Stroke and Cerebrovascular Disease-2

C-Reactive Protein and Fibrinogen
There is a clear association between elevated levels of C-reactive protein and fibrinogen and the incidence and severity of stroke. Also at the 2001 American Stroke Association meeting, researchers presented evidence that elevated C-reactive protein doubled or tripled the risk of stroke (Kelly PJ et al 2000). Another presentation showed that in those who have a major stroke, higher levels of C-reactive protein portended a high likelihood of having another vascular event, such as a heart attack or stroke, or of dying within the following year. Stroke patients with the highest C-reactive protein levels were nearly 2.4 times more likely to experience death or a vascular event within the next year than were patients with the lowest levels (Di Napoli N et al 2001).

Similarly, the Physician’s Health Study found that apparently healthy men with the highest C-reactive protein levels had twice the risk of stroke, three times the risk of future heart attack, and four times the risk of future peripheral vascular disease (Ridker PM et al 1997). The Women’s Health Study reported that C-reactive protein was the single strongest predictor of future vascular risk (Ridker PM et al 1998).

Elevated levels of fibrinogen are also associated with increased risk of stroke. Fibrinogen is a protein produced by the liver. It circulates in the blood and helps stop bleeding by helping blood clots form. Today’s standard laboratory reference range for fibrinogen is between 193 and 423 mg/dL. That means according to conventional standards, fibrinogen levels as high as 423 mg/dL are acceptable.

However, a study reported in the Journal of the American Medical Association found that no matter what a patient’s level was within the range tested (between 250 mg/dL and 562 mg/dL), an increase of 100 mg/dL was associated with a significantly increased risk of heart disease and stroke (Danesh J et al 2005). Another study found that those with high fibrinogen levels, above 343 mg/dL, had a twofold increase in the risk of heart attack (Ma J et al 1999). Fibrinogen levels can be reduced by taking dietary supplements such as fish oil and vitamin C and by lowering homocysteine.

Responding to a Stroke: Speed Matters
Most of the damage from a stroke occurs within 24 hours following the event, so it is crucial that people get adequate treatment as fast as possible to reestablish blood flow and limit the damage. If stroke-like symptoms last for more than 10 to 15 minutes or worsen, call 911 without delay even if it is unclear whether a stroke has occurred (NINDS 2005).

Once a patient has arrived at the hospital, physicians will quickly seek to determine what kind of stroke (ischemic or hemorrhagic) occurred, then take steps to treat it. Diagnostic imaging tests are usually performed as soon as possible to determine the kind of stroke.

Treatment of ischemic stroke. The goal of acute therapy in ischemic stroke is to dissolve the blood clot as rapidly as possible (a process called lysis). Studies show that when thrombolytic (clot-busting) agents are administered within three hours of symptom onset, they can dramatically decrease damage (Burger KM et al 2005). These drugs are still effective if given within 4.5 hours of the stroke (Davalos A 2005). Unfortunately, however, most stroke patients do not receive the appropriate thrombolytic agent quickly enough (Burger KM et al 2005; Davalos A 2005).

The most common thrombolytic agent used is tissue plasminogen activator. It is typically administered intravenously, and newer methods using ultrasound-enhanced delivery promise to make this drug even more effective (Davalos A 2005).

After stroke, there is a significant risk of a repeat stroke. To help prevent secondary strokes, people may be prescribed anticoagulant therapy, including low-dose aspirin or long-term warfarin (Coumadin®) therapy, or antiplatelet therapy (such as Plavix®).

Anticoagulants. These drugs work by preventing clot growth or preventing new clots from forming. Warfarin is the most common example. It is often used when a patient’s doctor suspects that a blood clot has originated in the heart and traveled to the brain and lodged in a vessel, blocking blood flow and causing an embolic stroke. Anticoagulants are not indicated when there is increased risk of bleeding or in patients with uncontrolled high blood pressure (NINDS 2005).
Antiplatelet agents. Antiplatelet agents work by preventing blood platelets from sticking to each other and forming a clot. Common examples are aspirin, dipyridamole, and clopidogrel. They are also often used to reduce the risk of stroke in individuals who have had a transient ischemic attack or to decrease the risk of a second ischemic stroke.
For more information on preventing blood clots, see the chapter titled Blood Clot Prevention.

Treatment of hemorrhagic stroke. Acute treatment of hemorrhagic stroke focuses on surgery and medications. Surgical procedures can help alleviate the damage (hematoma), but the condition of the patient before surgery is critical to the recovery rate. People who are conscious and have small blood clots often improve without surgery. But people in comas, who have large clots, do very poorly, regardless of treatment approach (National Stroke Association 2005)

After the acute treatment, medications may be prescribed to control blood pressure, which is a major risk factor for hemorrhagic stroke (Clarke CRA 1998). Prescription medications for lowering blood pressure include diuretics, calcium channel blockers, beta blockers, ACE inhibitors, and others. For more information on natural ways to lower blood pressure, see the chapter titled High Blood Pressure.

Stroke Prevention
Stroke prevention is a subject of much debate. Approximately 25 percent of people who recover from a first stroke will have a second within five years. While the chance of death and disability increases with each stroke, risk of another stroke appears to be greatest within the first year (National Stroke Association 2005).

Using measurements such as the degree of artery occlusion (how much of the carotid artery is blocked by atherosclerotic plaques), medical experts have sought to establish firm guidelines to help physicians choose between the various options, including medication, angioplasty, and surgery. Common prescription drugs used to help prevent stroke include antihypertensive agents (Gorelick PB et al 1999; Goldstein LB et al 2001), cholesterol lowering agents (statins), and antiarrhythmics to help control irregular heartbeats that might contribute to stroke risk. Angioplasty is a procedure in which a balloon is threaded into the artery and inflated rapidly, crushing the plaque against the arterial wall and opening the artery. The most common surgery used to prevent stroke is called carotid endarterectomy, in which the surgeon opens the arteries in the neck and strips away the inner lining of the artery.

While these strategies have been shown to work in specific circumstances, a common flaw also unites them: they are often used only after stroke risk has reached an unacceptable level. Life Extension prefers a much more proactive approach. By using advanced early screening tests to determine risk, then taking action to improve endothelial function and reduce blood risk factors (such as homocysteine and fibrinogen) and blood pressure, Life Extension seeks to maintain the lowest possible risk profile.

Diet. Multiple studies have found that a diet high in fruits and vegetables lowers risk of cerebrovascular disease and both ischemic and hemorrhagic stroke (Gariballa SE 2000; Sauvaget C et al 2003). Two major reviews recommended that public health policy promote increased dietary intake of antioxidant vitamin C, beta-carotene, vitamin E, B vitamins (including folate), potassium, calcium, magnesium, vitamin D, fiber, and omega-3 fatty acids to reduce risk of stroke (Gariballa SE 2000; Johnsen SP 2004). These vital nutrients can also be obtained through dietary supplements in conjunction with a healthy diet.

Nutritional Support for Healthy Arteries
Nutritional therapy in cerebrovascular disease associated with atherosclerosis has several interrelated goals. These include reversing endothelial dysfunction with nutrients that stimulate endothelial nitric oxide production, reducing inflammation, enhancing and restoring cerebral blood flow, and providing antioxidant support to reduce the level of damaging free radicals. A number of nutrients have been studied that often accomplish several of these goals.

The following nutrients protect the endothelium:

L-arginine. L-arginine is a basic amino acid found in many proteins and is essential to growth and maintenance in all vertebrates. There is evidence that L-arginine plays a major role in maintaining blood vessel dilation and reducing blood pressure, a major risk factor for stroke. L-arginine helps lower blood pressure by serving as a precursor to nitric oxide, which helps keep blood vessels dilated and blood flowing easily (Chionglo BM et al 2006; Boger RH et al 2005).
In an animal model of stroke, L-arginine was shown to induce an endothelium-dependent increase in cerebral blood flow (Willmot M et al 2005). Among humans, intravenous L-arginine has been shown to alleviate all stroke-like symptoms if administered within 30 minutes of their onset (Koga Y et al 2005). Another study showed that intravenous L-arginine given to patients undergoing carotid endarterectomy surgery was able to reduce the number of embolic signals (restrictions in blood flow) for up to 24 hours after the surgery (Kaposzta Z et al 2001). Although these results are encouraging, oral L-arginine has not been studied in human stroke patients—although human studies have been conducted in heart attack patients and patients with cardiovascular disease.

While the association between L-arginine and nitric oxide is clear, a few newer studies have suggested that supplemental L-arginine alone may not boost nitric oxide among patients who recently had a heart attack. One study from Johns Hopkins Medical Institutions in Baltimore was stopped after researchers found an increased risk of death in heart attack patients taking L-arginine. There are several possible reasons for this, including the important point that nitric oxide can generate free radicals. By generating production of nitric oxide, L-arginine can raise free radical levels. Life Extension, however, notes that studies questioning L-arginine’s effectiveness failed to provide the necessary antioxidants to counteract any elevation in free radicals caused by the supplement. Thus, Life Extension believes that any person taking L-arginine to lower blood pressure and improve blood flow should also take antioxidants, such as vitamin C and vitamin E.

Acetyl-L-carnitine. Acetyl-L-carnitine is a derivative of carnitine. It is involved in the transport of fatty acid across the cell membrane, and it is used as energy in the mitochondria of the cell (Rebouche CJ 2006). It also provides the acetyl component for the synthesis of acetylcholine, an important neurotransmitter. One study has shown evidence that among stroke patients, acetyl-L-carnitine has a beneficial effect on abstract and concrete thinking and memory. The study concluded that acetyl-L-carnitine possesses antioxidant activity that offers protection against lipid peroxidation (Suslina ZA et al 2003). Two other studies reported that large doses of intravenous acetyl-L-carnitine significantly improved cerebral blood flow in patients with chronic cerebrovascular disease who had experienced ischemic stroke (Postiglione A et al 1991, 1990).

Propionyl-L-carnitine. Like acetyl-L-carnitine, propionyl-L-carnitine plays an important role is fatty acid oxidation. Research has shown that propionyl-L-carnitine can help protect against endothelial dysfunction. One study in human endothelial cells showed that the carnitine derivatives stimulate the production of nitric oxide in the endothelium, which has an antioxidant, antiproliferative, and anti-inflammatory effect (Calo LA et al 2006). Another study found that propionyl-L-carnitine stimulated nitric oxide’s ability to relax hypertensive arteries in rats (Bueno R et al 2005).

The following nutrients enhance cerebral blood flow, reduce blood pressure, and reduce the size of stroke lesions:

Vinpocetine.
Vinpocetine has been widely studied for its ability to restore blood flow to the brains of stroke victims. It appears to have multiple effects that interfere with the ischemic cascade. Studies have shown that it reduces the depletion of adenosine triphosphate, which is the main cellular energy source, and functions as an antioxidant (Hadjiev D 2003; Vas A et al 2002). Recently, researchers have found that high-dose, intravenous vinpocetine (at doses up to 70 mg daily) is able to restore blood flow to the brain and reduce the size of ischemic stroke lesions, leading several researchers to identify vinpocetine as a potential therapy for the acute treatment of ischemic stroke (Szilagyi G et al 2005; Szapary L et al 2003; Dezsi L et al 2002). The protective effects are most pronounced in areas of the brain with the highest uptake (Szilagyi G et al 2005). These studies build on previous work showing that oral vinpocetine is also effective in enhancing cerebral blood flow (Dezsi L et al 2002).
CDP-choline. CDP-choline is a chemical compound present in a wide array of foods. It plays a life-sustaining role in the normal function of all cells and the structural integrity and signaling capacity of cell membranes, and it moves fats in and out of cells throughout the body (Zeisel SH et al 2006). More than 70 countries, including Japan, use CDP-choline as a prescription drug to treat stroke (Adibhatla RM et al 2005). It appears to have a neuroprotective and reparative effect on cerebral ischemic lesions, reducing the size of lesions during 12 weeks of treatment (Warach S et al 2000). Several additional studies indicate that CDP-choline leads to significant decreases in lesion size and can be used safely in acute stroke treatment (Clark WM et al 1997; Tazaki Y et al 1988). Regrettably, some U.S. studies failed to demonstrate efficacy, and the Food and Drug Administration did not approve it as a drug.
Potassium, calcium, and magnesium. Potassium can help lower blood pressure, decreasing risk of cerebrovascular disease and stroke (Sacks FM et al 2001; Suter PM 1999). Evidence has emerged that a balance of potassium, calcium, and magnesium may reduce platelet aggregation and improve insulin resistance. Other studies have shown that combining magnesium and calcium with potassium is more effective than any one of these supplements alone in reducing blood pressure, atherosclerosis, and risk of stroke (Ahsan SK 1998; Sacks FM et al 2001; Broadhurst CL 1997; Ravnskov U 1998; Gillman MW et al 1997; Ascherio A et al 1997; Tavani A et al 1997; Appel LK et al 1997).
Vitamin D.
There is evidence from clinical trials that vitamin D may play a modest role in blood pressure control and insulin metabolism, both important in slowing the progression of atherosclerosis and reducing risk of stroke (Dakshinamurti K et al 1996; Lind L et al 1995; Boucher BJ 1998). A recent study also showed that deficiencies in vitamin D and flavonoids may predict heart attack and stroke (Marniemi J et al 2005). This new finding is relevant because the NHANES III study, funded by the National Institutes of Health, estimated that 42 percent of African American women between 15 and 49 years of age and 32 percent of white men and women are vitamin D deficient. The overall average increases to 50 percent in the over-fifty population, and vitamin D deficiency is much higher than that in older people, who have decreased capacity to produce vitamin D from exposure to sunlight (Holick MF 2006).
Omega-3 fatty acids are another important nutrient for stroke victims and those at risk of stroke because of their ability to reduce inflammation. They are found in the oil of cold-water fish and in flaxseed oil. Most people get too much pro-inflammatory omega-6 fatty acids in their diet but not enough omega-3 fatty acids to balance the omega-6. The balance is essential in regulating blood pressure and also in reducing inappropriate platelet aggregation, inflammation, LDL, and other atherosclerosis risk factors (Knapp HR et al 1989; DeBusk RM 2000).

Randomized clinical trials have found that patients with high omega-3 fatty acid intake experienced decreased incidence of stroke (He K et al 2002; Jeerakathil TJ et al 2001). Omega-3 intake may also slow the progression of atherosclerosis (Kris-Etherton PM et al 2005). One study found that eating coldwater fish as little as once per month reduced risk of ischemic stroke (He K et al 2002). American Stroke Association data indicate that individuals may not get enough omega-3 fatty acids through diet alone; the association suggests that individuals who don’t should consider taking a supplement. Those who have high levels of triglyceride (blood fat) may need larger doses of fish oil supplements (more than 4 g daily) than normally recommended for general prevention purposes (Kris-Etherton PM et al 2005).

The following nutrients are antioxidants:

Coenzyme Q10.
Coenzyme Q10 (CoQ10) is a powerful antioxidant found in the energy-producing center of the body’s cells. It is involved in making the molecule known as adenosine triphosphate, which is the cell’s major energy source. CoQ10 provides several weapons against atherosclerosis and stroke; it prevents oxidation of LDL, reduces total cholesterol and triglyceride levels, improves insulin sensitivity, decreases glucose levels, and lowers blood pressure, among other things (Ernster L et al 1995; Digiesi V et al 1994, 1990; Langsjoen PH et al 1999; Morisco C et al 1993; Kontush A 1997). The primary food sources of CoQ10 are meat and seafood.

Green tea.
Green tea catechins, which are rich in flavonoids, possess powerful antioxidant properties that have been studied in the context of limiting damage due to ischemic stroke. Animal studies have shown that green tea extract limits the size of stroke lesions in a dose-dependent manner when administered immediately after an ischemic episode, leading researchers to suggest that green tea may have promise in the acute treatment of ischemic stroke (Suzuki M et al 2004; Lee SY et al 2003). Another study found that animals that had a high intake of green tea experienced less cerebral damage after a stroke than did their counterparts who weren’t consuming green tea (Hong JT et al 2001).
Beta-carotene.
Beta-carotene is an antioxidant. Large long-term studies have found that daily dietary intake of beta-carotene plays a protective role against atherosclerosis and decreases risk of ischemic stroke (Hak AE et al 2004; Hirvonen T et al 2000). Rich sources of beta-carotene include carrots, squash, green leafy vegetables, milk, lean meat, fish, and poultry.
Vitamin C.
Vitamin C, also known as ascorbic acid, is a water-soluble antioxidant that protects other compounds from oxidation by being oxidized itself. While it has been shown to lower blood pressure (Duffy SJ et al 1999), other long-term follow-up studies in human beings have found that vitamin C also reduces risk of cardiovascular and heart disease and stroke (Simon JA 1992; Enstrom JE et al 1992; Gale CR et al 1995). A small, well-designed study also found that giving antioxidant vitamins, particularly vitamin C, within 12 hours of an ischemic stroke increased antioxidant capacity, reduced inflammation, and reduced the oxidation of dangerous lipids (Ullegaddi R et al 2005). An earlier, 20-year follow-up study reported that higher vitamin C concentrations reduced incidence of both ischemic and hemorrhagic stroke (Yokoyama T et al 2000). Another study examined the benefit of vitamin C in overweight men with high blood pressure and found that low plasma levels of vitamin C were associated with increased risk of stroke (Kurl S et al 2002).
Although vitamin C provides cerebrovascular benefits when taken alone (Hirvonen T et al 2000), studies have shown that it may be more powerful when combined with other nutrients, vitamins, minerals, and antioxidants (Galley HF et al 1997; Sacks FM et al 2001; Fotherby MD et al 2000; Toivanen JL 1987; Hajjar IM et al 2001).

Vitamin E.
Vitamin E is an antioxidant. It regulates oxidation reactions and protects polyunsaturated fatty acids and vitamin A. A large study supplying people with foods that have high levels of vitamin E (plant oils, green leafy vegetables, whole grains, butter, liver, egg yolk, milk, nuts, and seeds) found that higher intake of vitamin E helped reduce risk of death from stroke (Yochum LA et al 2000). Another study reported that eating foods high in antioxidant vitamins C and E helped lower the incidence of stroke, especially notable in smokers (Voko Z et al 2003).
A study from Helsinki looked at vitamin E supplementation in high-risk individuals with high blood pressure and concluded that although vitamin E supplementation may increase the risk of hemorrhagic stroke, this small risk was outweighed by its protective effect against ischemic stroke (Leppala JM et al 2000). Studies have also shown benefits of vitamin E in improving insulin sensitivity and glucose metabolism, thereby lowering risk of atherosclerosis and stroke (Barbagallo M et al 1999).