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A New Paradigm for Stroke Prevention

By William Davis, MD, FACC

April 2005

• Small LDL, IDL, LDL Particle Number, and Lipoprotein(a). Even more than high cholesterol, various lipoprotein abnormalities carry a greater risk for carotid and aortic plaque growth and consequent stroke. Lipoproteins are fat-carrying proteins in the blood that cause plaque to grow. Powerful instigators of plaque growth and stroke include:

  1. Small LDL (low-density lipoprotein) particles encourage carotid plaque growth more so than large LDL particles. This important abnormality also triples heart attack risk. Small LDL often occurs as part of metabolic syndrome.14
  2. IDL (intermediate-density lipoprotein) particles, which are triglyceride-rich but can be present even when triglycerides are low, are a measure of how well fat is cleared from the blood after a meal. This lipoprotein fraction is among the most potent drivers of carotid plaque growth.15 Increased IDL also creates plaque high in soft, unstable fat that makes it more prone to rupture.16
  3. LDL particle number, also measured as apolipoprotein B, is the actual count of LDL particles (per milliliter of blood, for instance). This measure is superior to LDL or total cholesterol as a predictor of heart disease and stroke. Dr. Howard Hodis of the University of Southern California has shown that increased LDL particle number is associated with greater carotid plaque growth, and is a better predictive factor than LDL.17,18
  4. Lipoprotein(a) is a crucial yet underappreciated factor that is clearly associated with heightened risk of stroke and heart attack. Lipoprotein(a) promotes blood clotting and constricted arteries, and increases the dangers of cholesterol. Carotid ultrasound studies have shown that lipoprotein(a) causes accelerated plaque growth.19,20

• Fibrinogen. This blood-clotting protein not only promotes carotid plaque growth, but also contributes to the formation of unstable plaques. These volatile plaques have more inflammatory cells (called macrophages) and a thinner tissue covering, making them more prone to rupture. A pooled analysis from Oxford University with more than 5,000 participants confirmed the role of fibrinogen in increasing stroke risk.21 Fibrinogen levels exceeding 407 mg/dL heighten stroke risk sixfold.22

• C-reactive protein (CRP). This measure of inflammation is proving to be a useful marker for identifying people at higher risk for stroke. Increased risk begins at levels above 0.5 mg/L.23 High CRP also predicts more rapidly growing carotid plaque.24

• Homocysteine. Homocysteine is an important marker for increased likelihood of both carotid and aortic plaque, as well as stroke.25,26 In 1997, the European Concerted Action Project reported more than a doubling of stroke when homocysteine levels exceed 12 umol/L.27 As homocysteine increases to 20 umol/L, risk for stroke and heart attack increases an amazing fivefold over that at a level of 9 umol/L.28

• Cholesterol/LDL. While total cholesterol and LDL clearly contribute to heart disease risk, their role in stroke is less clear. Pooled data suggest that lowering cholesterol with statin drugs does, however, slow carotid plaque growth and reduces stroke risk by approximately 21%.29 In an interesting study from the Cardiovascular Institute at the Mt. Sinai School of Medicine in New York, magnetic resonance imaging (MRI) of the carotids and thoracic aorta showed an impressive 20% regression in plaque area when simvastatin (Zocor®) was taken for two years.30

Although treatment guidelines recommend reducing LDL to 100 mg/dL in high-risk individuals, a report from the Walter Reed Army Medical Center in Washington, DC, showed that carotid plaque was more effectively reduced when LDL was lowered to 70 mg/dL or less using statin drugs.31

“Carotid intima-media thickness and aortic calcifications were related most strongly to the risk of stroke.”4

“. . . carotid plaques are associated with increased risk of stroke, irrespective of their location. It is likely that carotid plaques in neurologically asymptomatic subjects are both markers of generalized atherosclerosis and sources of thromboemboli [debris].”5

— M. Hollander, MD
The Rotterdam Study

Treatment Strategies to Reduce Plaque

The essential question is how do we reduce carotid and aortic plaque, and thus the risk for stroke? If you have carotid or aortic plaque detected during a screening such as a carotid ultrasound, or aortic calcification as indicated by a CT heart scan, you are at increased risk for stroke. You also have a baseline for future comparison to gauge whether your stroke-prevention program is working.

Because most people have not one but several causes of carotid and aortic plaque, no single treatment effectively eliminates risk for stroke. Instead, most people require a comprehensive program of healthy diet, exercise, supplements, and medication when indicated. The following nutritional supplements can be critical components of your plaque-reduction and stroke-prevention program.

• Fish Oil. Fish oil is a cornerstone of any stroke-prevention program. Epidemiological observations suggest a strong relationship between fish intake and reduced stroke risk.32 Carotid ultrasound studies have demonstrated that less carotid plaque is present in those with the greatest intake of omega-3 fatty acids from fish.33

One cleverly designed study made the fascinating discovery that fish oil actually transforms the structure of carotid plaque. In this trial, 150 people with severe carotid plaque scheduled for carotid endarterectomy (surgical removal of the plaque) were given either fish oil, sunflower oil, or no treatment over several months while waiting for their procedures. Plaque was then removed surgically and examined microscopically. Participants who took fish oil had reduced inflammation in plaque and thicker tissue covering the fatty core, two markers of more stable plaque. Those taking sunflower oil or no treatment had unstable plaques with greater inflammation and thinner, less sturdy covering tissue. This suggests that consuming fish oil for just a few months substantially stabilizes carotid plaque, making it less likely to rupture and fragment.34

A standard fish oil capsule (containing 300 mg of EPA plus DHA) contains the same amount of omega-3 fatty acids as a three-ounce serving of cod or halibut; three capsules (containing 900 mg of DHA plus EPA) contain the equivalent of a serving of salmon. A daily dose of four capsules (1200 mg of EPA plus DHA) seems to provide the greatest benefits, including protection from stroke, lowering of triglycerides, and modest anti-coagulation effects, including reduction of fibrinogen (More concentrated fish oil capsules provide 2400 mg of EPA plus DHA per four capsules).35

• Coenzyme Q10 (CoQ10). Although no studies to date have addressed whether coenzyme Q10 reduces plaque, CoQ10 is a marvelously effective way to reduce blood pressure, a crucial factor contributing to carotid and aortic plaque growth. A pooled analysis of eight studies showed that, on average, CoQ10 in daily doses of 50–200 mg reduced systolic blood pressure by 16 mmHg and diastolic pressure by 10 mmHg.36 Other data suggest that CoQ10 can reverse abnormal heart muscle thickening (hypertrophy), another manifestation of high blood pressure. This strongly suggests that CoQ10 has benefits that go beyond reducing blood pressure.37,38

Supplements to Correct Metabolic Syndrome

Weight loss is, without question, the most immediate and direct way to correct metabolic syndrome. Weight loss of as few as 10–20 pounds can yield improvements across the board: increased sensitivity to insulin, increased HDL, and reductions in triglycerides, blood pressure, CRP, fibrinogen, and small LDL particles.39,40 Diet and exercise are fundamental components of any weight-loss program. Low-carbohydrate or reduced-glycemic diets (such as the South Beach and Mediterranean diets) that are rich in fibers are clearly effective.41 Several supplements can amplify these weight-reduction efforts and be useful adjuncts to your lifestyle program. They include:

• White bean extract blocks intestinal absorption of carbohydrates by up to 66%. Taking 1500 mg twice a day with meals results in, on average, three to seven pounds of weight loss in the first month of use. The only side effect of white bean extract is excessive gas, due to unabsorbed starches. Of course, because the blocking effect is partial, resist the urge to overeat carbohydrates.42

• Glucomannan is a unique viscous fiber that, when taken before meals, absorbs many times its weight in water and thereby fills the stomach, causing most people to eat less. Most people lose about four pounds a month by consuming 1500 mg of glucomannan before each meal.43 PGX™ combines glucomannan with xanthan and alginate to enhance the satiety effect. Interestingly, glucomannan also blunts the rise in blood sugar after meals, an effect that itself may lead to weight loss.44 Be sure to drink plenty of water when using fiber supplements.

• DHEA is an adrenal hormone that is essential to maintaining physical stamina, mood, muscle mass in men, and libido in women.45 A recent randomized, placebo-controlled study at Washington University found that 56 subjects taking 50 mg of DHEA daily experienced significant declines in abdominal fat associated with insulin resistance. The participants also demonstrated improved glucose control and lower insulin levels.46 DHEA supports physical and mental well-being, and improves insulin resistance, a risk factor for stroke.

• Pectin and beta-glucan are wonderful fibers that provide feelings of fullness while lowering cholesterol and slowing the release of sugars. Both can play a role in weight reduction. Pectin is the soluble fiber in citrus rinds, green vegetables, and apples, and is available as a supplement. Beta-glucan is the soluble fiber of oats and is also available as a supplement. A University of Southern California study in 573 subjects showed that higher intake of healthy fibers like pectin and beta-glucan is associated with less carotid plaque growth, as measured by ultrasound. Interestingly, the highest fiber intake among participants was 25 grams a day, a number you can easily achieve or exceed with attention to fiber intake.47

Folic Acid and Vitamins B6 and B12

A study conducted by Dr. Daniel Hackam at the Stroke Prevention and Atherosclerosis Research Centre in Ontario, Canada, used carotid ultrasound to measure plaque reduction. Daily treatment with folic acid (2500 mcg), vitamin B6 (25 mg), and vitamin B12 (250 mcg) resulted in modest plaque reduction in 101 participants. This was especially true in participants whose homocysteine levels exceeded 14 umol/L at the start of the trial when compared to untreated participants who experienced substantial plaque growth. Curiously, even participants with homocysteine levels of less than 14 umol/L saw reductions in plaque when taking the vitamin regimen, though the effect was about half of that in participants with homocysteine greater than 14 umol/L.48

A National Institutes of Health-sponsored study of stroke prevention sought to clarify the role of homocysteine treatment. In this study, 3,680 participants with a prior history of stroke were given either a “low-dose” vitamin regimen (20 mcg of folic acid, 0.2 mg of vitamin B6, and 6 mcg of vitamin B12) or a “high-dose” regimen (2500 mcg of folic acid, 25 mg of B6, and 400 mcg of B12). Although homocysteine levels at the start of the trial showed a graded association with stroke risk—with higher homocysteine levels predicting greater stroke risk—the high-dose treatment group experienced, on average, only a 2-umol/L drop in homocysteine levels, and both groups showed no reduction in stroke risk over two years. The study investigators, as well as critics of the study, have suggested that the study failed to show benefit due to an insufficient treatment period or because the vitamin doses used were too low to be of benefit, even in the “high-dose” group.49 (The doses used in the plaque-reduction program at my clinic are 2500-5000 mcg of folic acid, 50 mg of vitamin B6, and 1000 mcg of vitamin B12.)