Cerebral Vascular Disease, Stroke, Cerebral Aneurysm, Vascular Disease – Part A
25th June 2007 by Arrow Durfee Posted in Uncategorized
Cerebral Vascular Disease from Life Extension Foundation
Thrombotic (Ischemic) Stroke, Hemorrhagic Stroke, and Cerebral Aneurysm
A cerebral vascular event (stroke) is defined as a sudden neurological deficit in the brain caused by either ischemia (a lack of blood supply to the brain) or a hemorrhage: 80% of all strokes occur due to arterial blockage (ischemia), and 20% occur due to bleeding (hemorrhage). Hemorrhagic strokes are classified as either occurring within the brain tissue (intracerebral or intraparenchymal) or around the brain tissue (subarachnoid).
Incidence and Epidemiology
Stroke is the leading cause of disability in the United States and the third leading cause of death. While it was originally estimated that annual stroke incidents were approximately 550,000 cases, a study in 1998, through more rigorous counting in all racial and ethnic groups, increased the yearly estimate to 731,000 cases (Broderick et al. 1998). This study showed that African Americans have a higher stroke incidence and stroke mortality than other racial groups.
Women have lower stroke rates than men at all age ranges except 75 years and older, when stroke rates are at their highest. It is of concern that the overall declining rate of stroke-related deaths slowed over the past several decades and leveled off in the 1990s (Gillum 1999).
Individual approaches for the management of ischemic and hemorrhagic stroke are discussed under Thrombotic Stroke and Hemorrhagic Stroke in this protocol. Also, the terms thrombotic and ischemic stroke will be used interchangably.
Prognosis and Recovery
In spite of conventional advancement in acute stroke care, the majority of stroke survivors remain permanently partially disabled with neurological symptoms and limitations. While most patients develop some improvement, it is rarely complete. The more severe the initial stroke, the greater the chance of long-term disability. Recovery also varies depending on the size and location of the infarction or hemorrhage. Small infarctions, especially multiple small stroke sites, may result in little disability, whereas large infarctions may cause severe permanent disability.
It is interesting that other related conditions such as high blood pressure do not appear to affect recovery. However, younger patients have a better prognosis than older patients. Overall there is marked variability in recovery, making early disability predictions difficult. In general, recovery is greatest in the first 3 months and rarely occurs beyond 1 year after the stroke. This makes it essential that speech therapy, physical therapy, and occupational therapy be instituted as soon as possible after the stroke occurs and continued three to five times weekly throughout the first year of recovery. All too often, rehabilitative therapy is too infrequent and is stopped prematurely preventing optimal recovery.
Recovery from strokes is relatively poorly understood. While infarcted brain tissue is not able to repair itself, recovery has been theorized to occur by recruiting neighboring neurons (nerve cells) to serve new or additional functions. It is fascinating that electrical brain mapping in monkeys has demonstrated that the cerebral cortex can be functionally reorganized during recovery after an infarction (Nudo et al. 1996). In fact, MRIs in humans have shown increased activity in both hemispheres as patients improve after a stroke. This suggests recruitment of neighboring neurons as well as the corresponding larger regions of the cortex (Cramer et al. 1997).
If you or someone with you is possibly having a stroke, respond immediately! The time it takes to receive treatment is as important to stroke victims as it is for those who are having a heart attack. Not recognizing the symptoms of a stroke, or believing that stroke is untreatable, causes many people to fail to respond to the warning symptoms of stroke and to not seek immediate medical attention.
Regardless of whether the stroke is thrombotic (caused by a clot) or hemorrhagic, management at the onset is considered an acute medical emergency. Stroke patients receiving medical care within 6 hours of the onset of symptoms have a 32% greater chance for a reduced hospital stay (13 days versus 19 days) than those treated after this period (Davalos et al. 1995). Amazingly, 42% of stroke patients wait as long as 24 hours before presenting for medical treatment. That is 21 hours too late! The delay in presenting at the emergency room results in a missed opportunity to effectively treat, and possibly reverse, the damage caused by thrombotic stroke. According to one study, “patients with milder symptoms, for whom treatment might be more effective, were less likely to arrive in time for therapy” (Alberts et al. 1990).
From a preventive medicine and patient education perspective, it is therefore crucial that healthcare providers educate at-risk patients and their families about stroke-related symptoms and encourage them to call 911 if stroke symptoms occur. It is equally crucial that optimal emergency room intervention and treatment occur as soon as the patient arrives in the hospital emergency room.
From the time the patient arrives at the emergency room (ER) triage desk, a computerized tomography (CT) scan should be authorized as soon as possible (within 5 minutes). Multiple timely interventions are crucial in the acute emergency room. These vary based on a range of findings including the patient’s temperature, oxygen saturation, blood pressure, glucose levels, complete blood count, electrocardiogram, airway and pulse, medical history, and hydration status. Inclusion and exclusion criteria are reviewed for the consideration of intravenous (IV) thrombolytic therapy if a thrombotic CT scan pattern is identified. The CT scan is further reviewed distinguishing a thrombotic stroke from an intracranial or a subarachnoid hemorrhage. A neurosurgeon will be consulted if an aneurysm or blood pooling is present due to an intracranial hemorrhage. Surgery may be necessary for the evacuation of a hematoma (blood pooling from a hemorrhage). In the intensive care department, blood perfusion (hemodynamics) is continually monitored and assessed. Secondary stroke prevention is initiated based on National Institutes of Health (NIH) guidelines. The treatment of stroke patients in dedicated stroke units has been shown to reduce morbidity, mortality, and disability as well as other post stroke complications (Indredavik et al. 1999).
The sudden onset of neurological signs and symptoms developing over a few minutes or few hours are indicative of a stroke event. Most of these strokes will be ischemic, involving a thrombus (clot), rather than hemorrhagic. However, any of the following symptoms can result from a clot or bleed, depending upon the arteries in the brain involved in the stroke and their location.
According to the National Stroke Association (1999), strokes more often occur abruptly, with the following symptoms which often develop suddenly:
Difficulty standing or walking, dizziness, loss of balance, loss of coordination
Numbness in the face, arm or leg weakness, particularly on one side of the body
Confusion, difficulty speaking or understanding
Vision difficulty in one or both eyes
Severe headaches that have no known cause
Other important, but less common stroke symptoms include:
Nausea, fever, and vomiting that is different from a viral illness in the speed of onset (begins in minutes or hours instead of over several days)
Normal Functional Areas of Brain
The brain has two sides: a right hemisphere that controls the left side of the body and a left hemisphere that controls the right side of the body. Each hemisphere has four lobes and a cerebellum that control our daily functions. Depending on what part of the brain has been affected, stroke victims experience a variety of neurological deficits. Rehabilitation is crucial to the stroke patient’s recovery. Physical therapists and speech therapists help patients “relearn” their lost functions and devise ways to cope with the loss of those they cannot regain. (Anatomical Chart Company 2002®, Lippincott Williams & Wilkins)
A brief loss of consciousness or a period when there is a reduced level of consciousness (sudden fainting, increased confusion, convulsion, or coma)
Any of these signs may be only temporary and may last only a few minutes.
Hemorrhagic Stroke Symptoms
When a bleed occurs, causing a stroke, the symptoms are less abrupt over one or several hours. The most commonly associated symptoms include headaches, vomiting, and altered states of consciousness.
Cerebral Embolism Symptoms
Symptoms vary further depending upon the nature of the developing stroke. If the stroke is caused by a thrombus (clot) suddenly passing into arteries in the brain (cerebral embolism), the symptoms are of rapid onset, often intensifying over a few seconds, causing headaches on the affected side, seizures, or both. There is often a preexisting heart disease, such as mitral stenosis or atrial fibrillation, endocarditis (an inflamed heart), or a mitral valve prolapse, in which stagnant blood has had the chance to clot and then pass from the heart suddenly into arteries of the brain, blocking blood flow to the brain.
Cerebral Thrombotic Stroke Symptoms
When a cerebral artery becomes blocked from the progressive worsening of a localized clot or a hardened artery in the brain, the symptoms develop over minutes or hours and sometimes over days or weeks. Common causes include gradual hardening and narrowing of cerebral arteries (atherosclerosis) often associated with hypertension, diabetes, coronary artery disease, peripheral vascular disease, or head trauma.
Transient Ischemic Attacks
Often patients can experience temporary symptoms that are associated with a lack of adequate blood supply to the brain. These episodes are known as transient ischemic attacks (TIAs). When TIA-related symptoms occur, they occur suddenly and last from 5 minutes to several hours and then resolve completely. These symptoms are often due to reduced circulation and blood supply from the two main arteries leading into the brain–the carotid arteries located in the neck supply the brain from the front, and the vertebrobasilar arteries supply the brain from the back, passing through holes in the vertebrae of the cervical spine.
The peak age of onset for TIAs is 60-70 years of age. It is interesting that a third of the time, TIAs will lead to a subsequent stroke; a third of the TIAs continue and do not lead to a stroke; and a third of the time TIAs spontaneously remit and no longer occur.
It is commonly agreed that TIAs are due to microembolization (small clots moving into the brain), excessive platelet aggregation, or from ulcerations in the walls of atheromatous hardened arteries. Other causes include transient episodes of low blood pressure due to dehydration or adrenal insufficiency, mechanical kinking of arteries in the head and neck during head rotation, cervical spine bone spurs compressing the vertebrobasilar artery, or heart arrhythmias.
TIA symptoms are artery-location dependent. Here is a list of the arteries and brain regions that may be temporarily restricted in blood supply and the associated symptoms that develop.
Location Related Symptoms
Carotid artery Effects retina, cerebral hemisphere, or both.
Retinal Transient blackouts; the sense of a shade pulled over the eyes.
Cerebral Contralateral (opposite sided) paralysis of a single body part; paralysis of one side of the body; localized tingling, numbness; hemianopic visual loss; aphasia (loss of speech); rare loss of consciousness.
Vertebrobasilar Bilateral visual disturbance including dim, gray, or blurred vision or temporary total blindness; diplopia (double vision).
Labyrinth/medulla Vertigo; unsteadiness; nausea; vomiting.
Brainstem Slurring dysarthria (tongue weakness causing impaired speech); dysphagia (difficulty swallowing); numbness, weakness; all four limb paresthesia; drop attacks from sudden loss of postural tone are basilar in origin; a vertebrobasilar artery occlusion episode causes symptoms to be induced by abrupt position changes.
syndrome Symptoms of claudication (lameness or limping) of an exercised arm with symptoms of vertebrobasilar insufficiency described above.
Ischemic, Thrombotic, Embolic, and Transient Ischemic Attack
In this section, we will discuss methods of preventing primary and secondary thrombotic (ischemic) strokes, along with approaches to restoring function to brain cells that are damaged by a thrombotic stroke (i.e., inducing or accelerating rehabilitation, or both). Because some people may refer to this protocol if they have symptoms of an acute stroke, we will begin with the initial steps involved in diagnosis and immediate treatment.
Aggressive Stroke Therapy
Healthcare providers still do not treat stroke as aggressively as they do heart attack. Many therapies that are proven to work are not made available to the acute stroke patient presenting in the emergency room.
Further contributing to stroke deaths is the belief by many healthcare providers that stroke is untreatable, leading to an attitude of “watchful waiting” with an onset of a stroke instead of being focused on treating the stroke as a medical emergency. The National Stroke Association has described this opinion as being an outdated attitude that serves as the largest obstacle to effective prevention and emergency treatment of strokes.
The use of CT and Doppler ultrasonography has made radical changes in early diagnosis of ischemic and hemorrhagic strokes (Wintermark et al. 2002). These advances have resulted in declines in stroke mortality. In the 1980s, the development of magnetic resonance imaging (MRI) further improved evaluation of persons with cerebrovascular disease (Hesselink 1986; Welch et al. 2000).
Tissue Plasminogen Activator
The FDA approved the use of a tissue plasminogen activator (t-PA) in June 1996 to treat strokes. t-PA had already been approved to dissolve clots that occur in the coronary arteries (which cause an acute heart attack), but the FDA has delayed approving t-PA to treat ischemic stroke for many years. Millions of cases of death and permanent paralysis occurred because of the FDA’s delay in approving t-PA in treating stroke caused by abnormal blood clotting in the brain’s arteries. Physicians affiliated with the Life Extension Foundation were using t-PA in emergency rooms to treat ischemic stroke years before the FDA gave its official seal of approval.
t-PA (sold under the brand name Activase) should be administered immediately (or within 3 hours) after a stroke to dissolve the clot that is preventing blood from reaching a portion of the brain. t-PA is a natural clot-dissolving substance produced by the body and can literally “blow open” the blood clot in the brain that is causing the acute ischemic brain damage characteristic of a stroke. However, it is crucial that the attending physician review all of the inclusion and exclusion criteria associated with the use of t-PA in advance of its administration. Examples of exclusion criteria making t-PA absolutely contraindicated include an intracranial mass or hemorrhage; very low or high glucose; a previous stroke or head trauma within the last 3 months; current use of anticoagulant drugs; a seizure at the onset of the stroke; major surgery within the last 2 weeks; low platelets; gastrointestinal hemorrhage within the last 3 weeks; blood pressure greater than 185/110; or a previously known cerebral aneurysm (Adams et al. 1996).
One study has shown that 30% more stroke victims were able to regain full use of their faculties after receiving t-PA. In this study 45% of the stroke victims had a good result, defined as “complete regression or slight neurological sequelae.” The subgroups with poor prognosis outcomes in three parameters showed a good outcome in 30% of those patients with each of these characteristics (Trouillas et al. 1998). Even today, patients may encounter extreme resistance from emergency room physicians who are reluctant to administer it (Alberts 1998), even if a patient’s life is at stake. In some cases, surgery may be required to remove any blockage of blood vessels going to the brain because it is important to get the blood circulating to the brain.
While t-PA can dissolve the blood clot that causes a blood vessel blockage, there are other complications that occur during ischemic stroke that have to be addressed if permanent brain damage is to be prevented. Any interruption in blood flow causes an oxygen imbalance that results in massive free-radical damage. It is critically important to have antioxidants in your bloodstream when t-PA is administered to reduce the free-radical damage that will occur when blood flow is restored (Ozmen et al. 1999).
Heparin is a natural polysaccharide normally found in mast cells. Heparin increases the activity of antithrombin III, preventing the conversion of fibrinogen to fibrin. Heparin must be administered parenterally (by IV) because it is not absorbed in the GI tract. Because of this, heparin may be used in acute care situations, but not usually in stroke prevention.
Debilitating strokes depicted on television shows or in movies have severe symptoms. Most strokes, however, are not as dramatic. Often the symptoms are minor and transient and may be ignored or dismissed as unimportant. Over time these silent strokes lead to memory loss and other neurological problems. According to one study, by the time people reach their 70s, one in three has a silent stroke every year (Leary 2001).
Of particular concern to stroke victims is that silent strokes occur frequently, causing neurological damage days or weeks after the initial crisis. A 2001 study found that one fourth of stroke survivors had at least one silent stroke during the 2 years following their initial stroke (Corea et al. 2001).
The Underlying Causes
We usually consider a heart attack a life-or-death health event. Strokes have been given less attention, but the realization that stroke is an acute event has now led to stroke being referred to as a brain attack. Thrombotic strokes are a major cause of brain attacks and are caused in part by atherosclerosis, hypertension, and procedures that cause abnormal arterial blood clot formation (thrombosis), such as atrial fibrillation and heart valve replacement.
As with almost all cardiovascular disease, strokes are generally the result of several underlying diseases which result in stopping or reducing the flow of blood to the brain.
The majority of strokes occur when a blood clot blocks the flow of oxygenated blood to a portion of the brain. This type of stroke, caused by a blood clot blocking or “plugging” a blood vessel, is called ischemic stroke. An ischemic stroke can be caused by a blood clot that forms inside the artery of the brain (a thrombotic stroke) or by a clot that forms somewhere else in the body and travels to the brain (an embolic stroke). In healthy individuals, blood clotting is beneficial. When you are bleeding from a wound, blood clots work to stop the bleeding. In the case of ischemic stroke, abnormal blood clotting blocks large as well as small arteries in the brain, cutting off blood flow and resulting in a clinical diagnosis of ischemic, thrombotic, or embolic stroke.
Ischemic strokes account for 80% of all strokes and occur as either an embolic or thrombotic stroke. Thrombotic strokes represent 52% of all ischemic strokes. Thrombotic strokes are caused by unhealthy blood vessels becoming clogged with a buildup of fatty deposits, calcium, and blood-clotting factors such as fibrinogen and cholesterol. We generally refer to this as atherosclerotic disease. Simplistically, what happens with a thrombotic stroke is that our bodies regard these buildups as multiple, infinitesimal, repeated injuries to the blood vessel wall. Our own bodies react to these injuries, just as they would if we were bleeding from a small wound, and they respond by forming blood clots. Unfortunately, in the case of thrombotic strokes, these blood clots get caught on the plaque on the vessel walls and reduce or stop blood flow to the brain. That is when we experience a brain attack.
Two types of thrombosis can cause a stroke: large vessel thrombosis and small vessel disease. Thrombotic stroke occurs most often in the large arteries, magnifying the impact and devastation of disease. Most large vessel thrombosis is caused by a combination of long-term atherosclerosis followed by rapid blood clot formation. Many thrombotic stroke patients have coronary artery disease, and heart attacks are a frequent cause of death in patients who have suffered this type of brain attack.
The second type of thrombotic stroke is small vessel disease which occurs when blood flow is blocked to a very small arterial vessel. Little is known about the specific causes of small vessel disease, but it is often closely linked to hypertension and is an indicator of atherosclerotic disease.
In an embolic stroke, a blood clot forms somewhere in the body (usually the heart) and travels through the bloodstream to the brain. Once in the brain, the clot eventually travels to a blood vessel small enough to block its passage. The clot lodges there, blocking the blood vessel and causing a stroke.
The risk factors for thrombotic stroke are the presence of hypertension, atherosclerosis, high LDL-cholesterol, excessive blood-clotting factors (such as fibrin and fibrinogen), heart valve defects, diabetes, and aging. High serum levels of homocysteine, fibrinogen, or C-reactive protein may be the strongest predictive risk factors.
A 30-year study of male twins showed that elevated blood pressure in midlife predisposed men to an increase in stroke later in life. Men with even mildly elevated blood pressure 25 years before showed smaller brain volumes and more strokes compared to their twin brothers who did not have the elevation in blood pressure (DeCarli et al. 1999). This study in the journal Stroke emphasized the importance of aggressively treating elevated blood pressure even if it is not grossly abnormal (refer to the Cardiovascular Disease protocol for information about blood pressure control therapies and diets).
Uncontrollable Risk Factors
Increasing age. The chance of having a stroke more than doubles for each decade of life after age 55. While strokes are common among the elderly, substantial numbers of people less than 65 also have strokes.
Gender. Overall, men have about a 19% greater chance of a stroke than women. Among people under age 65, the risk for men is even greater when compared to that of women.
Family history. The chance of a stroke is greater in people who have a family history of strokes.
Race. African Americans have a much higher risk of death and disability from a stroke than Caucasians, in part because African Americans have a greater incidence of high blood pressure.
Diabetes mellitus. Diabetes is an independent risk factor for stroke and is strongly correlated with high blood pressure. While diabetes is treatable, having it still increases a person’s risk of a stroke. People with diabetes often also have high cholesterol and are overweight, increasing their risk even more.
Controllable Risk Factors
High blood pressure. High blood pressure is the most prominent risk factor for stroke. In fact, stroke risk varies directly with blood pressure. More widespread treatment of high blood pressure is a key reason for the decline in the death rates for strokes.
High blood levels of homocysteine, C-reactive protein, or fibrinogen. The safe ranges of these blood indicators will be described later in this protocol, along with steps that can be taken if excess levels of these stroke risk factors are detected.
Heart disease. A diseased heart increases the risk of a stroke. In fact, people with heart problems have more than twice the risk of a stroke as those with a heart that works normally. Atrial fibrillation (the rapid, uncoordinated beating of the heart’s upper chambers), in particular, raises the risk for stroke. Heart attack is also the major cause of death among survivors of a stroke.
High cholesterol. High cholesterol can directly and indirectly increase stroke risk by clogging blood vessels and putting people at greater risk of coronary heart disease, another important stroke risk factor.
Sleep disordered breathing. Sleep apnea is a major cardiovascular and stroke risk factor, increasing blood pressure rates, which may cause stroke or heart attack. Studies also indicate that people with sleep apnea develop dangerously low levels of oxygen in the blood while carbon dioxide levels rise, possibly causing blood clots or even strokes to occur. Diagnosing sleep apnea early may be an important stroke prevention tool.
Prior stroke. The risk of a stroke for someone who has already had one is several times that of a person who has not.
Carotid artery disease. The carotid arteries in your neck supply blood to your brain. A carotid artery damaged by atherosclerosis (a fatty buildup of plaque in the artery wall) may become blocked by a blood clot which may result in a stroke. If you have a diseased carotid artery, your healthcare provider may hear an abnormal sound in your neck (called a bruit) when listening with a stethoscope.
Transient ischemic attacks (TIAs). TIAs are mini-strokes that produce stroke-like symptoms, but no lasting damage. They are strong predictors of a stroke. A person who has had one or more TIAs is almost 10 times more likely to have a stroke than someone of the same age and sex who has not.
TIAs are extremely important stroke warning signs. Do not ignore them!
High red blood cell count. A moderate or marked increase in red blood cell count is a risk factor for stroke. The reason is that more red blood cells thicken the blood and make clots more likely.
Cigarette smoking. Studies have shown cigarette smoking, including secondhand cigarette smoke, to be an important risk factor for stroke. The nicotine and carbon monoxide in cigarette smoke damage the cardiovascular system in many ways. The use of oral contraceptives combined with cigarette smoking also greatly increases stroke risk.
Excessive alcohol intake. Excessive drinking (an average of more than one drink a day for women and more than two drinks per day for men) and binge drinking can raise blood pressure; contribute to obesity, high triglycerides, cancer, and other diseases; and cause heart failure, leading to stroke.
Weight. Excess weight puts a strain on the entire circulatory system. It also makes people more likely to have other stroke risk factors such as high cholesterol, high blood pressure, and diabetes.
Other potential risk factors
Geographic location. Stroke is more common in the southeastern United States than in other areas. These are the so-called stroke belt states. The age-adjusted death rates from a stroke are much higher in these states than in the rest of the country.
Season and climate. Stroke deaths occur more often during periods of extremely hot or cold temperatures.
Socioeconomic factors. There is some evidence that people of lower income and educational levels have a higher risk for stroke.
Certain kinds of drug abuse. IV drug abuse carries a high risk of stroke from cerebral embolisms. Cocaine use has been closely related to strokes, heart attacks, and a variety of other cardiovascular complications. Some of them have been fatal even in first-time cocaine users.
Recognizing stroke symptoms and realizing that the symptoms require immediate emergency treatment can save your life!
There are conventional drugs that can be prescribed to reduce the risk of a second stroke:
Appropriate treatment of hypertension (high blood pressure) clearly reduces the risk of stroke. Refer to the Hypertension section of the Cardiovascular Disease protocol for information about controlling blood pressure that your physician may be overlooking.
Low-dose aspirin is considered first-line therapy for the stroke prevention in those with high risk.
Anticoagulant drugs such as Coumadin (warfarin) interfere with the initiation of the coagulation cascade and significantly reduce the risk that a blood clot will form. Coumadin is so side-effect prone that it is reserved for extremely high-risk individuals such as those with mechanical aortic valve replacements.
Antiplatelet drugs such as Ticlid (ticlopidine) or Trental (pentoxifylline) inhibit platelet aggregation, thereby reducing the risk of a new blood clot forming in the brain.
The use of anticoagulant drugs involves frequent blood testing and adjusting of dose because the anticoagulating response to these drugs varies between individuals. These drugs do not do anything to the clots that may already have been formed. The side effects of anticoagulant drugs mandate careful monitoring, and some people avoid these drugs because of the risk of serious side effects.
A more benign approach is to combine aspirin with nutrients like ginkgo biloba, melatonin, fish oil, garlic, and green tea extract that are relatively free of side effects. A discussion of the pros and cons of Coumadin versus aspirin therapy can be found in the Thrombosis Prevention protocol. Those at very high risk for developing a blood clot often have to take Coumadin.
Low-dose aspirin is the antiplatelet agent of choice for stroke prevention. Doses of 160-325 mg daily administered within 48 hours of stroke onset have been shown to significantly reduce the risk of recurrent stroke during the first 2 weeks and possibly improve outcome at 6 months (CASTCG 1997; IST 1997). The Second European Stroke Prevention Study reported risk reductions for aspirin treatment, when compared with a placebo, to be as high as 27.6% (Sivenius et al. 1999).
Aspirin has shown such a potent effect in preventing strokes that the use of anticoagulants such as heparin to treat ischemic strokes decreased from 1985-1990, whereas the use of aspirin increased by more than 50% as reported in the Minnesota Stroke Survey, reported in the Journal of Stroke and Cerebral Diseases (McGovern et al. 1996).
An article in the journal Thrombosis Research described a study on patients who had survived a stroke or TIA. The research showed that the use of a low-dose aspirin (50 mg) reduced the incidence of stroke by 18-28% when study participants consumed aspirin over a period of time (Investigators 1998).
One of the main side effects of aspirin is unwanted bleeding. Tinnitus can also occur at high doses (Day et al. 1989). Aspirin is contraindicated for those at high risk of hemorrhagic stroke. Many health-oriented people are taking aspirin in combination with natural platelet aggregation inhibitors including vitamins C and E, bromelain, garlic, ginkgo biloba, curcumin, St. John’s wort, green tea, policosanol, vinpocetine (periwinkle), and fish oils. It is important to monitor template bleeding time to ensure stable blood thinning effects are consistent while avoiding fluctuations in platelet aggregation that may increase the risk of hemorrhagic stroke. The template bleeding time test is described later in this protocol.
Aspirin is considered by many to be a miracle drug and may have many undiscovered health benefits. Aspirin inhibits prosta n glandin E2 and C-reactive protein, both of which have been linked to many chronic inflammatory conditions (Ikonomidis et al. 1999).
Warfarin (Coumadin) is the most commonly prescribed drug for thrombosis prophylaxis (prevention) in very high-risk individuals. Its uses include prophylaxis for myocardial infarction, stroke, arterial thromboembolism, and deep venous thrombosis. Warfarin is also used in patients with prosthetic (artificial) heart valves.
Warfarin was originally isolated from sweet clover in 1939. It is the active ingredient in commercial rat poison and insecticide. Warfarin interferes with the synthesis of vitamin K which forms several essential coagulation factors. Warfarin prolongs prothrombin time (PT) and thromboplastin time (APTT). Prothrombin time is used to guide treatment. The International Normalization Ratio (INR) is becoming the new standard to monitor anticoagulation treatment.
Side-Effects and Contraindications for Warfarin
Bleeding is the primary adverse effect of warfarin therapy and is related to the intensity of anticoagulation, length of therapy, the patient’s underlying clinical state, and the use of other drugs that may affect blood coagulation or interfere with warfarin’s metabolism.
Minor bleeding complications include bleeding from mucous membranes, subconjunctival hemorrhage (bleeding under the mucous membranes covering the eyes and inner eyelids), hematuria (blood in the urine), epistaxis (nosebleed), and ecchymoses (purple patches on the skin).
Major bleeding complications include bleeding from the gastrointestinal tract, intracranial bleeding, and retroperitoneal bleeding. Massive hemorrhage usually involves the gastrointestinal tract, but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites.
Warfarin (Coumadin) has an extremely long list of contraindications and drug interactions (see below). Of particular concern is its use in elderly patients because they are more susceptible to the effects of anticoagulants and have an increased possibility of hemorrhage.
Warfarin is contraindicated in alcoholism, aneurysm, breast-feeding, the elderly, endocarditis, hemophilia, hemorrhage, hepatic disease, hypertension, intramuscular injections, leukemia, lumbar puncture, peptic ulcer disease, pericardial effusion, polycythemia vera, pregnancy, protein C deficiency, protein S deficiency, psychosis, surgery, vasculitis, vitamin C deficiency, and vitamin K deficiency.
Warfarin interacts with a large number of common drugs, including acetaminophen, aspirin, barbiturates, some antibiotics, estrogens, ethanol, heparin, influenza virus vaccine, lovastatin, NSAIDs, oral contraceptives, thrombolytic agents, and thyroid hormones. Your physician must be informed of all prescription and over-the-counter medications you are taking before beginning warfarin therapy.
Adverse side effects to warfarin include agranulocytosis, alopecia (hair loss), anorexia, bone loss, bleeding, chondrodysplasia punctata, cleft palate, diarrhea, exfoliative dermatitis, fetal abortion, intracranial hemorrhage, intraocular hemorrhage, leukopenia, nausea/vomiting, pruritus (itching), purple-toe syndrome, skin necrosis, and urticaria.
Warfarin may interact with natural platelet aggregation inhibitors including those mentioned earlier for aspirin. It is important to monitor template bleeding times to ensure stable blood thinning effects are consistent with supplementation to avoid fluctuations in platelet aggregation.
Combining Coumadin with Antiplatelet Therapies
A patient taking Coumadin has to be concerned that any food, drug, nutrient, or other substance that he puts into his body may not only increase the bleeding time, but also affect Coumadin metabolism, which may either increase or decrease the effect of Coumadin on the INR. The inherent variability that occurs in each individual taking Coumadin makes it difficult to provide general guidance. For instance, the underlying medical condition determines the degree of desired anticoagulation. No studies have correlated optimal anticoagulant doses of Coumadin (as measured by the INR blood test) with optimal doses of multiple antiplatelet agents (as measured by the template bleeding time [TBT]). The TBT is done in a physician’s office. A template device nicks the skin and the number of minutes it takes for blood flow to stop is assessed by a nurse or lab technician. The normal template bleeding time is up to 9 minutes. A bleeding time (BT) of 4-5 minutes might indicate increased thrombotic risk, while a bleeding time over 9 minutes may indicate an increased hemorrhagic risk. However, what is really important in this setting is the patient.
As it relates to antiplatelet agents such as fish oil and garlic, a BT of 4-5 minutes could suggest a benefit of taking higher amounts of these agents, whereas a BT over 9 minutes in a patient already on an antiplatelet agent might indicate that antiplatelet agent doses are having a biological effect and further dose increases should be avoided. The problem patients face today is that there are no standards that document the ideal balance between Coumadin and antiplatelet agents such as fish oil, garlic, vitamin E, and so forth. Too much Coumadin or antiplatelet agents can cause hemorrhage, whereas too little Coumadin or antiplatelet agents can cause thrombosis. In this context, as with many medical issues, balance is the key concept. The approach that a meticulous physician uses to achieve this balance is called titration. There is an art to titrating doses to a point where the happy medium is reached.
In an ideal setting, a physician would carefully monitor the INR and the template bleeding time to precisely measure the optimal level of anticoagulant and antiplatelet agents, respectively, in an individual patient. For instance, a patient with a heart valve replacement may have a desired INR range of 2.5-3.0, while an optimal template bleeding time may be between 7-9 minutes. If these tests were routinely conducted, a more scientific determination of the ideal intake of Coumadin, fish oil, garlic, vitamin E, and other supplements could be made.
An example of why prothrombin time (the result is presented as an INR) and template bleeding time testing are so important can be seen in a scenario of a patient taking Coumadin for one medical problem while at the same time using nutrients such as coenzyme Q10 (CoQ10) and fish oil for other medical conditions. A person who has congestive heart failure (a common complication with valve replacement) may require supplemental CoQ10 to improve cardiac function, for example, cardiac output. CoQ10 enhances the energy-producing organelles called mitochondria to more effectively produce energy within heart muscle (Rosenfeldt et al. 2002). Coumadin is being utilized to prevent a clot from forming on the donated heart valve which could break off, enter the blood circulation, and lead to a cerebral vascular accident (CVA)–what is commonly called a stroke.
In this same patient, CoQ10 is being used to optimize heart muscle performance to improve the heart’s function as a pump. CoQ10 is also helping this patient by preventing oxidation of LDL cholesterol which is felt to be part of the pathogenesis of vascular disease. In the context of this patient, the valve replacement surgery inflicts massive trauma on the body that can result in a chronic systemic inflammatory syndrome. High-dose fish oil and gamma-linolenic acid (GLA) can help suppress pro – inflammatory cytokines that are the underlying causes of so much degenerative disease. If periodic TBT tests are performed and Coumadin dosing is being properly titrated via the INR, then one can optimally adjust the antiplatelet agent (fish and borage oil) dose to guard against excess bleeding. The TBT test combined with the INR test would theoretically enable patients to take supplements they may need to sustain life (CoQ10), optimize the use of Coumadin, and reduce the risk of hemorrhage. The end result is therapy with an improved therapeutic index for the patient. This is an example of how listening to the biology of vital processes can enhance the quality and quantity of life.
Ticlopidine (Ticlid) inhibits platelet aggregation by interfering with the binding of fibrinogen to the platelet membrane. Ticlopidine is a prescription drug that may be of value as an alternative to aspirin. Ticlopidine is often considered in patients that have a high risk of thrombotic stroke and are intolerant of aspirin.
Ticlopidine is contraindicated in blood disorders such as hemorrhage, coagulopathy, intercranial hemorrhage, neutropenia, and thrombocytopenia. It is not used before surgery. Ticlopidine is also contraindicated in hepatic (liver) disease and hypercholesterolemia.
Ticlopidine has drug reactions with antacids, anticoagulants, aspirin, cimetidine, cyclosporine, digoxin, theophylline and thrombolytic agents.
Ticlopidine has a large number of side effects, including agranulocytosis, anemia, arthropathy, cholestasis, diarrhea, dyspepsia, elevated hepatic enzymes, hemolysis, hepatitis, hypercholesterolemia, hyponatremia, interstitial pneumonitis, jaundice, nausea or vomiting, nephrotic syndrome, neutropenia, pancytopenia, peripheral neuropathy, pruritus, purpura, serum sickness, throm-bocytopenia, thrombotic thrombocytopenic purpura (TTP), and urticaria vasculitis.
An analysis of 18 trials documented a 23% reduction in stroke risk with antiplatelet agents. The drug ticlopidine was found to be the most effective antiplatelet agent, but its adverse side effects frequently restrict its long-term use (Albers 1995).
A review of clinical trials compared aspirin and ticlopidine. Ticlopidine was found to be modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk, but there is uncertainty about the size of the additional benefit. Ticlopidine was associated with less gastrointestinal hemorrhage and other upper gastrointestinal upset than aspirin, but commonly had side effects of skin rash and diarrhea. Ticlopidine was also associated with developing side effects of neutropenia and thrombotic thrombocytopenic purpura (Hankey et al. 2000).
Studies have found that statin drugs (HMG-CoA reductase inhibitors) may be of benefit in reducing the incidence of ischemic stroke for patients with established coronary artery disease (Furberg 1999; Vaughan et al. 1999; Vaughan et al. 2001a; 2001b). Unfortunately, these trials have shown a reduction in risk of stroke only in patients enrolled in studies for coronary artery disease. Studies have not been done for primary stroke prevention or in patients without coronary artery disease. In patients with previous myocardial in-farction and cholesterol levels lower than 240 mg/dL, pravastatin reduced the risk of stroke by 31%, compared with placebo (Sacks et al. 1996). The beneficial effects of statin drugs in stroke prevention may be due to several mechanisms, including:
Lowering LDL cholesterol levels
Anti-inflammatory and antithrombotic actions of statins that occur within the blood and in plaque
Protecting against cerebral ischemia through beneficial modulation of the brain endothelial nitric oxide system. Statins both up-regulate endothelial nitric oxide synthase (eNOS) and inhibit inducible nitric oxide synthase (iNOS), effects that may protect the nervous system.
A study examined the protective effects of Mevacor ( mevastatin lovastatin ) in male mice. Mevastatin (2 mg/kg or 20 mg/kg a day) was administered to male mice for 7, 14, or 28 days before inducing a middle cerebral artery occlusion. Lo Me vastatin increased levels of endothelial nitric oxide synthase mRNA and protein, reduced infarct size, and improved neurological deficits in a dose- and time-dependent manner. The greatest protection was seen with 14- and 28-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were reduced after only 28 days of treatment and did not correlate with infarct reduction. Baseline absolute cerebral blood flow was 30% higher after 14-day high-dose treatment (Amin-Hanjani et al. 2001).
Mevacor ( lo me vastatin) and other statin drugs used to lower cholesterol are available by prescription.
Novel Factors that Contribute to Primary or Secondary Stroke Homocysteine
Homocysteine, an intermediate molecule formed from methionine, has been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke. Elevated homocysteine levels are found in 20-40% of patients with heart disease. Elevated homocysteine is present in as many as 50% of patients with stroke. Measuring and reducing homocysteine levels is an important preventive highly recommended by the Life Extension Foundation since as early as 1981 (more than a decade before it was recognized by conventional medicine) (Selhub et al. 1998; Boden-Albala et al. 2000; Hankey et al. 2001).
The exact mechanism by which homocysteine promotes arteriosclerosis is currently being investigated. Several mechanisms have been proposed (Sarkar et al. 1999):
Homocysteine accumulates in endothelial cells causing endothelial dysfunction and injury, followed by platelet activation and thrombus formation.
Homocysteine stimulates the proliferation of smooth muscle cells which line arteries, a central component in atherogenesis.
Homocysteine induces endothelial cell injury due to the generation of hydrogen peroxide which damages endothelial cells, exposing the underlying cell matrix and smooth muscle cells. This, in turn, promotes the activation of platelets and leukocytes to repair the injury (the blood clotting system).
Homocysteine increases nitric oxide production by activating transcription factor NF.
Homocysteine leads to an overproduction of oxidative radicals (reactive oxygen species) that cause lipid peroxidation and oxidation of LDL cholesterol. These oxidized lipids form dense particles which are consumed by macrophages that create foam cells that accumulate in plaques on the endothelial cells lining arteries.
Homocysteine also interferes with DNA repair which makes the blood vessels less pliable and more susceptible to plaque buildup.
Dr. Kilmer McCully (1996) reported that homocysteine plays a key role in every pathophysiological process that leads to arteriosclerotic plaque. Some consider homocysteine to be much worse than cholesterol.
Homocysteine, although toxic itself, is normally metabolized into other nutrients that are beneficial to the body, including cysteine, taurine, and glutathione. Several natural supplements (including vitamin B6, vitamin B12, folic acid, zinc, and methyl donors such as trimethylglycine, SAMe, and choline) are needed for homocysteine metabolism.
While it does make sense to take supplements that contain these important nutrients, one should not automatically assume that their homocysteine levels are fine without a specific laboratory test. For more information about homocysteine, see the Homocysteine and Hypertension section s of the Cardiovascular Disease protocol and the Hypertension protocol .
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.
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.
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.
CRP (mg/L) Future MI Future Stroke
> 2.11 2.9 1.9
1.15-2.10 2.6 1.9
0.56-1.14 1.7 1.7
< 0.55 1.0 1.0
CRP (mg/L) Future MI or Stroke
> 7.30 5.5
< 1.50 1.0
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.
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- 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.
For the last 50 years, medical doctors have concentrated on controlling blood pressure as the primary method of preventing stroke. As you can see, there are several other mechanisms involved. Assessing the status of the blood clotting system through laboratory testing is central to assessing the risk of stroke in high-risk individuals. The following tests are typically used:
Prothrombin time (PT) evaluates the time it takes for a clot to form after thromboplastin and calcium are added to the patient’s plasma. Normal values are between 11-13 seconds. Prothrombin time is commonly used to monitor Coumadin therapy.
The International Normalization Ratio (INR) standardizes prothrombin time to a control batch of thromboplastin (as the sensitivity of commercial thromboplastin reagents is variable) which allows comparisons between different samples and laboratories.
INR = (patient PT/control PT) × ISI
(International Sensitivity Index)
The target INR is 2.5 for those at risk for thromboembolic stroke, with a range of 2-3. A target of 2 with a range of 1.6-2.5 may be used in elderly patients to reduce the risk of hemorrhage. Some authorities, however, disregard age and recommend the higher target of 2.5.
The following may be predictive for the risk of stroke:
Fibrinogen levels are useful because fibrinogen is converted into fibrin under the influence of thrombin. Fibrinogen is often elevated after acute trauma or illness, inflammation, and as a side effect of birth control pills.
Triglyceride levels have been found to be a predictor of myocardial infarction, and elevated serum triglycerides have been specifically tied to the occurrence of atherothrombotic stroke and transient ischemic attacks.
Homocysteine levels have been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke.
C-reactive protein (CRP) is a sensitive marker of inflammation in the body. Inflammation may be a crucial factor in atherosclerosis and is consider.