Vascular Inflammation: The Other Half of the Heart Disease Equation

SEATTLE, WA—There’s little doubt that medicine’s near obsession with cholesterol and other lipids has reduced the incidence of myocardial infarction. But for all that fretting over fats, not to mention all those statin prescriptions, cardiovascular disease remains one of the nation’s biggest public health problems.

The reality is, approximately 40% of all people who have myocardial infarctions are not obese or dyslipidemic, and have no “red flag” risk factors. There are roughly 150,000 deaths each year due to silent ischemia, most of these in people who seem well from all appearances.

“Lipids are important, but the other big piece of the picture is inflammation, and in terms of diagnosis and treatment, we are only beginning to come to grips with that,” said Konrad Kail, ND, at the annual meeting of the American Association of Naturopathic Physicians.

“Inflammation fuels the development and progression of atherosclerosis. The older view—that lipids simply build up on passive vessel walls until there is occlusion—no longer holds. We really need to look at how we can reduce inflammation so we can prevent cardiovascular events,” said Dr. Kail, director of the Research Institute at Southwest College of Naturopathic Medicine, Tempe, Arizona. For the past several years, Dr. Kail has focused his attention on non-pharmaceutical strategies for down-regulating the inflammation that drives CVD.

In emphasizing the importance of inflammation, he stressed that he is not trying to downplay the role of dyslipidemia. There is no question that reducing elevated LDL, Lipoprotein (a), and triglycerides can make a big difference. But dyslipidemia, elevated blood glucose, family history of CVD, and other “traditional” risk factors at best only account for 50%–60% of total risk. Other factors such as endothelial and systemic inflammation, levels of fibrinogen and platelet activating factor, and oxidative stress complete the picture.

Cardiologists are beginning to recognize the need to look at measurable systemic markers of inflammation, such as c-reactive protein (CRP) and homocysteine, as well as indicators of fibrinogen activity and oxidative stress. Once considered “alternative,” the notion that inflammation and oxidative damage (ie. Lipid peroxidation) precipitate vessel occlusion and myocardial infarction is now more widely accepted.

But owing in part to the ready availability of cholesterol-lowering drugs, the treatment focus has been overwhelmingly on the lipid part of the equation. This needs to change, said Dr. Kail. Physicians need to realize that inflammation is part of the pathogenesis early on in the disease, and that it can be managed.

Excessive LDL can actually trigger vessel wall inflammation. The final manifestations of the disease—plaque rupture, thrombosis, occlusion, and infarction—are often the end result of a feed-forward loop in which lipid deposition and inflammation drive one another. Add in lipid peroxidation, and infiltration of lymphocytes, and you’ve got a coronary artery stenosis.

C-Reactive Protein and Homocysteine

Still, it is important to realize that elevated inflammatory signals like CRP and homocysteine confer significant risk of MI and stroke even if lipid levels are normal. In the Physician’s Health Study, subjects with the highest CRPs had a 3-fold increased risk of MI, and a 2-fold increased risk of stroke.

Paul M. Ridker, MD, of the Center for Cardiovascular Disease Prevention, Brigham & Women’s Hospital, Boston, is one of the nation’s leading investigators into the relationship between inflammation and CVD. His work has done much to push CRP closer to the mainstream in CV risk assessment.

He found that people in the highest quintile for cholesterol but the lowest quintile for CRP had a 4-fold higher risk of MI than those in the lowest quintile for cholesterol. Those in the highest quintile for CRP but the lowest quintile for cholesterol had a 2.2-fold increased relative risk. However, those in the highest quintiles for both cholesterol and CRP had an 8.7-fold increased risk of infarction. In other words, elevated CRP doubled the risk posed by high cholesterol alone.

Similarly, elevated homocysteine is emerging as a major risk factor for CVD. By some accounts, 10%–20% of all CV events are attributable to elevated homocysteine levels.

Homocysteine is an amino acid normally produced from methionine in small amounts by the body. Its main physiological roles are to regulate bone and tissue formation, and to stimulate formation of insulin-like growth factors. Its metabolism is regulated by folic acid. When homocysteine exceed a certain level, it begins to destroy endothelial cells, and stimulates formation of atherosclerotic plaques.

In some people, homocysteine is elevated because they have specific genetic polymorphisms that lead to dysfunctions of methyltetrahydrofolate reductase (MTHFR), an essential enzyme for the metabolism of folic acid. In many other cases, however, the homocysteine is high because of a poor diet lacking in folic acid and other B vitamins.

In 1969, when Kilmer McCully, MD, first made the connection between elevated homocysteine and heart disease, it was considered a very radical notion, and largely rejected by conventional medicine because it ran against the grain of the emerging cholesterol hypothesis. Fortunately, mainstream cardiology has come around to recognizing the role of homocysteine, and many physicians now routinely recommend folic acid to patients at risk.

Dr. Kail applauded this shift. “Roughly 21% of all Americans are at moderate risk for CVD because they’ve got high homocysteine levels.” While folic acid is certainly a good first step, he pointed to a 1994 study showing that while 650 mcg of folic acid alone could produce a 42% reduction in homocysteine, addition of 12.2 mg B6 and 400 mcg of B12 gave an additional reduction to over 50%.

Vitamin B2 is also involved in homocysteine metabolism. According to a study of healthy blood donors, those with the lowest riboflavin (B2) levels had the highest homocysteine levels.

A number of functional testing laboratories offer comprehensive cardiovascular risk panels that measure homocysteine, CRP, platelet aggregability and other indicators of inflammation and plaque formation. Several labs, including Great Smokies Diagnostic Laboratory and Integrative Genomics also provide information on the presence of single nucleotide polymorphisms (SNPs) related to specific cardiovascular risk factors. They present these data in a coherent and clinically relevant manner, in some cases offering recommendations for nutritional interventions to reduce risk.

Dr. Kail stressed that conventional heart imaging techniques won’t provide much useful information on the inflammatory aspect of the disease. Angiography only begins to reveal atherosclerotic lesions when the vessel is at least 45% occluded; PET scanning is no better. Arterial ultrasound and electron beam CT scans start picking up lesions at the 15%–20% occlusion stage. But even lesions at this relatively early stage are the result of longstanding inflammatory process.

Nutritional Interventions to Reduce Inflammation

Dietary improvements are an obvious step in reducing risk and preventing CVD. Beyond that, though, there are many nutritional and botanical supplements that can down-regulate chronic systemic inflammation and reduce CVD risk, said Dr. Kail.

Pay close attention to the balance between omega-6 and omega-3 fatty acids in a patient’s diet. The typical US diet, heavy on animal proteins, trans-fats, refined carbohydrates, with relatively little seafood or green vegetables, is heavily weighted toward the omega-6 fatty acids. These are metabolized first to arachidonic acid and then to prostaglandin E2 and other highly inflammatory cytokines. Arachidonic acid also produces thromboxanes, which promote clotting and platelet aggregation. Omega-3s, in contrast, are metabolized to prostaglandin E3 and other anti-inflammatory signaling molecules.

Nicotinic acid (niacin) is important for down-regulating LDL and increasing HDL, on the lipid side of the equation. It also reduces Lp (a). Dr. Kail also recommended L-carnitine, because it reduces triglycerides, increases ATP production, and increases metabolism of lipids. “It is particularly good for diabetics, but make sure to give antioxidants, as L-carnitine will increase oxidative stress.”

Magnesium can be a real help in high-risk patients. It relaxes the endothelium throughout the vascular tree, improving peripheral as well as cardiac perfusion. “Huge numbers of people are magnesium deficient,” he said, adding that clinicians should pay close attention to the elderly, people with poor diets, those who drink a lot of caffeinated drinks, those on multiple drugs, and diabetics.

Dr. Kail has been working with Western Research Laboratories, an Arizona-based pharmaceutical and nutritional company to develop nutraceuticals products that leverage the effects of nutritional, botanical, and enzyme ingredients to reduce cardiovascular risk. His CardioCare Lipid Formula includes Allium sativum (garlic), Monascus purpureus (red rice yeast), Cynara scolemus (artichoke), Policosanol, inositol hexaniacinate (a form of niacin), L-carnitine, docoxahexaenoic and eicosapentaenoic acids (the two main forms of omega-3), as well oat bran and several other heart-healthy ingredients.

The company is testing the CardioCare formula against prescription statin drugs as well as a number of other natural products. In terms of improving lipid profiles, preliminary data suggest that CardioCare is comparable to the statins, but without any elevation in liver enzymes.

Systemic Enzymes

Systemic enzyme supplements can make a tremendous difference for patients with elevated CRPs and elevated fibrinogen levels. Western Research Labs recently formed an alliance with World Nutrition to develop a product called Vitalzym, a combination of plant or bacterially-derived enzymes including serapeptase, protease, proteinases, bromelain, papain, lipase and amylase.

Though initially promoted as a natural anti-inflammatory for pain relief, Dr. Kail said the enzyme combination can produce major changes in CRP, on the order of 80% reductions, within 30 days. It also lowers prostaglandin E2 and other inflammatory cytokines. In his experience, this enzyme combination is very safe, the only major contraindications being use of warfarin or other anticoagulants. Patients who are on any sort of antithrombotic drug should not take Vitalzym or any other systemic enzyme products. These products may also alter the absorption and tissue distribution of antibiotic drugs.

Nattokinase, an enzyme derived from the Japanese fermented soy food called natto, is also an effective natural medicine for patients with vessel occlusions. “It works at the level of plasmin, and lyses fibrin directly. It is very fibrinolytic stuff.” Nattokinase, which is stable at a pH range from 6–12, has been very well studied in the context of CVD in Japan.

Several dietary supplements containing nattokinase have recently entered the US market. Western Research and World Nutrition are marketing a formulation specifically designed for reversal of atherosclerosis, called Nattovita. In addition to therapeutic doses of nattokinase, the product also includes Coenzyme Q10, vitamin E, folic acid, and several of the enzymes found in the Vitalzym formula.

As with Vitalzym or any other systemic enzyme product, one must be cautious in combining Nattovita or other nattokinase products with anticoagulant drugs. However, in his own practice, Dr. Kail has been able to wean patients off coumarin by gradually titrating up with Nattovita, while titrating down on the coumarin. The key, he said, is to monitor prothrombin times. “Whatever you do, you need to maintain prothrombin times of 18–20 seconds.”

For more information on Nattovita, CardioCare or Vitalzym, contact World Nutrition at: 800-548-2710 or

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