4 - Lipids and Stroke
Editors: Norris, John W.; Hachinski, Vladimir
Title: Stroke Prevention, 1st Edition
Copyright 2001 Oxford University Press
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4
Lipids and Stroke
John E. Nasrallah
Harold P. Adams Jr.
After making remarkable advances in preventing and curing infectious diseases that killed millions of people, modern medicine now is attacking the chronic diseases that have become more prominent as life expectancy has increased. Heart disease and stroke rank first second, respectively, as causes of death in the world.1 Annually, approximately 750,000 Americans have a stroke or recurrent stroke, and 150,000 of these persons die.2 During the last 30 years, incidence of and mortality from stroke declined in the United States, Canada, Australia, and Western Europe.3 These declines probably were, in part, secondary to improved treatment of hypertension. However, other countries the world have not seen a decrease in the frequency of stroke, and rates have increased eastern Europe. Now, the declines in North America and Europe have stopped, the number of persons who are having strokes is increasing around the world. The number of strokes will grow considerably during the next 50 years simply as a result of the increasing age of the population.4 The economic consequences of stroke are huge in terms of both health care costs and losses productivity. In costs of human suffering, the effects stroke are even greater. Thus, measures to prevent stroke have huge implications for society. A number of factors that increase the risk of stroke have been identified, and measures to control these factors have the potential to lessen likelihood of a potentially disabling or fatal brain injury. This chapter examines one of the modifiable risk factors for ischernic
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stroke elevated serum cholesterol. Recently, Gorelick estimated that up to 100,000 strokes could be avoided annually in the United States if hypercholesterolemia were treated better.5
Certain recurrent themes are worth noting at the outset. Although atherosclerosis is the major underlying arterial disease leading to ischemic stroke, the magnitude of the association between a high serum cholesterol value and stroke is much weaker than that between an elevated cholesterol level and coronary artery disease. Part of the problem in confirming a strong relationship between hypercholesterolemia and stroke relates to the heterogenous nature of stroke. In addition, a low level of serum cholesterol increases the risk of hemorrhagic stroke, whereas hypercholesterolemia probably increases the risk of ischemic stroke. Still, despite the apparent weakness of a cause-and effect relationship, evidence is mounting that the 3-hydroxy-3-methylyglutaryl (HMG) coenzyme A (CoA) reductase inhibitors are effective in lowering the overall risk of ischemic stroke without a concomitant increase in intracranial hemorrhage.
The term stroke encompasses a number of vascular diseases the brain. Because of the heterogenous nature stroke, some associations between risk factors and cerebrovascular events are not as clear as for heart disease. Approximately 80% of strokes involve an arterial occlusion leading to a focal area infarction (ischemic stroke), while the remaining strokes are due to a rupture of an intracranial vessel (hemorrhagic stroke). Some conditions that predispose to brain hemorrhage differ from those that increase the risk of ischemic stroke. For example, vascular malformations, aneurysms, and bleeding diatheses are etiologies of intracranial hemorrhage, while ischemic stroke can be secondary to a large number of vascular diseases, including embolism from the heart, prothrombotic states, nonatherosclerotic vasculopathies, and atherosclerosis. In addition, rather than a solitary disease, ischemic stroke should be considered symptom of a vascular occlusive process that may result from a diverse range of underlying causes.
Atherosclerosis and Stroke
Despite the large number of causes stroke, atherosclerosis is recognized as the leading cause of brain ischemia.6 Atherosclerosis preferentially affects both major intracranial and extracranial arteries also involves deep penetrating vessels that perfuse the brain. The most common sites for involvement include middle portion of the basilar artery, the origin and distal segment vertebral artery, the proximal segment of the middle cerebral intracranial portion of the internal carotid artery, and the origin artery at the bifurcation. The latter is the most common location. sites for severe atherosclerosis differ among ethnic groups. The origin of the internal carotid artery is the most common site for persons of European ancestry, while the intracranial arteries are more commonly implicated in persons of African or Asian
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background.7,8,9 A reappraisal of small vessel (lacunar) disease indicates that the underlying pathology usually is an atheroma rather than lipohyalinosis. Atherosclerotic disease of the aorta and its major brachiocephalic branches is being increasingly recognized as a frequent cause of stroke in the elderly. Advanced aortic atherosclerosis is also an important risk factor for cerebral ischemia as a complication of major cardiovascular procedures. Atherosclerotic coronary artery disease indirectly leads to stroke. Cerebral embolism is a complication of acute myocardial infarction, especially when the anterior wall is affected. Ischemic heart disease leads to atrial fibrillation, a well-known risk factor for cardioembolic stroke. Long-standing ischemic heart disease also leads to embolism from an intracardiac thrombus that develops in an akinetic ventricular segment or from an ischemic cardiomyopathy.
Atherosclerosis is an arterial disease that evolves over a lifetime. The first changes of atherosclerosis can be found in youths and young adults. The disease gradually progresses over an individual's life to become symptomatic and the cause of an ischemic stroke. Two major theories for the development and maturation of atherosclerosis have been advanced the lipid hypothesis and the injury-healing hypothesis.6 The lipid hypothesis postulates that an elevated blood level of cholesterol can initiate the atherosclerotic process by accumulating in endothelial cells. The injury-healing hypothesis proposes that the initial event is a disruption to the vascular endothelium by any number of potential assailants, including mechanical shear stress, toxins, homocysteine, viruses, and immunologic mediators. Rather than two independent processes, the lipid and injuryhealing mechanisms probably are synergistic.
The Genesis of the Atheromatous Plaque
The first stage in the formation of an atheroma is development a fatty streak characterized by the adhesion of monocytes to the endothelium and their subsequent migration to subendothelial portions of the arterial wall. The monocytes become tissue macrophages that develop a foamy appearance by accumulating intracellular lipids. Fatty streaks appear in the aorta and other major arteries as early as late childhood or adolescence. Subsequently, some fatty streaks, especially those located at vascular bifurcations or sites of turbulence, develop into fibrous plaques. These plaques usually are seen in middle-aged or older adults. The fibrous cap of the plaque consists of foam cells, transformed smooth muscle cells, lymphocytes, and a connective tissue matrix. The core of the plaque includes cellular debris, free extracellular lipid, and cholesterol crystals. An intact endothelial lining covers the luminal surface of the plaque. The plaque insidiously enlarges over decades, secondary to the elaboration of cytokines and growth factors released by endothelial cells, platelets, macrophages, and smooth muscle cells. These factors promote migration of smooth muscle cells from the adventitial
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surface of the artery. The smooth muscle cells accumulate in intimalmedial portions of the artery. Areas calcification can occur in plaque. Growth of the plaque leads to constriction vascular lumen (arterial stenosis), which, in turn, leads to diminution of flow and turbulence the circulating blood. The turbulence and sluggish flow promote activation of platelets clotting factors, which, in turn, promote thrombosis or growth of the arterial lesion.
Subsequently, an unstable atheromatous plaque can become acutely symptomatic by developing discontinuities of the endothelial surface (ulceration), fracturing of the fibrous cap, or by incipient intraplaque hemorrhage.10,11 Both ulceration and rupture result in acute clot formation by exposing the highly thrombogenic subendothelial surface. Pieces of atherosclerotic debris (cholesterol embolism) can be released from a complex, highly ulcerated plaque and embolize to distal vascular beds. The intramural hemorrhage can cause sudden arterial occlusion, while the fracture of the plaque disrupts endothelium and leads to thrombosis.
Fracture (or rupture) of an atherosclerotic plaque is now recognized as a leading cause of acute coronary artery thrombosis and myocardial infarction. Based on a pathological evaluation of carotid endarterectomy specimens, Carr et al.12 found that symptomatic patients had significantly higher rates of plaque rupture, thinning of the fibrous cap, infiltration cap with foam cells, and intraplaque fibrin deposition than did asymptomatic patients. They concluded that fracture of the atherosclerotic plaque could be as important in promoting thrombosis of the carotid artery as it is in thrombosis coronary arteries.
The Course of Atherosclerosis
Atherosclerotic disease becomes symptomatic in different vascular territories at different ages. In general, coronary artery disease becomes symptomatic approximately one decade before the appearance of symptoms cerebrovascular atherosclerosis. This clinical phenomenon is confirmed by post-mortem studies that show that the aorta and coronary arteries are involved before peripheral and cerebrovascular arteries. Recent evidence suggests that advanced atherosclerotic disease of the aorta is a significant cause stroke.13 Thus, stroke secondary to atherosclerosis can occur even when the cerebrovascular arteries do not show advanced changes.
The course of atherosclerosis is not uniform between persons. Some individuals have accelerated atherosclerosis while others may never have symptoms from the arterial disease despite living to an advanced age. Epidemiologic studies have identified several factors that accelerate the course of atherosclerosis. Some factors that predict advanced atherosclerosis are not modifiable, including age, sex, ethnicity, and family history. Atherosclerosis is more common in older persons, men, African Americans, and among those who have first-degree relatives who
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have had coronary artery disease or stroke. Inherited disorders, such as familial hyperlipoproteinemia, also may be implicated. Other conditions that can be controlled or treated, such as arterial hypertension, diabetes mellitus, and smoking, also promote atherosclerosis and ischemic stroke. Some conditions, such as hypertension and smoking, are potent risk factors for several types of stroke, including intracranial hemorrhage. On the other hand, until recently, the role of elevated blood lipids, or cholesterol, on the frequency of stroke was less clear. Now, recent data have clarified the critical importance of elevated levels cholesterol in promoting premature cerebrovascular atherosclerosis.
Interactions Between Cholesterol and Atherosclerosis
Elevated serum cholesterol has been recognized as a potent risk factor for myocardial infarction.14,15,16,17 Below the age of 60, the incidence of coronary artery disease increases dramatically with rising levels of total serum cholesterol. A majority of persons who have a myocardial infarction before the age of 60 abnormalities of serum lipids. For example, Genest et al.18 studied levels lipoproteins in men with a mean age of 50 angiographically documented coronary artery disease; levels of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B were significantly increased compared to controls. An elevated level of cholesterol or LDL now is recognized as the single most important forecaster of premature coronary artery disease. The Lyon Diet Heart Study found that each 1 mmol/L increase in total cholesterol was associated with an 18% to 28% increase in the risk of recurrent myocardial ischemia.19
The definition of elevated serum total cholesterol that portends an increased risk of ischemic events has changed; in the past, a total serum cholesterol greater than 6.20 mmol/L (240 mg/dl) was considered high. Now, a level above 5.17 mmol/L (200 mg/dl) is considered as elevated. Although it is a potent risk factor for myocardial infarction in men or women under the age of 60, above this age the relationship between ischemic heart disease and total serum cholesterol wanes. However, the association between abnormalities of lipoprotein subtractions, particularly, low concentrations of high-density lipoprotein (HDL) cholesterol, and coronary artery disease persists among older persons. Aronow20 noted a relationship for new coronary events and high serum total cholesterol triglyceride levels and low HDL cholesterol in older women.
Because lipids are insoluble in blood, they incorporated into protein-lipid complexes called lipoproteins. A lipoprotein consists of a core lipid surrounded by a coat of proteins, cholesterol, and phospholipids. The lipoproteins include chylomicrons, very low-density lipoprotein (VLDL) cholesterol, LDL cholesterol, and HDL cholesterol. Each lipoprotein subfraction has a specific function in the overall system of cholesterol and lipid metabolism. Because cholesterol must be
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packaged in these lipoproteins to be transported the blood, the measured total cholesterol represents the sum of the cholesterol contained in each of the subfractions. Since each of the different lipoproteins plays distinct roles in cholesterol transport and accumulation in tissues versus removal from tissues, measurement of the proportions lipoproteins is the most specific way to assess the risk for vascular disease.
Chylomicrons serve as the vehicle of transport dietary triglycerides and cholesterol from the intestine to the liver. The chylomicrons are modified and taken up by the liver cells. Cholesterol delivery from the to other tissues is accomplished by VLDL cholesterol that is changed intravascular enzymes into LDL cholesterol. LDL cholesterol is the predominant lipoprotein in the blood and accounts for approximately two-thirds of the total cholesterol level. Cells, including those in the arterial wall, bind LDL cholesterol, and it is subsequently oxidized by macrophages. Oxidized LDL cholesterol enters the endothelium and promotes the accumulation of foam cells in the arterial wall. Hypercholesterolemia is associated with endothelial cell dysfunction and arterial stiffness.21 Oxidized LDL cholesterol also can promote vasoconstriction by reducing the stores of nitric oxide in the endothelium. HDL cholesterol is smallest lipoprotein. Its role as a protectant against atherosclerosis may relate to its property of transporting lipids from peripheral sources in the body to liver, where the cholesterol can be metabolized. HDL cholesterol also protects LDL from oxidation and thus limits the deleterious actions of the oxidized form LDL cholesterol. HDL cholesterol also helps arterial constriction by activating endothelial production of prostacyclin.
Role of Lipoproteins
Lipoprotein a is a variant of LDL cholesterol,22 and its role in the development of atherosclerosis is controversial. Some studies suggest that elevations of lipoprotein are associated with an increased risk of coronary artery disease,15,18,23,24 but there is no evidence that this a potent risk factor for either atherosclerosis or thrombosis. At present, the atherogenic role of lipoprotein a appears to be most closely related to concentrations of LDL cholesterol.
A number of lipoprotein abnormalities lead to elevation blood lipids. Some are inherited while others are secondary to medication or acquired diseases. Familial hypercholesterolemia, in particular type Il-a hyperlipoproteinemia, is implicated as an important risk factor for premature coronary artery atherosclerosis.25-26 Among the medications that lead to hyperlipidemia are diuretics, betablockers, and androgens. Estrogens can lower blood lipids by reducing lipoproteins. Obesity, diets high in saturated fats and cholesterol, physical inactivity, alcohol consumption, diabetes mellitus, liver disease, and renal disease also promote elevations of cholesterol or lipoproteins. Lipid disorders that are characteristic
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of non-insulin dependent diabetes mellitus (low HDL cholesterol, high LDL cholesterol, high triglycerides, and high apolipoprotein /3 levels) are predictive of cardiovascular events among this group patients.27,28 Both total cholesterol and HDL cholesterol levels change with advancing age and may be part of the natural aging process.29
Role of Cholesterol
Elevated LDL cholesterol correlates with increased risk of coronary artery disease, while elevated HDL cholesterol appears to be cardioprotective.30 A serum LDL cholesterol level >3.30 mmol/L (130 mg/dl) is generally considered too high, while a serum HDL cholesterol <0.87 mmol/L (35 mg/dl) is usually considered too low. The ratio of total cholesterol to HDL cholesterol is the best predictor and correlates with the risk of coronary artery disease for persons up to the age of 80; the desired ratio is > 1:5. For example, the risk of heart disease increased by a factor of 1.6 among men and 1.875,76,77,78,79 women aged when the ratio is < 1:4. Still, the predictive value of total cholesterol or the lipoprotein fractions is low in forecasting cardiovascular events in the very elderly. The Leiden 85-plus study showed that although cardiovascular disease is a leading cause of death among persons older than 80 years, the rates of cardiac events were similar among patients with low, medium, and high levels of total cholesterol.31
Because of the strong relationship hypercholesterolemia and ischemic heart disease, lowering total serum cholesterol and increasing HDL are critical in managing patients at risk of myocardial infarction. Because of the strong interactions between coronary artery disease and ischemic cerebrovascular disease, patients with ischemic stroke, particularly those with carotid disease, should be considered at high risk for myocardial infarction.32,33,34,35 For example, patients with stroke followed for five years in the Northern Manhattan Stroke Study were twice as likely to die of cardiac disease from recurrent stroke.36 Thus, even if elevated total cholesterol and LDL cholesterol levels are not associated with an increased stroke risk, the implicit high risk of coronary artery disease mandates their treatment in patients with stroke.6 Treatment of hypercholesterolemia is called for regardless of the patient's age or the presence other risk factors atherosclerosis if for no other reason, to prevent myocardial infarction or cardiac death.
Interactions Between Cholesterol and Stroke
The epidemiologic data regarding the relationship between serum levels of cholesterol and the risk of stroke are controversial.37 Early clinical studies generally ignored the lipoprotein subfractions and attempted to correlate total cholesterol with the risk of stroke, regardless of type. The results were contradictory due to
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differences in geographic location, ethnicity, age, sex, and demographic characteristics of subjects and because differences in study design, some included all strokes, irrespective of the type.38
The Prospective Studies Collaboration performed a large meta-analysis based on more than 45 studies and did not find a correlation between serum cholesterol levels and the risk of stroke.39 However, they did not differentiate ischemic from hemorrhagic stroke. Some studies used data of doubtful value collected from death certificates or hospital records and looked only at fatal cerebrovascular events, while three-quarters of all strokes in this meta-analysis consisted only fatal stroke cases.39
Because of the diverse nature stroke, it is difficult to establish a cause-and effect relationship from a single risk factor, unlike that of elevated cholesterol in atherosclerosis.38 Some studies included all ischemic strokes, regardless of cause, yet arterial dissection and vasculitis have little association with the traditional risk factors for stroke. Also, stroke from large artery atherosclerosis must be differentiated from cardioembolism and lacunar stroke. In a case control study, Hachinski et al.40 found a strong correlation between total serum cholesterol and stroke when patients with lacunar or cardioembolic events were excluded.
In addition, the shared risk of coronary artery disease and cerebrovascular disease may dilute any association between cholesterol and stroke, high-risk patients often die prematurely of heart disease. In a study cholesterol as risk factor for heart disease and stroke among men of Japanese ancestry living in Hawaii, a strong positive relationship was found between total cholesterol level and ischemic stroke.41 The rates of stroke were similar to those men of European heritage, but the Hawaiian men had very low rates of symptomatic coronary artery disease. The absence of cardiac events during a long period observation allowed the demonstration of a strong correlation between serum cholesterol levels and ischemic stroke.
The Role of Elevated Lipids in Stroke
Recent data support the relationship of elevated lipids as a risk factor for ischemic stroke.40,42 Blood levels of total and LDL cholesterol triglycerides were significantly elevated, and those of HDL cholesterol significantly reduced in patients with atherothrombotic strokes or transient ischemic attack (TIA).
An association among high levels of lipoprotein and LDL cholesterol and low levels of HDL cholesterol in ischemic stroke was also reported.24 Levey et al.43 found an association between a low serum HDL cholesterol level and severe carotid atherosclerosis among persons younger than 50 who underwent carotid endarterectomy. Patients with stroke secondary to large artery atherosclerosis had higher total cholesterol levels than did those with lacunar strokes.
The Northern Manhattan Stroke Study36 found that patients with levels of 35
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to 50 mg/dl (0.875 1.25 mmol/L) of HDL cholesterol had a 0.81% stroke risk compared to those with levels of <35 mg/dl (0.875 mmol/L). Those with levels of HDL >50 mg/dl (1.25 mmol/L) had a stroke risk of only 0.39. The benefit was greatest for lowering the risk of large artery atherosclerosis.
A large clinical trial evaluating the benefit of treatment for hypertension, Systolic Hypertension in the Elderly Program, revealed that low HDL cholesterol is associated with an increased risk of TIA and ischemic stroke.44 A study in Australia had similar results: a 36% reduction in the risk for stroke was noted for each 1 mmol/L (40 mg/dl) increase in HDL cholesterol.45 The influence of concentrations of total cholesterol, HDL and triglycerides was evaluated in 19,698 men and women enrolled in the Copenhagen City Heart Study.46,47 The investigators were able to correlate an increased risk of nonhemorrhagic stroke only among patients with total cholesterol levels greater than 8 mmol/L (240 mg/dl); no relationships to the incidence of stroke were seen at lower levels. On the other hand, they found a strong protective effect from HDL cholesterol concentrations; the relative risk was 0.53 (95% CI 0.34 0.83). For each 1 mmol/L (90 mg/dl) increase in triglyceride concentration, the relative risk of stroke rose by 1.12 (95% CI 1.07 1.16). Based on an overview of 10 trials, Qizilbash37 found a strong association between elevations of serum total cholesterol and the risk of ischemic stroke. A total cholesterol >5.50 mmol/L (220 mg/dl) predicted a relative risk of 1.31 (95% CI 1.11 1.54) of stroke compared to persons with lower levels.
The data on the relationship between serum cholesterol levels and the risk of stroke among women are even less clear than the data among men. Women have a lower risk for coronary artery disease and carotid atherosclerosis than men.48 At all ages, the incidence of stroke is higher in men than women. Even among patients with symptomatic atherosclerosis of the extracranial internal carotid artery, women have a better prognosis than do men. With lower risk for stroke and fewer strokes among women, along with generally lower levels of cholesterol, establishing a cause and effect relationship in women can be difficult. Bostrom et al.49 found that an elevated lipoprotein was a strong independent predictor of cerebrovascular disease in women. The Framingham Study also found a strong association between total cholesterol values and coronary artery disease in women under the age of 70, but no relationship to stroke mortality could be found.50 Both stroke and myocardial infarction are relatively uncommon among women under the age of 55, and the relative risk from an increased cholesterol concentration may be somewhat exaggerated. For older women, no association could be ascribed. The lack of relationship may be because ischemic stroke among older women is most commonly secondary to atrial fibrillation and large artery atherosclerosis appears to be a less common factor. Lindenstrom et al.47 found similar effects from cholesterol and triglycerides on stroke risk among men and women.
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The information about the role of elevated lipoprotein levels and the likelihood of stroke is mixed. Markus et al.51 found no relationship between lipoprotein concentrations and TIA, stroke, or carotid atherosclerosis. Nguyen et al.52 found that lipoprotein was a weak risk factor for cerebrovascular disease in men and not a significant forecaster of stroke in women. Similarly, Dutch and American studies could not find a relationship between lipoprotein levels and stroke.53,54 Conversely, a Japanese study showed that elevated lipoprotein levels were accompanied by an increased risk of atherothrombotic strokes, especially among patients under the age of 50.55 Christopher et al.56 found that elevated lipoprotein levels are an important risk factor for the development of ischemic stroke among persons aged less than 40 years. Further research is required to evaluate the role of lipoprotein a as a risk factor for ischemic stroke.
Differentiating hemorrhagic from ischemic stroke is important because of the U-shaped relationship described between total serum cholesterol value and stroke.57,58,59,60 While an elevated serum cholesterol value is associated with increased risk for ischemic stroke, a low level of total cholesterol predicts an increased risk for intracerebral hemorrhage.61,62 Brain hemorrhage probably is the only major cause of mortality that is correlated with a low serum total cholesterol value.61 Yano et al.59 found that the relative risk of intracerebral hemorrhage was 2.55 (95% CI 1.58 4.12) among men with a total cholesterol under 4.72 mmol/L (189 mg/dl) compared to higher levels. The relationship persisted even when controlled for age, blood pressure, tobacco use, and alcohol consumption. The Multiple Risk Factor Intervention Trial (MRFIT) found that the risk of intracerebral hemorrhage was inversely related to serum total cholesterol.57 The trial evaluated the frequency of vascular events among 350,977 men aged 35 57 years (90.1% white and 6.4% African American) in the United States. The rate of intracranial hemorrhage was three times higher among men whose serum total cholesterol was below 4.14 mmol/L (160 mg/dl) than among men with higher levels. This association was observed despite considerable competition from cardiovascular disease in the study cardiac mortality was 60.5/10,000, while deaths secondary to hemorrhagic stroke occurred at a rate of 2.36/10,000 and ischemic stroke at a rate of 2.62/10,000. Ibibarren et al.63 described similar results involving 61,576 persons aged 40 89 years who lived in California. Serum total cholesterol levels below 4.62 mmol/L (178 mg/dl) increased the risk of hemorrhagic stroke among men older than 65 by a rate of 2.7 (5% CI 1.4 5.0) compared to similarly aged men with higher values. A parallel, but not statistically significant, trend was noted among elderly women. No association between hemorrhage and total cholesterol levels could be found among younger men or women. The inverse association between serum total cholesterol and intracranial hemorrhage has been confirmed by Japanese studies. Konishi et al.60 reported that the mean total cholesterol level among patients with cerebral hemorrhage was 4.10 mmol/L (164 mg/dl); with lacunar infarction it was 4.61 mmol/L
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(177 mg/dl); and with cortical infarction it was 4.99 mmol/L (200 mg/dl). The Eastern Stroke and Coronary Heart Disease Collaborative Research Group found the risk of hemorrhagic stroke increased by a rate 1.27 (0.84 1.91) with each decrease of total cholesterol 0.6 mmol/L (22 mg/dl).65 Hemorrhagic stroke is a leading cause of death in Japan, but its incidence has dropped recent years.58 This decline has been attributed to shifts in the Japanese diet. With increased intake of animal fats and rising serum cholesterol levels, the frequency of brain hemorrhage has fallen, while the incidence of myocardial infarction risen in Japan.64
Serum Cholesterol Level as a Prognostic Factor after Stroke
Dyker et al.66 performed a retrospective study on outcomes of 977 patients with acute stroke. They found that higher concentrations of serum total cholesterol were associated with a lower mortality after stroke regardless of type, patient age, or vascular territory. The relative hazard was 0.91 for each 1 mmol/L (40mg/dl) increase in cholesterol. The significance of this finding has not been established. It is possible that patients with low serum cholesterol had more serious co-morbid diseases and may have had some element of malnutrition prior to their cerebrovascular event.67 The elevated cholesterol may represent inflammation after stroke.68 A negative interaction in relation to atrial fibrillation also has been proposed.69 Additional information about the importance of this finding is needed.
Interactions Between Serum Cholesterol Levels and Carotid Intima-Media Thickness and Atherosclerosis
The severity of atherosclerosis, including the extent detected by ultrasound, in the carotid artery is strongly associated with risk of severe coronary artery disease.70,71,72 In particular, the extent of atherosclerotic disease in other circulations can be predicted by the severity of intimal-medial thickness (IMT) in the common carotid artery and proximal internal carotid artery.73,74 In one study, the relative risk for myocardial infarction increased by a rate of 2.2 (95% CI 1.4 3.6) for each 0.03 mm increase in carotid IMT. The relationships are found both men and women.71 Thus, an association between lipid levels and carotid artery atherosclerosis should not be surprising. The prevalence and severity of atherosclerotic plaques of the internal carotid artery are significantly correlated with elevated total cholesterol or lowered HDL cholesterol values, especially at younger ages.43-75 Sacco et al.36 also found a relationship between high LDL cholesterol concentrations and the thickness of carotid artery plaques in African Americans, Hispanics, and whites. The relationship was strongest among Hispanic patients. Gronholde76 found that LDb cholesterol concentrations are the
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best predictor of the extent atherosclerosis carotid artery detected by ultrasound. Grotta et al.77 reported that an elevated level of LDL cholesterol was a strong predictor of progressing carotid stenosis. Hodis et al.78 found that progression of IMT in the carotid artery wall is strongly associated with levels triglyceride-rich lipoproteins.
Evaluation of Serum Cholesterol in Patients with Stroke
Aull et al.79 reported that lipid and lipoprotein levels among patients with TIA or stroke often are unreliable if they measured after 48 hours but within several days following the neurologic event. They recommended delaying assessments of blood lipid concentrations for several weeks after stroke. Mendez et al.80 reported similar results and concluded that important lipoprotein abnormalities can be missed during the first days after stroke. The reported magnitude in the drop of both total cholesterol and LDL cholesterol was approximately 10% at 24 hours and 25% at seven days compared to samples measured three months after stroke. However, Kargman et al.81 did not find changes in lipoprotein a, total cholesterol, HDL LDL or triglycerides by serial measurements during the first weeks after stroke.
Treatment of Elevations Serum Cholesterol and Prevention of Stroke
General measures
Measures aimed at lowering LDL cholesterol, triglycerides, or lipoprotein a, halting oxidation of LDL cholesterol, and increasing HDL cholesterol may slow the progression of atherosclerosis and reduce the risk of myocardial infarction, vascular death, and ischemic stroke.82,83,84,85 Success in modification of risk factors, however, including total cholesterol levels, is hard to achieve among persons at high risk for stroke.86 The choices include modification in diet and lipid-lowering medications. In addition, weight control, increased exercise, reduced alcohol consumption, and control of concomitant diseases, such as diabetes mellitus, are part of the strategy to lower blood lipids.
Evidence is strong that a traditional Western diet, which includes consumption of large amounts of saturated and animal fats, plays a role in fostering development of atherosclerosis. It is unclear whether the amount fats or types consumed is the critical factor.87 A very low-fat diet has been recommended to reduce total cholesterol levels. Still, data are lacking about the efficacy of a very low-fat diet in preventing either myocardial infarction or stroke.87 A surprising report from the Framingham Heart Study noted lowest risk of stroke among
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those men who consumed the largest amounts of saturated and monounsaturated fats.88 The report by Gillman et al. is buttressed an autopsy-based study from Greenland that found a significant interaction between high levels of polyunsaturated fatty acids and the occurrence of fatal hemorrhagic stroke.89 Considerable additional research is needed to define the value of a severe restriction in dietary fats in the prevention of ischemic stroke. The possibility an increase a risk for hemorrhagic stroke with a low fat diet needs to be considered. Some carbohydrates may have positive effects and others have negative on HDL cholesterol levels.90 Thus, dietary measures to treat hypercholesterolemia may require more than changes in consumption of saturated fats.
A diet similar to that consumed in eastern Asia, which includes high consumption of vegetables, carbohydrates, and fish with limited meat, has been advocated. The traditional Japanese diet, which involves consumption of large amounts of polyunsaturated fats and fatty acids, has not shown a reduction in the risk of stroke despite low levels serum cholesterol.91 However, other parts the traditional Japanese diet, including the consumption of large amounts salt, may contribute to the high risk of stroke in that country. Recently, a Mediterranean-style diet has been shown to be superior a prudent Western-type diet in reducing cardiovascular events.19 The Mediterranean diet substitutes vegetable oils, in particular olive oil, for animal fats and usually limits the amount of meat consumption. It also emphasizes consumption of fish, vegetables, fruit, and wine. Diets high in consumption of fresh fruits and vegetables have been shown to lower the risk of stroke. While these diets' effects are ascribed to increased ingestion of potassium and antioxidant vitamins, a concomitant lowering dietary fats also may play a role.
Modest alcohol consumption can reduce the risk of coronary artery disease, possibly because of its effects on blood lipids, particularly an increase in HDL cholesterol.92 Similar beneficial effects from consumption of modest amounts alcohol, particularly wine, may reduce the risk of ischemic stroke.93 Still, consumption of large amounts alcohol has other health implications, including hemorrhagic stroke, liver disease, and the possibility of increasing serum lipids. Alcohol abuse and binge alcohol consumption also predispose to ischemic stroke. A patient who drinks approximately one glass of wine per day does not need to change his or her practice. Wine may be more protective against stroke than either beer or distilled spirits.94 However, a patient who does not consume alcohol should not be encouraged to start drinking in order reduce the likelihood of a stroke. At present, alcohol consumption should not be viewed as a method to reduce the risk of stroke.
Estrogen is reported to be protective against the development of coronary artery disease and atherosclerosis in premenopausal women.48 Estrogen supplementation in women does lower LDL cholesterol and increase HDL levels. However, despite an 11% drop in LDL cholesterol and 10% rise in HDL
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cholesterol concentrations, the benefit of estrogen treatment in reducing cardiovascular events and stroke has not been demonstrated.
The levels of total cholesterol, LDL cholesterol, and HDL cholesterol that should prompt initiation of a lipid-lowering medication are not easy to establish.95-96 Poor compliance with dietary recommendations may lower the threshold at which it is necessary to start medications. On the other hand, dietary modifications are cheaper and more physiologic than medications. It would seem prudent to start medication when an individual has a total cholesterol level >6.20 mmol/L (240 mg/dl), an LDL cholesterol level >3.30 mmol/L (130 or an HDL cholesterol level <0.87 mmol/L (35 mg/dl).
Traditional medications to lower cholesterol
Before the development of the statins, treatment hyperlipidemia included adminstration of cholestyramine, colestipol, nicotinic acid, gemfibrozil, or clofibrate. Despite their usefulness in lowering serum levels of total cholesterol, the benefit of these agents in lowering the risk stroke has not been established.97,98 Cholestyramine and colestipol have been used for approximately 40 years were the primary medications used to lower LDL cholesterol before development of the statins. These anion exchange resins act primarily within the intestine to sequester bile acids. A decline in the concentration of bile acids leads to an increased hepatic conversion of cholesterol into bile acids. Clinical studies have shown that cholestyramine and colestipol can lower LDL cholesterol levels by approximately 6% to 20% and raise HDL cholesterol levels by 2% to 3%. Regrettably, cholestyramine can increase serum levels of triglycerides. The daily doses of cholestyramine and colestipol are approximately 8 24 grams and 10 30 grams, respectively. These agents can cause gastrointestinal side effects, including constipation. Many patients do not tolerate these medications, and their role has become secondary following the introduction of the statins. The monthly costs of these medications are approximately US$80 to $200.
The primary mechanism of action nicotinic acid (niacin) on lipids is reduction in the production of VLDL cholesterol. It indirectly reduces LDL cholesterol and triglyceride levels by 20% to 25% and 20% to 50%, respectively. Simultaneously, HDL cholesterol levels are increased by 25% to 50%. In clinical trials, nicotinic acid has reduced cardiovascular mortality and nonfatal myocardial infarction, but no information is available about its effectiveness in preventing stroke. Nicotinic acid is a potent vasodilator that can lead to marked flushing of the skin, which many patients cannot tolerate. While this symptom is bothersome and often leads to halting treatment, it is not life threatening. The administration of aspirin in conjunction with nicotinic acid can lessen the problem of skin flushing. Other side effects include gastritis, hepatitis, elevated serum glucose, and an increased serum uric acid. The usual daily dose of nicotinic acid for lowering cholesterol is 2 to 3 grams. It is inexpensive, the monthly cost being approximately $8.
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Gemfibrozil and clofibrate increase lipoprotein lipase activity. These medications are metabolized by the liver and excreted from the kidneys. They reduce triglyceride levels by 20% to 70%, but their effect on LDL-cholesterol is modest. These agents can increase HDL cholesterol levels approximately 10% to 20%. In clinical trials, these agents have shown no major benefit in reducing either cardiac death or myocardial infarction. Conversely, they have been associated with an increased rate of nonvascular death and a trend toward risk of stroke.98 The mechanism that leads to a cloflbrate-related increase in risk of fatal stroke is not known.98 Most side effects of these agents are gastrointestinal and include an increased risk of gallstones. The usual daily dose of gemfibrozil is 1200 mg, and the monthly cost approximately $10.
HMG-COA reductase inhibitors
These agents (the statins) suppress 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase, the rate-limiting step in the hepatic biosynthesis of cholesterol. At present, six statin agents (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) are available. They vary in their pharmacodynamic properties, including solubility. Pravastatin is the most hydrophilic, and simvastatin is the most lipophilic. All six agents reduce LDL cholesterol levels by approximately 20% to 40% and increase HDL cholesterol levels by approximately 5% to 10%. In addition, atorvastatin, pravastatin, and simvastatin also can reduce levels of triglycerides. Pravastatin may allow for increased stability of the fibrous cap of an atheroma.
These agents also appear to have antiatherogenic effects over and above their capacity to lower atherogenic lipoproteins.99,100 Statins lessen the inflammatory, thrombogenic, and proliferative properties of atherosclerotic plaque, which reduces the likelihood of plaque rupture.101,102 The Multicentre Anti-Atheroma Study reported that administration of simvastatin improved the morphology arterial walls.101 The statins also appear to improve endothelial function, affect inflammatory reactions, decrease platelet thrombus formation, and improve fibrinolytic activity.99,101,103 They also affect fibrinogen concentrations and levels of C-reactive protein, which is a marker of inflammation.104,105 Kaesemeyer et al.106 reported that pravastatin reduces platelet aggregation and causes vasodilation through activation of endothelial nitric oxide synthase independently its cholesterol-lowering properties. In a small, randomized, diet-controlled study, Anderson et al.107 found that cholesterol-lowering medications improved endothelium-dependent vasomotion. These features may explain some of the efficacy of the statins in reducing the risk of myocardial infarction and ischemic stroke.
Clinical trials have shown that the addition of a statin to other medical therapies can lessen the likelihood of fatal or nonfatal myocardial infarction.17-108 They also have reduced the need for cardiovascular interventions, including bypass grafting and angioplasty.108 The agents can reduce the risk of an acute coronary
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event among asymptomatic men and women with average cholesterol values.109 They are effective in both men and women and regardless of the presence hypertension or diabetes mellitus.110 The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group found a 24% reduction in death from coronary artery disease and a 22% decline in overall mortality with treatment with pravastatin among a group of patients with symptomatic coronary artery disease and a wide range of cholesterol levels.111
Clinical trials have tested the usefulness of the statins in slowing progression or reversing the growth of atherosclerotic plaques in the internal carotid artery. These studies have recruited asymptomatic patients and those with a history of symptomatic coronary artery disease, but they have not included patients who had a history of stroke or TIA. MacMahon et al.112 noted that pravastatin reduced the development of carotid atherosclerosis among persons with ischemic heart disease and a broad spectrum of cholesterol levels. During the four-year study, the investigators noted an increase in mean thickness of the carotid artery wall of by 0.048 mm in the placebo-treated group and a decrease of 0.014 pravastatin-treated group. The Asymptomatic Carotid Artery Progression Study tested the effects of lovastatin on changes IMT among asymptomatic patients with mild carotid artery plaques and elevated total cholesterol.113 All patients received low-dose aspirin. By three years, the trial found a modest regression in IMT among those treated with lovastatin and a modest progression of plaques in the placebo-treated group. Concomitantly, the trial found a significant reduction of vascular events among the treated patients. Hodis et al.114 also found that lovastatin reduced IMT among patients with preintrusive atherosclerosis of the carotid artery. The Kuopio Atherosclerosis Prevention Study found that pravastatin slowed the progression of carotid atherosclerotic plaques; responses were greater among patients who smoked.115
Several studies have examined the usefulness of the statins in reducing incidence of ischemic stroke among patients with elevated cholesterol and a history of coronary artery disease (Table 4.1). In general, the use of statins has been shown to lower the risk of stroke by approximately 30%. 17,17,42,101,106 118 Several meta-analyses examined the cumulative results of clinical trials for the effectiveness of statins in preventing stroke; all yielded similar results.98,119,120,121,122,123,124 The degree of benefit in preventing thrombotic stroke with treatment with the statins was greater in the meta-analyses because the number of cerebrovascular events was small in each of the individual trials.125 In addition, most trials focused on prevention of cardiac events, with prevention stroke a secondary goal. In the meta-analyses, reduction in the risk of stroke with statin therapy was 24% to 31% (95% CI 8% 41%, p = .001). The similarity of the results these analyses is due in large part to their mutual inclusion of the three largest trials, which accounted for approximately 90% of all strokes.126,127,128 The other studies included in these analyses examined the influence of the statins on progression
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of carotid artery atherosclerosis and either enrolled a limited number subjects or followed them for short periods of time. The meta-analyses revealed similar reductions in total cholesterol level (approximately 20%) and LDL cholesterol level (30%) and increases in HDL cholesterol level (5%). The results of the metaanalyses provide conclusive evidence that the statins do lower risk of ischemic stroke among persons with heart disease. The likelihood is high that these agents will be equally effective among persons with symptomatic cerebrovascular atherosclerosis.
TABLE 4.1. Reduction in Rates of Stroke: Clinical Trials of HMG-Co A Reductase Inhibitors | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The Scandinavian Simvastatin Survival Study enrolled 4,444 patients with a history of angina pectoris or myocardial infarction.126 Patients received a lipidlowering diet and either simvastatin or a placebo, they were followed for a median period of 5.4 years. The primary purpose the study was to test total mortality, and stroke data were evaluated in a post-hoc analysis. Men accounted for 81% of the subjects, and 51% were older than 60. These numbers are important when looking at the effects of the medication on stroke because these patients were at high risk for large artery atherosclerosis. Use of simvastatin was associated with a 25% and 35% reduction in total cholesterol and HDL cholesterol levels, respectively. HDL cholesterol levels increased by 8%. There was a 30% reduction in the risk of death treatment group (95% CI 15% 44%, p = 0.0003), due largely to fewer cardiac deaths. Fatal or nonfatal strokes occurred in 70 simvastatin-treated and 98 placebo-treated patients (relative risk 0.70 95%, CI 0.52 0.96, p = .024). The beneficial effects of treatment were discernible at one year and persisted throughout the follow-up period.
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The West of Scotland Coronary Prevention Study (WOSCOPS) was a primary prevention trial that studied the ability of pravastatin to prevent cardiovascular events among 6595 men aged 45 to 64 who had a mean plasma cholesterol level of 7.0 0.6 mmol/L (272 23 mg/dl).128 The men received a placebo or pravastatin at 40 mg/day and were followed for a mean of 4.9 years. Pravastatin lowered total cholesterol levels and LDL cholesterol levels by 20% and 26%, respectively. This study noted significant declines in myocardial infarction and cardiovascular death, but an 11% reduction in stroke risk did not reach statistical significance.
The LIPID study, whose data were not included in the meta-analyses, tested pravastatin (40 mg/day) or placebo for up to 6.1 years in 9014 patients who were 31 to 75 years old.111 The patients had a history of symptomatic heart disease and initial total cholesterol of 4.00 7.00 mmol/L (155 271 mg/dl). A relative reduction in risk of death from ischemic heart disease 24% was found. The trial also noted a 19% reduction in the risk of stroke among patients treated with pravastatin 40 mg/day.
In a placebo-controlled study, the Cholesterol and Recurrent Events (CARE) Trial, investigators noted that pravastatin lowered total cholesterol by 20%, LDL cholesterol by 32%, and triglycerides 14% among a group of 4159 patients with a history of myocardial infarction and an average total cholesterol (total cholesterol <240 mg dl).108,127 This was the first study that included stroke as a prespecified endpoint. The primary endpoint of the study, coronary artery disease-related death or myocardial infarction, was reduced by 24% among the pravastatin-treated patients. During the follow-up, strokes were diagnosed among 52 subjects treated with pravastatin and 76 persons given placebo, a 32% reduction (95% CI 4% 52%). The reduction in either stroke or TIA was 27%. There were too few strokes of each stroke subtype to make any inference about the efficacy of pravastatin on these subtypes, but there were fewer events with treatment in all subgroups. Importantly, pravastatin had benefit despite concomitant use of antithrombotic medications in both arms the study: approximately 83% of the patients were taking aspirin daily. The mean total serum cholesterol level reached 4.32 mmol/L (167 mg/dl) among the pravastatin-treated patients, which is very close to the cut-off of 4.14 mmol/L (160 mg/dl), below which increased risks for hemorrhage were noted by the MRFIT study.57 Still, the investigators did not note an increase in risk of hemorrhagic stroke with treatment.127
Lewis et al.129 tested the usefulness of pravastatin in the prevention recurrent ischemic events among 576 postmenopausal women with a history of myocardial infarction who had normal levels of total and LDL cholesterol. Pravastatin at 40 mg per day reduced coronary events by 46% compared to placebo. While the number of strokes in both arms the study was small, a 56% reduction the rate of stroke was seen with pravastatin treatment. In a subgroup analysis, the same investigators found that pravastatin reduced the absolute incidence of
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stroke from 7.3% to 4.5% (2.9% reduction, [CI 0.3% 4.5%], relative risk reduction of approximately 40%) among persons older than 65.130 This analysis is important because this age group represents the population at greatest risk for stroke. The relative risk reduction with pravastatin was as great as that seen with some of the medications that are given to prevent stroke in high-risk older persons.
Currently, trials are testing the ability of atorvastatin to prevent recurrent brain ischemic events among persons with stroke or TIA. Taken together, these studies and the meta-analyses reveal several important points. First, with the exception of WOSCPOS, the individual studies show a fairly consistent reduction approximately 30% in the risk of stroke. This risk reduction became apparent within 12 to 18 months after starting treatment. The magnitude in and the timing of the reduction in risk of stroke are comparable to statins' ability lessen the risk of myocardial infarction and cardiac death. In general, trials demonstrate that the statins are well tolerated, and the frequency of serious adverse experiences with treatment was not higher than that among the placebotreated patients. The studies, which included measures to discriminate hemorrhagic stroke from ischemic stroke, did not show an increase in brain hemorrhage.
Overall, the HMG-CoA reductase inhibitors are relatively safe.110 Some have questioned whether the HMG-CoA reductase inhibitors may increase risk of violent death.123 Current data are insufficient to establish such a relationship. Experimental models in rodents have suggested that lipid-lowering drugs, including the HMG-CoA reductase inhibitors, may cause cancer.131 Still, clinical data are limited. One trial, the Cholesterol and Recurrent Events Study, reported that 12 cases of breast cancer were reported in the treatment group versus one case in the placebo-treated patients.108 The absolute numbers are small and the confidence intervals for these data are very wide, so further study will be needed to determine if the association is solid. The other clinical trials testing the statins have not reported high rates of malignancies. At present, no significant increase in risk of cancer can be ascribed to the use of the statins.123
The most important adverse experiences from the HMG-CoA reductase inhibitors include hepatotoxicity, myopathy, dyspepsia, and skin eruption. Approximately 1% of patients develop elevated blood levels liver enzymes, which usually are asymptomatic. The hepatic side effects more common in persons who also regularly consume alcohol or who are taking other medications that may affect the liver. Still, because of the risk of hepatic adverse experiences, patients who are taking a statin should have transaminase level measured approximately six weeks and three months after starting treatment approximately every six months thereafter. A threefold rise in transaminase should prompt discontinuance or a lowering of the dosage statin. A myopathy complicating the use of a statin usually presents with marked generalized weakness and myalgias. Serum levels of creatine kinase are markedly elevated in these patients.
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In severe cases, rhabdomyolysis and myoglobinuria may be detected. This complication can occur with the administration of any of the agents, but the risk of a myopathy increases if the patient also is using cyclosporin, gemfibrozil, or nicotinic acid. The cause of myopathic complication is not clear.
These medications are expensive.132 The monthly costs range from $50 to more than than $200. Still, pharmacoeconomic studies have demonstrated that the statins are cost-effective because of their ability to reduce cardiovascular morbidity and mortality. The cost-effectiveness of the statins is significantly greater when the costs of stroke care are included.133
Conclusions
The impact of elevated blood levels cholesterol on the incidence stroke is smaller than its influence on coronary artery disease. Accumulating evidence indicates that it is an important risk factor for ischemic stroke, especially due to large artery atherosclerosis and cardioembolism secondary to ischemic heart disease.82-96 Because a large percentage of persons living in North America have elevated serum cholesterol values, the potential for public health benefit is substantial from modification of this risk factor. Robust evidence is available indicating that the use of statins reduces risk ischemic stroke and lessens progression of extracranial carotid artery disease in adults who do or do not have symptomatic coronary artery disease. These agents also dramatically lower the risk of serious cardiac events. Therefore, statin therapy has the potential to help lower the risk of ischemic events (myocardial infarction and recurrent stroke) among patients with an asymptomatic carotid stenosis, TIA, or prior ischemic stroke. The agents should be prescribed to patients with concomitant symptomatic coronary artery disease and cerebrovascular atherosclerosis. The usefulness of these agents in persons who have had a stroke but show no evidence coincident coronary artery disease is uncertain. Clinical trials are testing the efficacy of the agents in such a situation. The role statins treatment patients with stroke not secondary to atherosclerosis is unknown. While the use of the statins should be tied to dietary modifications and control of other risk factors, the role of the other cholesterol-lowering medications has become secondary. Their use should be restricted to those patients who cannot take the statins or as possible adjuncts to the HMG-CoA reductase inhibitors.
Looking further ahead, additional research in the role of lipids course of cerebrovascular disease is needed. Among the issues the possible relationship between intracranial hemorrhage and low cholesterol values. In addition, the revolution in neurogenetics provides the opportunity to identify those individuals with particular genetic polymorphisms that could interact with factors such as dietary cholesterol to place a person at very high risk for stroke.
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