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Low serum cholesterol and the risk of cerebral haemorrhage
atherosclerosis Atherosclerosis 119 (1996) l-6
Review article
Low serum cholesterol and the risk of cerebral haemorrhage Ian B. Puddey Depurtment of’ Medicine, University of Western Australia, GPO Box X2213, Perth, WA, 6001, Australia Reozived 21 March 1995; revision received 19 May 1995; accepted 21 June 1995
Abstract In addressingthe potential for any hazardsassociatedwith lowering serumcholesterol,a recent meta-analysisby Law and colleagues(Br Med J 1994;308:373) concludedthat that there wasno evidencethat a low or reducedserum cholesterolconcentration increasesmortality from any causeother than haemorrhagicstroke. In this review, the evidencefor this unexpectedassociationwill be addressed,and possiblemechanisms discussed.Overall implications of the phenomenon,particularly for the hypertensivepatient, will be addressedin the context of the anticipated consequences of lipid-loweringtherapy for all stroke, haemorrhagicand non-haemorrhagic,aswell asischaemicheart disease(IHI)). Keywords:
Serumcholesterol;Cerebralhaemorrhage;Lipid lowering therapy
1. The evidence 1.1. Prospective population studies The earliest evidence for an inverse relationship
between serum cholesterol level and increased risk of stroke came from prospective studies of Japanese populations [2,3]. In one study over a 16 year period in 16 491 citizens of Hiroshima and Nagasaki, all new cases of cerebrovascular disease were classified according to type. A subsequent examination for risk factors confirmed the paradox of an inverse correlation between risk of cerebral haemorrhage and serum cholesterol, with the authors attributing a declining incidence of cerebral haemorrhage in this population to both a decrease in systolic blood pressure and an increase in serum cholesterol levels with time.
The risk for stroke has historically been very high in the Japanese population, whereas the risk for myocardial infarction has been relatively low. Evidence that this paradox may be accounted for, in part at least, by the relatively lower cholesterol of Japanese has been provided by the Honolulu Heart Program, a prospective study with 18 years of follow-up of 7850 Japanese-American men living in Hawaii [4]. A higher incidence of haemorrhagic stroke was seen in men in the lowest quintile for serum cholesterol ( < 4.88 mM/l ( < 188 mg/dl)) with a relative risk of 2.55. Using data accumulated during the long-term follow-up, associations between autopsy-measured myocardial infarctions, cerebral infarction, and cerebral haemorrhage were all examined and showed patterns similar to those found for clinical disease.
OOZI-9150/96/$09.50 Q 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI 002 I-91 50(95)05634-Z
2
I.B. Puddey
1 Atherosclerosis
with a paradoxically high risk of stroke observed in those with low risk of coronary heart disease (CHD) [5]. This was not due to atherosclerosis in the major cerebral arteries, but was thought more likely due to lesions in the small intracerebral arteries consequent on low levels of serum cholesterol. Clinical findings from Japanese studies have been repeated and confirmed in a recent report of the Akita Pathology Study [6]: serum cholesterol levels were lower in the men with cerebral haemorrhage, but higher in subjects with significant atherosclerosis of their basal and penetrating cerebral arteries. Reports of this phenomenon have not, however, been confined to Japanese populations. An inverse relationship between low density lipoprotein (LDL) cholesterol and all forms of stroke was observed in 1584 American women followed up for 6 years in the Framingham Heart Study [7]. Similarly, there was an inverse relationship between serum cholesterol level and risk of death from haemorrhagic stroke among the 350 977 American men screened for the Multiple Risk Factor Intervention Trial (MRFIT) and followed up for six years [8], a finding replicated in three Chicago prospective epidemiological studies [91. Recent reports from Scandinavia have also suggested that a low cholesterol level predicts death from intracranial bleeding [ 10,111, but in both the Copenhagen study of 19 698 Danish women and men followed from 1976 through 1988 [lo], and a 20.5 year follow-up study of 54 385 Swedish participants in a health survey [ll], the association between cholesterol and risk of haemorrhagic stroke was U-shaped. 1.2. Cholesterol reduction trials Atkins et al. [12] conducted a meta-analysis of 13 published trials of cholesterol-lowering interventions (dietary modification, drugs, or both) to determine their combined effects on fatal and non-fatal stroke. No significant overall reduction of stroke morbidity or mortality could be demonstrated. When the three trials which utilized clofibrate were analyzed separately treatment significantly increased the risk for fatal stroke (odds ratio 2.64) but not for non-fatal stroke
I19 (1996)
l-6
(odds ratio 0.87). The only trial included in the analysis which reported specific data on haemorrhagic versus non-haemorrhagic stroke was the Helsinki Heart Study, in which fatal intracranial haemorrhage was more common among patients treated with gemfibrozil than in the placebo group, although this difference was not statistically significant [ 131. Law et al. [1] reviewed 10 cohort studies and 28 randomized trials of cholesterol lowering and concluded that there was an almost two-fold increase in the relative risk of haemorrhagic stroke at cholesterol concentrations less than 5.0 mmol/l ( < 193 mg/dl), an effect deemed relevant for an estimated 6% of people in Western populations [ 11. Hebert et al. [14] identified 11 trials for inclusion in an overview of the effects of lipid-lowering on the endpoint of all fatal and non-fatal strokes. The majority of the trials included did not provide information on the type of stroke and confidence intervals in a meta-analysis for fatal stroke were so wide as to include either a small protective effect or a potential harmful effect of cholesterol lowering. 2. Mechanism In any discussion of potential mechanisms, it is assumed that the relationship between intracerebra1 haemorrhage and a low serum cholesterol is one of cause and effect. This may be so but it is far from proven. Studies to date have not shown a dose response relationship, the heightened risk being confined to the lowest quintile of cholesterol in several of the populations studied [4,8]. Low cholesterol levels may be a marker for specific dietary habits (e.g., a low intake of fat and protein from animal sources, or a high intake of fish) or lifestyle (e.g., high alcohol consumption) which could be simultaneously influencing the risk for cerebral haemorrhage. Furthermore patients with extremely low concentrations of serum cholesterol as in abetalipoproteinaemia or patients with familial hypobetalipoproteinaemia, do not appear to be at increased risk of cerebral haemorrhage. In fact, those with familial hypobetalipoproteinaemia have overall longevity. Similarly although patients with abetalipoproteinaemia have red cell abnor-
I.B. Puddey
/Atherosclerosis
malities attributable to alterations in the lipid content of erythrocyte membranes, they do not appear to be at increased risk of cerebral haemorrhage. It must be acknowledged, however that prior to the recognition of the association between vitamin E deficiency and the neurological disorder, particular to patients with abetalipoproteinaemia, most patients with this disorder succumbed from complications of their neuropathy or immobility and did not survive into later years. This argument cannot be applied, however, to individuals with familial hypobetalipoproteinaemia, who have total cholesterol concentrations less than 3 mmol/l and LDL concentrations typically about 0.5 mmol/l. These caveats aside, there is evidence that the inverse association between a low serum cholesterol and risk of haemorrhagic stroke may be due to weakening of the arterial wall leading to the rupture of small intraparenchymal cerebral arteries [5]. Animal studies suggest that a hypercholesterolaemic diet in hypertensive rats reduces both cerebral arterionecrosis and the incidence of stroke u51. Hyperlipidaemic subjects have been reported to demonstrate increased plasma fibrinogen levels and enhanced fibrinolysis [ 161. Conversely, fibrates can both reduce plasma fibrinogen activity [17] and platelet aggregability [ 181, although whether this is a direct effect or mediated through their ability to lower triglycerides is unclear. Fibrate-induced alterations in haemostasis may have accounted for the particularly strong association with fatal stroke seen in those cholesterol-lowering trials that used clofibrate [7], as well as the increase in fatal haemorrhagic strokes seen in patients treated with gemfibrozil in the Helsinki Heart Study [ 131. 3. Clinical implications 3.1. Cholesterol
and cerebrovascular
disease
Haemorrhagic strokes represent only about 10% of all strokes and hence any discussion of the clinical implications of low cholesterol levels and increased risk of haemorrhagic stroke must consider the overall impact of cholesterol on risk for both haemorrhagic and non-haemorrhagic stroke. There is continuing controversy as to whether
119 (1996)
l-6
3
cholesterol is a risk factor for ischaemic stroke, given that several prospective population studies have failed to identify a consistent association between baseline serum cholesterol and subsequent risk of stroke [7,9,19,20]. One important reason for this outcome may have been the inability to classify accurately the major subtypes of stroke in some of these studies. However, total serum cholesterol emerged as a risk factor for stroke mortality in some large prospective studies, such as the 12 year follow-up of the Oslo study
Pll.
Case-control studies of patients with stroke, although variable in their conclusions [22-261, lend further support for elevated total cholesterol and low high density lipoprotein (HDL) cholesterol as risk factors for ischaemic stroke. One important confounder in this regard has been the lack of consideration of the acute effects of a stroke on the lipid profile [27] and the failure to standardize lipid measurement in relation to the time of onset of stroke. Self-initiated changes in diet and lifestyle following a stroke, or relative immobilization imposed by the stroke, may also complicate matters. Other recent studies have attempted to reduce the confounding influence of an acute stroke by studying subjects with transient or minor ischaemic attacks alone [28] or alternatively, performing case-control or population studies of subjects with either angiographic [29,30] or ultrasound [31,32] evidence of cerebrovascular disease. In general, these studies have confirmed that both elevated total cholesterol and a low HDL cholesterol are risk factors for ischaemic stroke. These results have not translated into a predictable benefit for stroke outcomes when cholesterol levels are lowered, with no effect of cholesterol-lowering on stroke morbidity and mortality reported in the previously cited meta-analysis of 13 separate trials [12]. The authors of this study did cautiously suggest however, that more aggressive lipid-lowering over longer periods of time may possibly confer significant protection against ischaemic stroke. This prediction has received some support from the recently completed Scandinavian Simvastatin Survival Study, Simvastatin lowered cholesterol by 35% during 5 to 6
4
I.B. Puddey
/ Atherosclerosis
years of follow-up, and post-hoc analysis revealing a significant reduction in total (i.e., fatal plus non-fatal) cerebrovascular events in the treatment group (relative risk 0.70) [33]. The recent identification of lipoprotein(a) (Lp(a)) as an independent risk factor for coronary artery disease has led to several studies of its potential role in the pathogenesis of stroke [25,34]. Further consideration of Lp(a) in studies of the nature of the association between lipids and haemorrhagic stroke is indicated, given its homology with plasminogen and its potential role as a competitive inhibitor of fibrinolysis. 3.2. Cholesterol
and coronary
artery disease
In the report of the Framingham Heart Study [7], it was felt unwarranted to conclude that a low level of LDL cholesterol while conferring a benefit for coronary artery disease risk carried a counterbalancing increased risk of death from haemorrhagic stroke. Similarly, in the MRFIT Study [8], the increased risk of death from haemorrhagic stroke was eclipsed by the public health impact of the positive association of higher serum cholesterol levels with death from both nonhaemorrhagic stroke and total cardiovascular disease. These conclusions have been consolidated by the recent meta-analysis of Law et al. [l] in which the balance of benefit was clearly in favour of the anticipated reduced mortality from coronary artery disease following a reduction in serum cholesterol. 3.3. The hypertensive patient
The risk-benefit ratio of cholesterol-lowering therapy has not been clearly determined for the patient with established hypertension. In the MRFIT Study, the increased risk of death from intracranial haemorrhage was confined to those men with diastolic blood pressure greater than 90 mmHg [8]. By contrast the inverse association between serum cholesterol and haemorrhagic stroke was significant only in normotensive men in the Honolulu Heart Study, with a similar but non-significant trend evident in hypertensive men [4]. In their meta-analysis of the effects of cholesterol lowering, Law et al. concluded that the increase in haemorrhagic risk at lower cholesterol
I19 (1996)
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concentrations was greatest in those with relatively higher blood pressure [l]. The recommendation that adequate control of blood pressure in hypertensive patients should be instituted in parallel with cholesterol-lowering therapy would therefore appear to’ be prudent advice in the context of current epidemiological evidence, particularly if the hypolipidaemic agents to be used have known influences on coagulation or fibrinolysis. Moreover, the relative potency of the 3-hydroxy-3-methylglutaryl-co-enzyme A (HMGCoA) reductase inhibitors in lowering serum cholesterol compared with the less effective modalities of diet, fibrates and nicotinic acid utilized in most of the cholesterol-lowering trials to date further underlines the need for adequate antihypertensive and lipid-lowering therapy to go hand in hand. In the recently published safety and efficacy study of lovastatin [35], 718 hypercholesterolaemic patients were treated with lovastatin alone or in combination, including 129 receiving antihypertensive therapy. It is reassuring that over the course of 5.2 years, 16 patients died from CHD but not one instance of cerebral haemorrhage or stroke was reported. Similarly, no haemorrhagic strokes were reported among the 4444 patients treated for a median 5.4 years in the Simvastatin Survival Study including 1154 patients with hypertension [33]. 4. Conclusion The consistency of results from longitudinal population studies together with meta-analyses of pooled data from several prospective trials of the effects of long-term cholesterol lowering therapy, provide persuasive and comprehensive support for the hypothesis that a low serum cholesterol is associated with an increased risk of haemorrhagic stroke. This phenomenon may account in part for the continuing controversy as to whether a reduction in serum cholesterol will predictably reduce risk from cerebrovascular disease. However, in drawing this conclusion, one must encompass the knowledge that the reduction afforded from risk of coronary artery disease and total cardiovascu‘lar disease by reducing serum cholesterol is so
I.B. Puddey
/ Atherosclerosis
substantial as to outweigh any increased risk of intracranial haemorrhage. This may not apply to individuals or populations where the risk of coronary artery disease is substantially less than the risk of haemorrhagic stroke (e.g., the Japanese population) and hence further epidemiologic evaluation of the phenomenon is essential, particularly given the relative potency of the newer lipid-lowering drugs. References [I] Law MK, Thompson SC, Wald NJ. Assessing possible hazards of reducing serum cholesterol. Br Med J 1994;308:373. [2] Lin CH. Shimuzu Y, Kato H, Robertson TL, Furonaka H Kodama K, Fukunaga Y. Cerebrovascular diseases in a fixed population of Hiroshima and Nagasaki, with special reference to relationship between type and risk factors. Stroke 1984;15:653. [3] Okada 11, Horibe H, Ohno Y, Hayakawa N, Aoki N. A prospective study of cerebrovascular disease in Japanese rural communities, Akabane and Asahi. 1. Evaluation of risk factors in the occurrence of cerebral haemorrhage and thrombosis. Stroke 1976;7:599. [4] Ya.no K. Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989;20:1460. [5] Reed DM. The paradox of high risk of stroke in populations with low risk of coronary heart disease. Am J Epidemics1 1990; 131:579 [6] Konishi M, lso H, Komachi Y, Iida M, Shimamoto T Jacobs DR Jr, Baba S, Sankai T, Ito M. Associations of serum total cholesterol, different types of stroke, and stenosis distribution of cerebral arteries. The Akita Pathology Study. Strokt: 1993;24:954. [7] Gordon T, Kannel WB, Castelli WP, Dawber TR. Lipoproteins, cardiovascular disease, and death. The Framingham Study. Arch Int Med 1981;141:1128. [8] Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six year mortality from stroke in 350 977 men screened for the multiple risk factor intervention trial. New Engl J Med 1989;320:904. [9] Dyer AR. Stamler J, Paul 0, Shekelle OB, Schoenberg JA Berkson DM. Serum cholesterol and risk of death from cancer and other causes in three Chicago epidemiologic studies. J Chron Dis 1989;34:249. [IO] Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: The Copenhagen city heart study. Br Med J 1994;309:11. [l I] Gatchev 0, Rastam L, Lindberg G, Gullberg B, Eklund GA, Isacsson SO. Subarachnoid hemorrhage, cerebral hemorrhage and serum cholesterol concentration in men and women. Ann Epidemiology 1993;3:403.
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5
[I21 Atkins D, Psaty BM, Koepsell TD, Longstreth WT. Larson EB. Cholesterol reduction and the risk for stroke in men. A meta-analysis of randomized, controlled trials. Ann lnt Med 1993;119:136. [I31 Frick MH, Elo 0, Haapa K, Heinonen OP, Heinsalmi P Helo PN. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidaemia. New Engl J Med 1987;317:1237. u41 Hebert PR, Gaziano JM, Hennekens CH. An overview of cholesterol lowering and risk of stroke. Arch Int Med 1995;155:50. [I51 Yamori Y, Horie R, Ohtaka M, Nara Y, Fukase M. Effect of hypercholesterolaemic diet on the incidence of cerebrovascular and myocardial lesions in spontaneously hypertensive rats (SHR). Clin Exp Pharmacol Physiol 1976;3(Suppl):205. U61Fletcher A, Alkjaersig N. Schonfeld G, Witztum J. Fibrinogen catabolism in patients with Type II and Type IV hyperlipidaemia. Arteriosclerosis 198 1;1:202. [I71 Branchi A, Rovellini A, Sommariva D, Gugliandolo AG Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolaemia. Thromb Haemost 1993;70:241, [181Pazzucconi F, Mannucci L, Gianfranceschi G. Maderna P Werber P, Franceschini G, Sirtori CR, Temoli E. Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregation in hypertriglyceridaemia. Eur J Clin Pharmacot 1992;43:219. [I91 Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. Br Med J 1991;303:276. [201Harmsen P. Rosengren A, Tsipogianni A, Wilhelmsen L. Risk factors for stroke in middle-aged men in Goteborg, Sweden. Stroke 1990;21:223. 1211Haheim LL, Holme I, Hjermann I, Leren P. Risk factors of stroke incidence and mortality. A 12-year follow-up of the Oslo Study. Stroke 1993;24:1484. WI Tilvis RS, Erkinjuntti T, Sulkava R, Farkkila M Miettinen TA. Serum lipids and fatty acids in ischemic strokes. Am Heart J 1987;113:615. ~231 Lindgren A, Nilsson-Ehle P, Norrving B. Johansson BB. Plasma lipids and lipoproteins in subtypes of stroke. Acta Neurol Stand 1992;86:572. v41 Sridharan R. Risk factors for ischemic stroke: a case control analysis. Neuroepidemiology 1992;11:24. 1251 Woo J. Lau E, Lam CW, Kay R, Teoh K, Wong HY, Pratt WY, Kreel L. Hypertension, lipoprotein(a), and apolipoprotein A-I as risk factors for stroke in the Chinese. Stroke 1991;22:203. WI Aronow WS, Ahn C. Correlation of serum lipids with the presence or absence of atherothrombotic brain infarction and peripheral arterial disease in 1834 men and women aged > 62 years. Am J Cardiol 1994;73:995. ~271 Woo J. Lam CW, Kay R, Wong HY, Teoh R, Nicholls MG. Acute and long-term changes in serum lipids after acute stroke. Stroke 1990;21:1407.
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[28] Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischaemic strokes. Br Med J 1991;303;605. [29] Homer D, Ingall TJ, Baker HL, O’Fallon WM, Kottke BA Whisnant JP. Serum lipids and lipoproteins are less powerful predictors of extracranial carotid atherosclerosis than are cigarette smoking and hypertension. Mayo Clinic Proc 1991;66:259. [30] Palomaki H, Kaste M, Raininko R, Salonen 0, Juvela S Sarna S. Risk factors for cervical atherosclerosis in patients with transient ischemic attack or minor ischemic stroke. Stroke 1993;24:970. [31] Szirmai IG, Kamondi A, Magyar H, Juhasz C. Relation of laboratory and clinical variables to the grade of carotid atherosclerosis. Stroke 1993;24: I81 I.
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[32] Prati P, Vanuzzo D, Casaroli M, Di Chiara A, De Biasi F, Feruglio GA. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke 1992;23: 1705. 1331 The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4s). Lancet 1994;344: 1383. [34] Pedro-Botet J, Senti M, Nogues X, Rubies-Prat J Roquer J, Olive J. Lipoprotein and apolipoprotein profile in men with ischemic stroke. Role of lipoprotein(a), triglyceriderich lipoproteins, and apolipoprotein E polymorphism. Stroke 1992;23: 1556. [35] Lovostatin Study Groups I-IV: Lovostatin 5-year safety and efficacy study. Arch Intern Med 1993;153:1079.
Review article
Low serum cholesterol and the risk of cerebral haemorrhage Ian B. Puddey Depurtment of’ Medicine, University of Western Australia, GPO Box X2213, Perth, WA, 6001, Australia Reozived 21 March 1995; revision received 19 May 1995; accepted 21 June 1995
Abstract In addressingthe potential for any hazardsassociatedwith lowering serumcholesterol,a recent meta-analysisby Law and colleagues(Br Med J 1994;308:373) concludedthat that there wasno evidencethat a low or reducedserum cholesterolconcentration increasesmortality from any causeother than haemorrhagicstroke. In this review, the evidencefor this unexpectedassociationwill be addressed,and possiblemechanisms discussed.Overall implications of the phenomenon,particularly for the hypertensivepatient, will be addressedin the context of the anticipated consequences of lipid-loweringtherapy for all stroke, haemorrhagicand non-haemorrhagic,aswell asischaemicheart disease(IHI)). Keywords:
Serumcholesterol;Cerebralhaemorrhage;Lipid lowering therapy
1. The evidence 1.1. Prospective population studies The earliest evidence for an inverse relationship
between serum cholesterol level and increased risk of stroke came from prospective studies of Japanese populations [2,3]. In one study over a 16 year period in 16 491 citizens of Hiroshima and Nagasaki, all new cases of cerebrovascular disease were classified according to type. A subsequent examination for risk factors confirmed the paradox of an inverse correlation between risk of cerebral haemorrhage and serum cholesterol, with the authors attributing a declining incidence of cerebral haemorrhage in this population to both a decrease in systolic blood pressure and an increase in serum cholesterol levels with time.
The risk for stroke has historically been very high in the Japanese population, whereas the risk for myocardial infarction has been relatively low. Evidence that this paradox may be accounted for, in part at least, by the relatively lower cholesterol of Japanese has been provided by the Honolulu Heart Program, a prospective study with 18 years of follow-up of 7850 Japanese-American men living in Hawaii [4]. A higher incidence of haemorrhagic stroke was seen in men in the lowest quintile for serum cholesterol ( < 4.88 mM/l ( < 188 mg/dl)) with a relative risk of 2.55. Using data accumulated during the long-term follow-up, associations between autopsy-measured myocardial infarctions, cerebral infarction, and cerebral haemorrhage were all examined and showed patterns similar to those found for clinical disease.
OOZI-9150/96/$09.50 Q 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI 002 I-91 50(95)05634-Z
2
I.B. Puddey
1 Atherosclerosis
with a paradoxically high risk of stroke observed in those with low risk of coronary heart disease (CHD) [5]. This was not due to atherosclerosis in the major cerebral arteries, but was thought more likely due to lesions in the small intracerebral arteries consequent on low levels of serum cholesterol. Clinical findings from Japanese studies have been repeated and confirmed in a recent report of the Akita Pathology Study [6]: serum cholesterol levels were lower in the men with cerebral haemorrhage, but higher in subjects with significant atherosclerosis of their basal and penetrating cerebral arteries. Reports of this phenomenon have not, however, been confined to Japanese populations. An inverse relationship between low density lipoprotein (LDL) cholesterol and all forms of stroke was observed in 1584 American women followed up for 6 years in the Framingham Heart Study [7]. Similarly, there was an inverse relationship between serum cholesterol level and risk of death from haemorrhagic stroke among the 350 977 American men screened for the Multiple Risk Factor Intervention Trial (MRFIT) and followed up for six years [8], a finding replicated in three Chicago prospective epidemiological studies [91. Recent reports from Scandinavia have also suggested that a low cholesterol level predicts death from intracranial bleeding [ 10,111, but in both the Copenhagen study of 19 698 Danish women and men followed from 1976 through 1988 [lo], and a 20.5 year follow-up study of 54 385 Swedish participants in a health survey [ll], the association between cholesterol and risk of haemorrhagic stroke was U-shaped. 1.2. Cholesterol reduction trials Atkins et al. [12] conducted a meta-analysis of 13 published trials of cholesterol-lowering interventions (dietary modification, drugs, or both) to determine their combined effects on fatal and non-fatal stroke. No significant overall reduction of stroke morbidity or mortality could be demonstrated. When the three trials which utilized clofibrate were analyzed separately treatment significantly increased the risk for fatal stroke (odds ratio 2.64) but not for non-fatal stroke
I19 (1996)
l-6
(odds ratio 0.87). The only trial included in the analysis which reported specific data on haemorrhagic versus non-haemorrhagic stroke was the Helsinki Heart Study, in which fatal intracranial haemorrhage was more common among patients treated with gemfibrozil than in the placebo group, although this difference was not statistically significant [ 131. Law et al. [1] reviewed 10 cohort studies and 28 randomized trials of cholesterol lowering and concluded that there was an almost two-fold increase in the relative risk of haemorrhagic stroke at cholesterol concentrations less than 5.0 mmol/l ( < 193 mg/dl), an effect deemed relevant for an estimated 6% of people in Western populations [ 11. Hebert et al. [14] identified 11 trials for inclusion in an overview of the effects of lipid-lowering on the endpoint of all fatal and non-fatal strokes. The majority of the trials included did not provide information on the type of stroke and confidence intervals in a meta-analysis for fatal stroke were so wide as to include either a small protective effect or a potential harmful effect of cholesterol lowering. 2. Mechanism In any discussion of potential mechanisms, it is assumed that the relationship between intracerebra1 haemorrhage and a low serum cholesterol is one of cause and effect. This may be so but it is far from proven. Studies to date have not shown a dose response relationship, the heightened risk being confined to the lowest quintile of cholesterol in several of the populations studied [4,8]. Low cholesterol levels may be a marker for specific dietary habits (e.g., a low intake of fat and protein from animal sources, or a high intake of fish) or lifestyle (e.g., high alcohol consumption) which could be simultaneously influencing the risk for cerebral haemorrhage. Furthermore patients with extremely low concentrations of serum cholesterol as in abetalipoproteinaemia or patients with familial hypobetalipoproteinaemia, do not appear to be at increased risk of cerebral haemorrhage. In fact, those with familial hypobetalipoproteinaemia have overall longevity. Similarly although patients with abetalipoproteinaemia have red cell abnor-
I.B. Puddey
/Atherosclerosis
malities attributable to alterations in the lipid content of erythrocyte membranes, they do not appear to be at increased risk of cerebral haemorrhage. It must be acknowledged, however that prior to the recognition of the association between vitamin E deficiency and the neurological disorder, particular to patients with abetalipoproteinaemia, most patients with this disorder succumbed from complications of their neuropathy or immobility and did not survive into later years. This argument cannot be applied, however, to individuals with familial hypobetalipoproteinaemia, who have total cholesterol concentrations less than 3 mmol/l and LDL concentrations typically about 0.5 mmol/l. These caveats aside, there is evidence that the inverse association between a low serum cholesterol and risk of haemorrhagic stroke may be due to weakening of the arterial wall leading to the rupture of small intraparenchymal cerebral arteries [5]. Animal studies suggest that a hypercholesterolaemic diet in hypertensive rats reduces both cerebral arterionecrosis and the incidence of stroke u51. Hyperlipidaemic subjects have been reported to demonstrate increased plasma fibrinogen levels and enhanced fibrinolysis [ 161. Conversely, fibrates can both reduce plasma fibrinogen activity [17] and platelet aggregability [ 181, although whether this is a direct effect or mediated through their ability to lower triglycerides is unclear. Fibrate-induced alterations in haemostasis may have accounted for the particularly strong association with fatal stroke seen in those cholesterol-lowering trials that used clofibrate [7], as well as the increase in fatal haemorrhagic strokes seen in patients treated with gemfibrozil in the Helsinki Heart Study [ 131. 3. Clinical implications 3.1. Cholesterol
and cerebrovascular
disease
Haemorrhagic strokes represent only about 10% of all strokes and hence any discussion of the clinical implications of low cholesterol levels and increased risk of haemorrhagic stroke must consider the overall impact of cholesterol on risk for both haemorrhagic and non-haemorrhagic stroke. There is continuing controversy as to whether
119 (1996)
l-6
3
cholesterol is a risk factor for ischaemic stroke, given that several prospective population studies have failed to identify a consistent association between baseline serum cholesterol and subsequent risk of stroke [7,9,19,20]. One important reason for this outcome may have been the inability to classify accurately the major subtypes of stroke in some of these studies. However, total serum cholesterol emerged as a risk factor for stroke mortality in some large prospective studies, such as the 12 year follow-up of the Oslo study
Pll.
Case-control studies of patients with stroke, although variable in their conclusions [22-261, lend further support for elevated total cholesterol and low high density lipoprotein (HDL) cholesterol as risk factors for ischaemic stroke. One important confounder in this regard has been the lack of consideration of the acute effects of a stroke on the lipid profile [27] and the failure to standardize lipid measurement in relation to the time of onset of stroke. Self-initiated changes in diet and lifestyle following a stroke, or relative immobilization imposed by the stroke, may also complicate matters. Other recent studies have attempted to reduce the confounding influence of an acute stroke by studying subjects with transient or minor ischaemic attacks alone [28] or alternatively, performing case-control or population studies of subjects with either angiographic [29,30] or ultrasound [31,32] evidence of cerebrovascular disease. In general, these studies have confirmed that both elevated total cholesterol and a low HDL cholesterol are risk factors for ischaemic stroke. These results have not translated into a predictable benefit for stroke outcomes when cholesterol levels are lowered, with no effect of cholesterol-lowering on stroke morbidity and mortality reported in the previously cited meta-analysis of 13 separate trials [12]. The authors of this study did cautiously suggest however, that more aggressive lipid-lowering over longer periods of time may possibly confer significant protection against ischaemic stroke. This prediction has received some support from the recently completed Scandinavian Simvastatin Survival Study, Simvastatin lowered cholesterol by 35% during 5 to 6
4
I.B. Puddey
/ Atherosclerosis
years of follow-up, and post-hoc analysis revealing a significant reduction in total (i.e., fatal plus non-fatal) cerebrovascular events in the treatment group (relative risk 0.70) [33]. The recent identification of lipoprotein(a) (Lp(a)) as an independent risk factor for coronary artery disease has led to several studies of its potential role in the pathogenesis of stroke [25,34]. Further consideration of Lp(a) in studies of the nature of the association between lipids and haemorrhagic stroke is indicated, given its homology with plasminogen and its potential role as a competitive inhibitor of fibrinolysis. 3.2. Cholesterol
and coronary
artery disease
In the report of the Framingham Heart Study [7], it was felt unwarranted to conclude that a low level of LDL cholesterol while conferring a benefit for coronary artery disease risk carried a counterbalancing increased risk of death from haemorrhagic stroke. Similarly, in the MRFIT Study [8], the increased risk of death from haemorrhagic stroke was eclipsed by the public health impact of the positive association of higher serum cholesterol levels with death from both nonhaemorrhagic stroke and total cardiovascular disease. These conclusions have been consolidated by the recent meta-analysis of Law et al. [l] in which the balance of benefit was clearly in favour of the anticipated reduced mortality from coronary artery disease following a reduction in serum cholesterol. 3.3. The hypertensive patient
The risk-benefit ratio of cholesterol-lowering therapy has not been clearly determined for the patient with established hypertension. In the MRFIT Study, the increased risk of death from intracranial haemorrhage was confined to those men with diastolic blood pressure greater than 90 mmHg [8]. By contrast the inverse association between serum cholesterol and haemorrhagic stroke was significant only in normotensive men in the Honolulu Heart Study, with a similar but non-significant trend evident in hypertensive men [4]. In their meta-analysis of the effects of cholesterol lowering, Law et al. concluded that the increase in haemorrhagic risk at lower cholesterol
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concentrations was greatest in those with relatively higher blood pressure [l]. The recommendation that adequate control of blood pressure in hypertensive patients should be instituted in parallel with cholesterol-lowering therapy would therefore appear to’ be prudent advice in the context of current epidemiological evidence, particularly if the hypolipidaemic agents to be used have known influences on coagulation or fibrinolysis. Moreover, the relative potency of the 3-hydroxy-3-methylglutaryl-co-enzyme A (HMGCoA) reductase inhibitors in lowering serum cholesterol compared with the less effective modalities of diet, fibrates and nicotinic acid utilized in most of the cholesterol-lowering trials to date further underlines the need for adequate antihypertensive and lipid-lowering therapy to go hand in hand. In the recently published safety and efficacy study of lovastatin [35], 718 hypercholesterolaemic patients were treated with lovastatin alone or in combination, including 129 receiving antihypertensive therapy. It is reassuring that over the course of 5.2 years, 16 patients died from CHD but not one instance of cerebral haemorrhage or stroke was reported. Similarly, no haemorrhagic strokes were reported among the 4444 patients treated for a median 5.4 years in the Simvastatin Survival Study including 1154 patients with hypertension [33]. 4. Conclusion The consistency of results from longitudinal population studies together with meta-analyses of pooled data from several prospective trials of the effects of long-term cholesterol lowering therapy, provide persuasive and comprehensive support for the hypothesis that a low serum cholesterol is associated with an increased risk of haemorrhagic stroke. This phenomenon may account in part for the continuing controversy as to whether a reduction in serum cholesterol will predictably reduce risk from cerebrovascular disease. However, in drawing this conclusion, one must encompass the knowledge that the reduction afforded from risk of coronary artery disease and total cardiovascu‘lar disease by reducing serum cholesterol is so
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substantial as to outweigh any increased risk of intracranial haemorrhage. This may not apply to individuals or populations where the risk of coronary artery disease is substantially less than the risk of haemorrhagic stroke (e.g., the Japanese population) and hence further epidemiologic evaluation of the phenomenon is essential, particularly given the relative potency of the newer lipid-lowering drugs. References [I] Law MK, Thompson SC, Wald NJ. Assessing possible hazards of reducing serum cholesterol. Br Med J 1994;308:373. [2] Lin CH. Shimuzu Y, Kato H, Robertson TL, Furonaka H Kodama K, Fukunaga Y. Cerebrovascular diseases in a fixed population of Hiroshima and Nagasaki, with special reference to relationship between type and risk factors. Stroke 1984;15:653. [3] Okada 11, Horibe H, Ohno Y, Hayakawa N, Aoki N. A prospective study of cerebrovascular disease in Japanese rural communities, Akabane and Asahi. 1. Evaluation of risk factors in the occurrence of cerebral haemorrhage and thrombosis. Stroke 1976;7:599. [4] Ya.no K. Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989;20:1460. [5] Reed DM. The paradox of high risk of stroke in populations with low risk of coronary heart disease. Am J Epidemics1 1990; 131:579 [6] Konishi M, lso H, Komachi Y, Iida M, Shimamoto T Jacobs DR Jr, Baba S, Sankai T, Ito M. Associations of serum total cholesterol, different types of stroke, and stenosis distribution of cerebral arteries. The Akita Pathology Study. Strokt: 1993;24:954. [7] Gordon T, Kannel WB, Castelli WP, Dawber TR. Lipoproteins, cardiovascular disease, and death. The Framingham Study. Arch Int Med 1981;141:1128. [8] Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six year mortality from stroke in 350 977 men screened for the multiple risk factor intervention trial. New Engl J Med 1989;320:904. [9] Dyer AR. Stamler J, Paul 0, Shekelle OB, Schoenberg JA Berkson DM. Serum cholesterol and risk of death from cancer and other causes in three Chicago epidemiologic studies. J Chron Dis 1989;34:249. [IO] Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: The Copenhagen city heart study. Br Med J 1994;309:11. [l I] Gatchev 0, Rastam L, Lindberg G, Gullberg B, Eklund GA, Isacsson SO. Subarachnoid hemorrhage, cerebral hemorrhage and serum cholesterol concentration in men and women. Ann Epidemiology 1993;3:403.
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[I21 Atkins D, Psaty BM, Koepsell TD, Longstreth WT. Larson EB. Cholesterol reduction and the risk for stroke in men. A meta-analysis of randomized, controlled trials. Ann lnt Med 1993;119:136. [I31 Frick MH, Elo 0, Haapa K, Heinonen OP, Heinsalmi P Helo PN. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidaemia. New Engl J Med 1987;317:1237. u41 Hebert PR, Gaziano JM, Hennekens CH. An overview of cholesterol lowering and risk of stroke. Arch Int Med 1995;155:50. [I51 Yamori Y, Horie R, Ohtaka M, Nara Y, Fukase M. Effect of hypercholesterolaemic diet on the incidence of cerebrovascular and myocardial lesions in spontaneously hypertensive rats (SHR). Clin Exp Pharmacol Physiol 1976;3(Suppl):205. U61Fletcher A, Alkjaersig N. Schonfeld G, Witztum J. Fibrinogen catabolism in patients with Type II and Type IV hyperlipidaemia. Arteriosclerosis 198 1;1:202. [I71 Branchi A, Rovellini A, Sommariva D, Gugliandolo AG Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolaemia. Thromb Haemost 1993;70:241, [181Pazzucconi F, Mannucci L, Gianfranceschi G. Maderna P Werber P, Franceschini G, Sirtori CR, Temoli E. Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregation in hypertriglyceridaemia. Eur J Clin Pharmacot 1992;43:219. [I91 Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. Br Med J 1991;303:276. [201Harmsen P. Rosengren A, Tsipogianni A, Wilhelmsen L. Risk factors for stroke in middle-aged men in Goteborg, Sweden. Stroke 1990;21:223. 1211Haheim LL, Holme I, Hjermann I, Leren P. Risk factors of stroke incidence and mortality. A 12-year follow-up of the Oslo Study. Stroke 1993;24:1484. WI Tilvis RS, Erkinjuntti T, Sulkava R, Farkkila M Miettinen TA. Serum lipids and fatty acids in ischemic strokes. Am Heart J 1987;113:615. ~231 Lindgren A, Nilsson-Ehle P, Norrving B. Johansson BB. Plasma lipids and lipoproteins in subtypes of stroke. Acta Neurol Stand 1992;86:572. v41 Sridharan R. Risk factors for ischemic stroke: a case control analysis. Neuroepidemiology 1992;11:24. 1251 Woo J. Lau E, Lam CW, Kay R, Teoh K, Wong HY, Pratt WY, Kreel L. Hypertension, lipoprotein(a), and apolipoprotein A-I as risk factors for stroke in the Chinese. Stroke 1991;22:203. WI Aronow WS, Ahn C. Correlation of serum lipids with the presence or absence of atherothrombotic brain infarction and peripheral arterial disease in 1834 men and women aged > 62 years. Am J Cardiol 1994;73:995. ~271 Woo J. Lam CW, Kay R, Wong HY, Teoh R, Nicholls MG. Acute and long-term changes in serum lipids after acute stroke. Stroke 1990;21:1407.
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[28] Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischaemic strokes. Br Med J 1991;303;605. [29] Homer D, Ingall TJ, Baker HL, O’Fallon WM, Kottke BA Whisnant JP. Serum lipids and lipoproteins are less powerful predictors of extracranial carotid atherosclerosis than are cigarette smoking and hypertension. Mayo Clinic Proc 1991;66:259. [30] Palomaki H, Kaste M, Raininko R, Salonen 0, Juvela S Sarna S. Risk factors for cervical atherosclerosis in patients with transient ischemic attack or minor ischemic stroke. Stroke 1993;24:970. [31] Szirmai IG, Kamondi A, Magyar H, Juhasz C. Relation of laboratory and clinical variables to the grade of carotid atherosclerosis. Stroke 1993;24: I81 I.
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[32] Prati P, Vanuzzo D, Casaroli M, Di Chiara A, De Biasi F, Feruglio GA. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke 1992;23: 1705. 1331 The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4s). Lancet 1994;344: 1383. [34] Pedro-Botet J, Senti M, Nogues X, Rubies-Prat J Roquer J, Olive J. Lipoprotein and apolipoprotein profile in men with ischemic stroke. Role of lipoprotein(a), triglyceriderich lipoproteins, and apolipoprotein E polymorphism. Stroke 1992;23: 1556. [35] Lovostatin Study Groups I-IV: Lovostatin 5-year safety and efficacy study. Arch Intern Med 1993;153:1079.