, ground flaxseed, and green vegetable sources, are easy and powerful suppressors of inflammation.   

Besides statin drugs, other medications that reduce inflammation and CRP include aspirin, which reduces CRP modestly, usually no more than 15%; glitazones (Actos™ and Avandia™) for diabetes or insulin resistance; anti-hypertensive drugs in the ACE inhibitor or angiotensin-receptor blocker categories (lisinopril, enalapril, valsartan, irbesartan, etc.); anti-hypertensive agents in the beta-blocker category (metoprolol, atenolol, etc.).26 One fascinating agent that has shown promise in preliminary studies is the antibiotic, doxycycline. At low doses (too low to treat infections except gingivitis), doxycycline suppresses an important class of inflammatory enzymes called matrix metalloproteinases. It also lowers CRP dramatically. Preliminary studies from England suggest that doxycycline, 20 mg twice per day for 6 months, shuts down the inflammation that drives heart attack and abdominal aneurysm expansion.26

In addition, lifestyle practices can also substantially reduce inflammation and CRP:

•  Weight loss—the number one most powerful factor of all. Returning to an ideal weight or BMI<25 leads to profound reductions of C-reactive protein.28 The magnitude of CRP reduction is roughly proportional to the amount of weight lost, i.e., the more you lose, the greater the reduction.
•  Saturated fats have been shown to increase inflammation. Reduce saturated fat from cheeses, red meats, sausage, bacon, butter, and full-fat dairy products).29
•  Choose low-glycemic index foods like lean proteins (egg whites or free-range eggs, lean red meats, baked skinless chicken and turkey, fish); flaxseed, oat bran or slow-cooked oatmeal; vegetables; raw nuts and seeds. Reduce or eliminate high-glycemic index foods, particularly processed starches like cookies and crackers, candies, cakes, breads, bagels, and breakfast cereals. Note that whole grain products are only slightly better than refined white products in this regard.29
•  Exercise leads to a modest reduction in inflammation; the longer the better.

Dr. William Davis is an author and cardiologist practicing in Milwaukee, Wisconsin. He is author of the book, Track your Plaque: The only heart disease prevention program that shows you how to use the new heart scans to detect, track, and control coronary plaque. He can be contacted through www.trackyourplaque.com.