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Cerebral Vascular Disease

Fibrinogen
Fibrinogen is a blood protein that forms fibrin in a reaction that initiates the formation of blood clots. The entire mechanism is called coagulation (the process of changing from a liquid into a solid). If fibrinogen levels are too high, blood clots can form. If fibrinogen levels are too low, the blood will be too thin and a hemorrhage can result (see the Hemorrhagic Stroke section for more information).

An article in the New England Journal of Medicine showed that those with high levels of fibrinogen were more than twice as likely to die of a heart attack. Large studies have confirmed that fibrinogen is a risk factor of equal or higher value than total cholesterol (Wilhelmsen et al. 1984; Rosengren et al. 1996; Beamer et al. 1998; Ma et al. 1999).

Fibrinogen can be increased by several factors:

• Smoking increases fibrinogen (Wilhelmsen et al. 1984; Lip 1995).
• Homocysteine can make fibrinogen more dangerous by inhibiting the production of plasminogen activators (substances that break down fibrin).
• Infections and exposure to cold have been shown to increase fibrinogen levels, which may explain why cardiovascular mortality is increased during the winter months (Khaw 1997; Zhu et al. 2001).
• Psychological and mental stress can increase fibrinogen levels (Lip 1995).
• There appears to be a hormonal influence on fibrinogen. Increased fibrinogen levels and elevated platelet aggreg r ation (with an increased risk of thrombosis) have been found in individuals that use oral contraceptives (Lip 1995).

A study of 34 patients with thrombotic stroke and 58 matched controls found that stroke victims had a significantly higher level of fibrinogen. The researchers also found a correlation between fibrinogen levels and white blood cell aggreg r ation. The authors proposed that enhanced white blood cell adhesion and aggreg r ation with the subsequent release of free radicals may be one of the mechanisms of fibrinogen in the development of stroke (Belch 1998).

The Life Extension Foundation long ago recognized the importance of monitoring fibrinogen levels both as a preventive measure in otherwise healthy individuals and for those at risk of stroke. Elevated fibrinogen levels, particularly in a non-smoker, deserve particular attention. The optimal level of fibrinogen is under 300 mg/dL, compared with the standard reference range of up to 460 mg/dL used by conventional medicine.

Lipoprotein (a)
Lipoproteins are small molecules that carry lipids (fats, including cholesterol and triglycerides) in the blood. Lipoprotein (a) is an altered form of LDL that contains the apolipoprotein, B-100, linked with apolipoprotein (a), which is structurally similar to plasminogen (a key protein in fibrinogen). Because of this similarity, lipoprotein (a) is considered to be very "sticky" and has been found to be a key component in blood clots (Rath et al. 1989; Beisiegel et al. 1990; Rath et al. 1990a; 1990b).

The lipoprotein (a) theory of heart disease was a central part of Linus Pauling's work. Drs. Pauling and Rath proposed that lipoprotein (a) acts as a surrogate (substitute) for vitamin C. They hypothesized that a deficiency of vitamin C resulted in the increased production of lipoprotein (a) which both hardened the arteries and caused blood clots. Pauling recommended the use of high doses of pure vitamin C and lysine to suppress lipoprotein (a) levels.

Insulin Resistance, Syndrome X
Syndrome X is a cluster of symptoms (high triglycerides, reduced HDL, increased blood pressure, central obesity, and elevated LDL) characterized by insulin resistance. The insulin does not have as strong an effect on lowering blood glucose. The pancreas responds by producing more insulin to stabilize blood glucose levels, but at a significant cost in terms of increased risk of cardiovascular disease. Syndrome X is considered to be a precursor of diabetes mellitus, a known risk factor for stroke. The question about whether Syndrome X is an independent risk factor for stroke has been the subject of several research studies. While some have found a moderate increase in stroke risk, others have found no significant relationship (Shinozaki et al 1996; Pyorala et al. 2000; Adachi et al. 2001).

Syndrome X is associated with carbohydrate metabolism problems and can be managed with dietary changes that focus on reducing total and simple carbohydrates (e.g., sugar, sweets, bread, pasta, and other "junk foods") and increasing protein and beneficial fats. Syndrome X is discussed in more detail in the protocol, Diabetes Type II and the Syndrome X Connection.

Inflammation
Chronic inflammation is associated with a variety of systemic diseases, including increased fibrinogen levels. C-reactive protein (CRP) is an early marker for systemic inflammation that rises before the erythrocyte sedimentation rate (ESR), the marker of inflammation used in conventional medicine. C-reactive protein appears to bind with LDL cholesterol, increasing its stickiness and vascular adherence. C-reactive protein is considered to be a highly sensitive risk factor for cardiovascular disease.

An article in the journal Stroke described a study of 193 patients in whom serum CRP was measured within 24 hours after an ischemic stroke, within 48-72 hours, and at discharge. CRP levels at admission and discharge were found to be predictors of new vascular events or death at 1 year. The CRP level at hospital discharge was the strongest indicator, with a hazards ratio of 7.42 (95% confidence interval) (Di Napoli et al. 2001).

An article in the journal Circulation described the Women's Health Study in which CRP was measured in 122 healthy participants and in 244 age- and smoking-matched controls. Higher CRP levels were found in women who developed cardiovascular events. Those with the highest levels had a fivefold increased risk of any vascular event and a sevenfold increased risk of myocardial infarction (MI) or stroke. The authors concluded that CRP was a strong independent risk factor for cardiovascular disease (Ridker et al. 1998).

An article in the journal Stroke described a study in which CRP levels were measured in patients diagnosed with ischemic stroke. Survival in those with higher CRP levels (the average was 10.1 mg/L) was significantly worse than those with lower levels. Higher CRP levels were found to be an independent predictor of mortality together with age and stroke severity (Muir et al. 1999).

Chronic inflammation is a component of most chronic diseases, including arthritis. Several herbs that have multiple beneficial effects are anti-inflammatory. These include aspirin (derived from the bark of the white willow tree), turmeric (the yellow spice which contains curcumin), and the essential fatty acids found in fish, flax, perilla, and borage oils.

Several studies have examined the relationship between CRP levels and the risk of future strokes or myocardial infarction. One article related plasma CRP levels to incidence of first ischemic stroke or TIA in the Framingham Study original cohort. CRP levels were measured in the previously frozen plasma samples of 591 men and 871 women free of stroke/TIA during their 1980-1982 clinic examinations, when their mean age was 69.7 years. During 12-14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had two times the risk of ischemic stroke/TIA (RR = 2.0), and women had almost 3 times the risk (RR = 2.7) compared with those in the lowest quartile (Rost et al. 2001).

The following tables show the relative risk of a future myocardial infarction (MI) or stroke in both men and women. A lower relative risk is desirable and is correlated with lower values of CRP. Men have a much lower CRP level corresponding to the same relative risk as women. For a relative risk of 1.0, men would have to achieve CRP levels less than 0.55. Women needed to achieve CRP levels less than 1.50. The difference reflects the higher incidence of myocardial infarction and stroke in men.

Of particular interest is that the standard reference range for CRP levels is less than 4.9 mg/L. This would correspond to a very high relative risk of future stroke or MI for both men and women, especially for men. The optimal range that knowledgeable researchers and the Life Extension Foundation recommend is for CRP levels to be less than 1.3 mg/L and preferably less than 0.5 mg/L.

The Life Extension Foundation, recognizing the central role inflammation plays in disease, highly recommends that C -reactive protein RP levels be measured. High sensitivity testing for CRP can assess the risk of cardiovascular and peripheral vascular disease. The optimal range for both men and women is as low as possible. To learn more about how to suppress the underlying inflammatory factors that may be contributing to these excess levels of C -reactive protein RP , refer to the Inflammation: Chronic protocol.

Hormonal Deficiency
Hormones play a central role in regulating the body's metabolism, including neurological function and repair. DHEA and pregnenolone help coordinate brain cell activity and protect neurons from damage. Aging causes a severe deficiency in pregnenolone and DHEA production.

Conventional medicine has focused on the role of estrogen and stroke risk. At present, a controversy exists over the increased risk of stroke associated with hormone replacement therapy and oral contraceptive use. Much of the information was based on early studies with high-dose preparations, particularly with oral contraceptives containing more than 50 mcg of estradiol (Goldstein et al. 2001).

It is clear that hormones play a role in neurological function and repair. The Life Extension Foundation highly recommends that its members make health decisions based on specific laboratory tests, particularly with regard to hormone replacement therapy. Natural hormone replacement therapy can be based on the results of these laboratory tests. For more information, see the Male and Female Hormone Modulation protocols.

Nitric Oxide Synthesis
Nitric oxide is a soluble free gas naturally produced in the body (from the amino acid arginine) by endothelial cells, macrophages, and specific neurons in the brain. Nitric oxide plays several key roles in the body, including:

• Nitric oxide relaxes vascular smooth muscle, which causes vasodilation.
• Nitric oxide reduces platelet aggreg r ation and adhesion.
• Nitric oxide produced by macrophages is cytotoxic to certain microbes and tumor cells.

Nitric oxide is synthesized from the amino acid arginine by the enzyme nitric oxide synthase. The reaction requires several nutritional cofactors, including:

• NADPH (nicotinamide adenine dinucleotide phosphate, a form of niacin)
• Thiol (a sulfhydryl group, composed of sulfur and hydrogen)
• Tetrahydrobiopterin (a chemical derived from folate)
• FAD (flavin adenine dinucleotide, a chemical derived from riboflavin)
• FMN (flavin mononucleotide, also derived from riboflavin)

Thus, nitric oxide synthesis requires vitamin B2 (riboflavin), vitamin B3 (niacin), and folate (Ganong 1995).

Nitric oxide has been identified as having a key role in blood pressure regulation. Nitric oxide lowers blood pressure by stimulating the release of calcium from vascular smooth muscle cells, thereby causing the blood vessels to relax and dilate. There is now evidence that nitric oxide deficiency can cause hypertension and may also be involved in the pathogenesis of atherosclerosis. Nitric oxide donors (such as nitroglycerine and arginine) lower blood pressure and increase cerebral blood flow in patients with acute ischemic stroke.

Uncontrolled nitric oxide production, however, can lead to massive peripheral vasodilation and shock. Nitric oxide can oxidize sulfhydryl groups on proteins and cause a depletion of cytosolic glutathione. It can also react with hydroxyl radicals to form the strong oxidant, nitrogen dioxide. Nitric oxide has also been implicated in a variety of inflammatory diseases. Inhibitors of nitric oxide production are being tested clinically and may be of use in controlling conditions associated with excess oxidant production, such as in acute ischemic stroke. Interestingly, nitric oxide donors are also being tested for the same conditions due to their vasodilation effects. Nitroglycerine, a well-known drug for angina, is a nitric oxide donor.

Modulating Nitric Oxide
The best naturally occurring source of nitric oxide is the amino acid arginine. A study examined the use of L-arginine to prevent experimental ischemic stroke in rats. L-arginine was administered at the time of ischemia and at 6 and 24 hours later. The areas of neuronal necrosis were reduced by 99%, 96%, and 89%, respectively. The study also examined L-arginine in combination with a calcium antagonist (TMB-8) and found that the combination of TMB-8 and L-arginine is more effective in treating ischemic stroke by simultaneously reducing calcium-activated proteolysis and improving cerebral blood flow than using TMB-8 or L-arginine alone (Hong et al. 2000).

However, to avoid the potentially harmful free-radical damage that can result from excessive nitric oxide, one of the vitamin E fractions, gamma tocopherol, has been found to function as the best antioxidant for nitric oxide. Therefore, for best stroke, heart disease, and hypertension protection, consider arginine, 2700 mg 3 times per a day with plenty of B complex as cofactors and 400 IU of gamma tocopherol for optimal protection.

Certain precautions must be exercised when supplementing with arginine:

• Diabetics and borderline diabetics should use arginine with care because it may worsen diabetes.
• Children, teenagers, and pregnant or lactating women should not use arginine (or growth hormone stimulators) except under the care of a knowledgeable physician.
• Arginine sometimes reactivates latent herpes virus infections. Those with ocular or brain herpes should avoid it. Persons with herpes benefit from lysine which competes with arginine in amino acid metabolism. If you have herpes and use arginine at all, use lysine at a separate time of day on an empty stomach to avoid lysine depletion and herpes exacerbations.
• Arginine should be used with care in those with psychosis because they may experience a worsening of symptoms.
• Arginine should always be taken with antioxidants.

Nitroglycerin (glyceryl trinitrate) is a drug commonly used to treat angina. Nitroglycerin is a nitric oxide donor (Ikeda et al. 1997; Castillo et al. 2000).

A double-blind, randomized, controlled trial examined the effects of the nitric oxide donor glyceryl trinitrate (Nitroglycerin), a known systemic and cerebral vasodilator, on 37 patients with recent (<5 days) ischemic or hemorrhagic stroke. Transdermal glyceryl trinitrate significantly lowered blood pressure by 13.0/5.2 mmHg at day 1 and 9.3/5.0 mmHg at day 8. The lesser reduction at day 8 than day 1 suggests that tolerance to glyceryl trinitrate was developing. The authors concluded that transdermal glyceryl trinitrate lowered blood pressure by 5-8%, a clinically significant and relevant, but not excessive, degree in patients with acute stroke (Bath et al. 2001).

Nitric oxide and its role in blood pressure regulation is the subject of scientific research, both with European drugs (aminoguanidine, discussed in the Innovative Drug Strategies section) and natural supplements (arginine, folic acid, and vitamins B2 and B3).

Nitroglycerine, being a nitric oxide donor, works best with B complex as supporting cofactors along with gamma - tocopherol to quench the excessive and potentially damaging free radical effects of nitric oxide.