Light-to-Moderate Alcohol Consumption and the Risk of Stroke among U.S. Male Physicians
Klaus Berger, M.D., M.P.H., Umed A. Ajani, M.B., B.S., M.P.H., Carlos S. Kase, M.D., J. Michael Gaziano, M.D., Julie E. Buring, Sc.D., Robert J. Glynn, Ph.D., and Charles H. Hennekens, M.D., D.P.H.
Background Several studies have shown U- or J-shaped relationsbetween alcohol consumption and the risk of stroke. We evaluatedthe effect of light-to-moderate alcohol intake on the risk ofstroke, with separate analyses of ischemic stroke and hemorrhagicstroke.
Methods Our analyses were based on a prospective cohort studyof 22,071 male physicians, 40 to 84 years old, who were participatingin the Physicians' Health Study. At base line, the participantsreported that they had no history of stroke, transient ischemicattack, or myocardial infarction and were free of cancer. Alcoholintake, reported by 21,870 participants at base line, rangedfrom none or almost none to two or more drinks per day.
Results During an average of 12.2 years of follow-up, 679 strokeswere reported. As compared with participants who had less thanone drink per week, those who drank more had a reduced overallrisk of stroke (relative risk, 0.79; 95 percent confidence interval,0.66 to 0.94) and a reduced risk of ischemic stroke (relativerisk, 0.77; 95 percent confidence interval, 0.63 to 0.94). Therewas no statistically significant association between alcoholconsumption and hemorrhagic stroke. The overall relative risksof stroke for the men who had one drink per week, two to fourdrinks per week, five or six drinks per week, or one or moredrinks per day were 0.78 (95 percent confidence interval, 0.59to 1.04), 0.75 (95 percent confidence interval, 0.58 to 0.96),0.83 (95 percent confidence interval, 0.62 to 1.11), and 0.80(95 percent confidence interval, 0.64 to 0.99), respectively,in an analysis in which we controlled for major risk factorsfor stroke.
Conclusions Light-to-moderate alcohol consumption reduces theoverall risk of stroke and the risk of ischemic stroke in men.The benefit is apparent with as little as one drink per week.Greater consumption, up to one drink per day, does not increasethe observed benefit.
Stroke is a leading cause of morbidity and mortality in manycountries.1 Among the risk factors for stroke, potentially hazardousbut modifiable behavior such as alcohol consumption has drawnincreasing attention in recent years, especially after a U-shapedrelation was suggested between alcohol consumption and coronaryheart disease.2 Alcohol consumption is a modifiable behavior,and drinking moderate amounts of alcohol may have protectiveeffects against subtypes of stroke.3,4,5,6 Although most studiesshow a positive correlation between drinking and the risk ofhemorrhagic stroke,3,7,8,9,10 the relation with ischemic strokeis less clear.
Studies in North America and Europe have found a U- or J-shapedassociation, suggesting that moderate consumption of alcoholprovides protection against ischemic stroke.6,7,9,11,12,13,14,15However, the definition of moderate consumption has differedsubstantially among studies. Some definitions were based onthe frequency of alcohol consumption16 and others on the amount(in grams or units per day).15 In various studies, the categoriesassociated with the lowest risk of ischemic stroke were 1 to150 g per week,15 1 to 33 g per day,17 1 to 10 units per week,18two drinks per day,4,6 and consumption of alcohol less thanonce a day.16 The reports of a protective effect of drinkingwith respect to cardiovascular and cerebrovascular disease werecriticized, since most of the studies compared alcohol drinkerswith nondrinkers. The latter group might have included peoplewho abstained from alcohol because of poor health.3,19,20,21However, subsequent studies that excluded "sick quitters" fromthe analysis found the same J-shaped relation.22,23,24
Using data from the Physicians' Health Study, we prospectivelyexamined the associations between alcohol consumption and strokeand evaluated potential modifications of these relations byother risk factors for stroke.
Methods
Study Design
The Physicians' Health Study25 was a randomized, double-blind,placebo-controlled trial designed to test the effect of low-doseaspirin on the risk of cardiovascular disease and the effectof beta carotene on the risk of cancer.26 Briefly, 22,071 U.S.male physicians, who were 40 to 84 years of age at the timeof enrollment in 1982, were randomly assigned to receive aspirin,beta carotene, both agents, or placebo according to a two-by-twofactorial design. All participants reported at base line thatthey did not have a history of stroke, transient ischemic attack,myocardial infarction, active liver disease, or peptic ulcerdisease. In January 1988 the aspirin component of the studywas terminated early because of a statistically significant44 percent reduction in the risk of a first myocardial infarctionamong physicians in the aspirin group.25 The beta carotene componentof the study continued until its scheduled termination on December31, 1995. This report includes data available as of October1995, when the participants had been followed for an averageof 12.2 years. Follow-up data on morbidity and mortality wereavailable for more than 99 percent of the study participants.
Information was collected at base line by means of a mailedquestionnaire, which included questions about alcohol consumption;age; height; weight; systolic and diastolic blood pressure;history of angina pectoris, diabetes mellitus, and hypertension;and cigarette smoking. At base line, 21,870 of the physiciansresponded to the following question about alcohol consumption:"How often do you usually consume alcoholic beverages (beer,wine, or liquor)?" The possible responses were rarely or never,one to three per month, one per week, two to four per week,five or six per week, one per day, or two or more per day.27These responses were interpreted as the number of drinks consumedper unit of time. Alcohol consumption was reassessed at 84 monthsof follow-up, and a high correlation was found between theseresponses and the responses at base line. Systolic and diastolicblood pressure were self-reported blood-pressure levels at baseline. Validation studies of physician-measured blood pressureshow a high correlation with self-reports of systolic pressure(r=0.72) and diastolic pressure (r=0.60, P<0.001 for bothcomparisons).28
Every six months for the first year and annually thereafter,the participants were mailed questionnaires requesting informationabout their compliance with the randomized treatment assignmentand about newly diagnosed conditions, including stroke and transientischemic attack. Deaths were usually reported by family membersor by the postal authorities and were verified by a review ofall available medical records, death certificates, and eyewitnessaccounts, if relevant. Only first cases of stroke were counted.A diagnosis of stroke was confirmed only after medical recordsand all other available information had been reviewed by theEnd Points Committee (consisting of two internists, one cardiologist,and one neurologist, who were unaware of the treatment assignments).A stroke was defined as a focal neurologic deficit of vascularmechanism that lasted more than 24 hours. Strokes were classifiedaccording to the probable mechanism (ischemic or hemorrhagic)on the basis of medical records, reports of brain imaging, andthe judgment of the neurologist on the End Points Committee.There was a high level of interobserver agreement in the diagnosisof hemorrhagic and ischemic stroke throughout the study.29 Casesof fatal stroke were documented by evidence of a cerebrovascularmechanism obtained from all available sources, including deathcertificates and hospital records.
Statistical Analysis
Since only 674 physicians reported that they consumed alcoholtwo or more times a day, this highest category of alcohol intakewas combined with the second highest category (once a day).The categories rarely or never and one to three times a monthwere also combined to form a larger reference group. Cox proportional-hazardsmodels30 were used to estimate the relative risk of stroke associatedwith alcohol consumption. We calculated relative risks for thetotal group of participants with stroke (ischemic or hemorrhagic,hereafter referred to as total stroke) and for participantswith each subtype of stroke when age, systolic blood pressure,smoking, body-mass index (defined as the weight in kilogramsdivided by the square of the height in meters), exercise, historyof diabetes, current treatment for hypertension, and randomizedtreatment assignment were controlled for. Tests of linear trendwere performed by using each category as an ordinal variablein the proportional-hazards models. The assumption of proportionalhazards was tested and was not violated. Age, body-mass index,smoking, systolic blood pressure, and exercise were analyzedfor their effect on the association between alcohol consumptionand stroke. For this analysis, an interaction term for alcoholconsumption and each variable was included in separate models.
Results
During an average of 12.2 years of follow-up, 679 first strokeswere reported (557 ischemic strokes, 88 hemorrhagic strokes,and 34 strokes of unknown type). Table 1 shows base-line characteristicsof the participants according to categories of alcohol consumption.The mean systolic and diastolic blood pressures were lowestamong participants who had one to four drinks per week and werehighest among those in the two highest categories of alcoholconsumption. The proportion of participants with hypertensionwas higher among those in the two highest categories of alcoholconsumption than among those in the other categories. The percentageof men who had never smoked decreased consistently with increasingalcohol intake. The percentage of current smokers was significantlyhigher among the men who had at least one drink per day thanamong those who consumed less alcohol. The percentage of menwho were overweight (body-mass index, 27.8) decreased with increasingalcohol intake.
Table 1. Base-Line Characteristics of the Study Participants According to Alcohol Consumption.
The overall effect of alcohol consumption on the risk of totalstroke, ischemic stroke, and hemorrhagic stroke is shown inTable 2. The men who had less than one drink per week were chosenas the reference group. After adjustment for major risk factorsfor stroke, there were significant reductions in the risk oftotal stroke (21 percent) and ischemic stroke (23 percent) amongthe men who had one or more drinks a week. No statisticallysignificant association was observed between alcohol consumptionand hemorrhagic stroke.
Table 2. Relative Risk of Ischemic or Hemorrhagic Stroke (Total Stroke) and Subtypes of Stroke According to Alcohol Consumption.
The relative risk of total stroke according to the level ofalcohol consumption is shown in Table 3. After adjustment forage and treatment assignment, the largest risk reductions werefound among the men who had one to four drinks per week. Furtheradjustment for systolic blood pressure, current treatment forhypertension, smoking, body-mass index, diabetes, and exerciserevealed an L-shaped, almost flat association, with similarrisk reductions of about 20 percent for all categories of alcoholconsumption (Table 3 and Figure 1).
Figure 1. Relative Risk of Ischemic or Hemorrhagic Stroke (Total Stroke), According to Alcohol Consumption.
The reference category of alcohol consumption was less than one drink a week. Bars denote 95 percent confidence intervals.
The relative risk of subtypes of stroke, after adjustment forimportant confounders, is shown in Table 4. Reductions in therisk of ischemic stroke were similar in magnitude to those inthe risk of total stroke and were of borderline significance.Alcohol intake was not significantly associated with the riskof hemorrhagic stroke.
Table 4. Relative Risk of Subtypes of Stroke According to Alcohol Consumption.
In secondary analyses (data not shown), we examined the effectsof other risk factors for stroke on the relation between alcoholintake and stroke. No interactions with age, body-mass index,or smoking were found. We found significant interactions withsystolic blood pressure (P=0.02) and exercise (P= 0.03). Ananalysis stratified according to systolic blood pressure (<130,130 to 139, or 140 mm Hg) showed a risk reduction only amongparticipants with blood pressure of 140 mm Hg or higher (relativerisk for men who had one to six drinks per week, as comparedwith those who had less than one drink per week, 0.57; 95 percentconfidence interval, 0.42 to 0.79; relative risk for men whohad one or more drinks per day, 0.54; 95 percent confidenceinterval, 0.39 to 0.75). With respect to exercise, drinkinghad a beneficial effect only in the group of physicians whoexercised at least once a week.
Discussion
The focus of this analysis was the relation between light-to-moderatealcohol consumption and the risk of stroke. The Physicians'Health Study offered the opportunity to evaluate the relativelynarrow range of alcohol intake of one to seven drinks per week(i.e., light-to-moderate intake, accounting for about 97 percentof our sample27), corresponding to the beneficial part of theU- or J-shaped relation between alcohol consumption and strokethat other studies have suggested. We found an L-shaped associationbetween alcohol intake and total stroke, with a risk reductionof about 20 percent after adjustment for important confounders.The shape of this relation corresponds to the first part ofthe J-shaped curve shown by other studies.3,6 The benefit wasobserved among physicians who had only one alcoholic drink perweek, and the magnitude of this protective effect did not increasewith increased alcohol consumption. The relation between alcoholconsumption and ischemic stroke had the same flat shape, andthe risk reductions were similar in magnitude.
The protective effect of light-to-moderate drinking with respectto total stroke or ischemic stroke has varied considerably,with risk reductions of 20 to 90 percent found in other studies.3,4A recent population-based case–control study reportedan odds ratio of 0.51 for ischemic stroke in the group withmoderate alcohol consumption.6 Most cohort studies have reportedrisk reductions of 20 to 40 percent. Our result is similar inmagnitude. However, our population differs from that in otherstudies in that it consists of healthy men of high socioeconomicand education-al status. Their risk-factor profile differs substantiallyfrom that of men in the general U.S. population. In particular,only 3.1 percent of the participants in our study reported thatthey had more than one drink per day,27 confirming that heavydrinking was very rare in this population. For this reason,it is not possible to draw any conclusions about the participantswho reported having two or more drinks per day.
Like other studies involving predominantly white populations,our study showed that the majority of strokes were ischemic;only 13 percent were hemorrhagic. This finding explains thesimilarity of the relations of alcohol consumption with totalstroke and with ischemic stroke.
In prior studies, the beneficial effect of alcohol on the riskof stroke was observed over a rather broad range of alcoholintake (e.g., 1 to 150 g per week15), as a consequence of definingcategories broadly or combining them to provide stable estimatesin the analysis. In contrast, our analysis had the power toexamine risks within five narrowly defined categories of alcoholconsumption, with four of them corresponding to the beneficialpart of the suggested associations. With this approach, we foundthat alcohol had a beneficial effect in men who had as littleas one drink per week, a finding that would have been maskedif we had used broader categories. The flat shape of the associationwith total stroke also suggests that the nadir of the observedbenefit is not a single category of alcohol consumption butrather a range of consumption from one to seven drinks per week.
Our study has a number of limitations. First, there may havebeen some incorrect reports of alcohol consumption by the participantsat base line, leading to a certain degree of misclassificationof this variable. However, since all information was assessedat base line, before the occurrence of stroke, any misclassificationdue to an incorrect report was nondifferential.31 In addition,studies have shown that the reliability of self-reported alcoholconsumption in the general population, including health careprofessionals, is good32,33 and also that physicians accuratelyreport their own cardiovascular risk factors.28,34 Furthermore,both high-density lipoprotein (HDL) cholesterol and blood pressure,measures known to be correlated with levels of alcohol use,had the expected associations with the reported amounts of alcoholconsumption in the Physicians' Health Study,27 providing furtherevidence of the reliability of self-reporting in this cohort.
Nonetheless, the possibility of systematic underreporting ofalcohol consumption must be considered. If it occurred, theobserved association between alcohol use and reduced risk ofstroke would be artificially shifted toward lower drinking categories,leading to an erroneous, lower nadir for the relation betweenalcohol intake and the risk of stroke. However, since we observeda beneficial effect at a very low level of alcohol intake (onedrink a week), a slight shift of the curve to the right wouldstill reveal an effect over a range of moderate levels of alcoholintake.
Misclassification due to a change in the level of alcohol consumptionafter base line is also possible. However, if there was suchan effect in this cohort, it was probably small, since we founda high correlation between alcohol consumption at base lineand at 84 months.
The use of persons who never drank as the reference group inepidemiologic studies of the health effects of alcohol consumptionis often questioned, because some of these abstainers mighthave given up drinking for reasons of health. However, the physiciansin our study reported at base line that they had no historyof myocardial infarction, transient ischemic attack, or strokeand that they were free of active liver disease and peptic ulcer,conditions that could lead to abstention from drinking alcohol.
Finally, the questionnaire asked about the frequency of drinking,but the participants may have consumed more than one drink ona particular occasion. However, since the nadir of the riskreduction was observed over a range of categories of moderatedrinking, rather than a single category, the shape of the associationwould not be affected.
We could not assess the possibility of a differential effectof specific types of alcohol on the risk of stroke, as somestudies have suggested,35,36 since the questionnaire did notask about the type of beverage. We also had no information aboutdrinking patterns. Since binge drinking may be a risk factorfor stroke, especially for hemorrhagic stroke in young adults,37,38,39this risk could not be specified. However, since our cohortconsisted of middle-aged and elderly men of high socioeconomicstatus, a group with a low incidence of binge drinking,40 anyeffect of such drinking would probably have been small. Finally,the possibility of residual confounding was substantially reducedby our use of a cohort of physicians that was homogeneous withrespect to education and socioeconomic status.
The effects of alcohol on the body are complex and involve anumber of biologic mechanisms. Moderate alcohol consumptionhas an inverse relation with arteriosclerosis of the large arteriesof the circle of Willis and the carotid arteries41,42 but notwith arteriosclerosis of the small, intracerebral arteries.43This effect could be due to a reduction of Lp(a) lipoprotein,since Lp(a) lipoprotein levels are related to the extent ofcarotid arteriosclerosis.44 Elevated levels of Lp(a) lipoproteinare a risk factor for coronary heart disease,45,46,47 have beenfound to be elevated in survivors of stroke,48 and are reducedby alcohol intake.49 In addition, there is evidence that vascularendothelial factors, especially nitric oxide, provide protectionagainst atherosclerosis.50,51 In experimental studies, the activityof nitric oxide at the vessel wall was enhanced by ethanol throughthe induction of the enzyme nitric oxide synthase.52
Another explanation for the effect of alcohol on the risk ofstroke is the finding that alcohol increases HDL cholesterollevels,53,54 which are inversely related to arteriosclerosisat many sites, including the carotid arteries.41,55 HDL cholesterollevels are lower in survivors of stroke than in controls.56,57,58However, changes in HDL cholesterol levels only partially explainthe inverse relation between alcohol consumption and death fromcardiovascular causes.53 Furthermore, a recent study6 suggestedthat the observed association between moderate alcohol consumptionand a reduced risk of stroke was independent of the HDL cholesterollevel.
These findings suggest that hemostasis plays a part in the protectiveeffect of alcohol on the risk of stroke. Alcohol alters coagulationin a number of ways. It reduces platelet aggregation59,60 byincreasing the ratio of prostacyclin to thromboxane,60 and itdecreases the aggregation and increases the deformability ofred cells.61 In addition, alcohol decreases the risk of clottingby reducing fibrinogen levels and increasing the levels of tissueplasminogen activator.62,63,64 The latter effect is paradoxical,since elevated levels of tissue plasminogen activator are correlatedwith an increased risk of ischemic stroke,65 yet alcohol consumption,although it reduces the risk of stroke, is associated with increasedplasma levels of tissue plasminogen activator.63 Although elevatedlevels of tissue plasminogen activator increase the risk ofischemic stroke, with moderate alcohol use the deleterious effectof tissue plasminogen activator is probably outweighed by theother beneficial effects of alcohol on HDL cholesterol, Lp(a)lipoprotein, platelet aggregation, and fibrinogen, resultingin a net benefit of alcohol use. Thus, the relative magnitudeof the effect of the individual factors, both positive and negative,and their interplay probably determine the ultimate effect ofalcohol on the risk of stroke.
In summary, light-to-moderate consumption of alcohol (one toseven drinks per week) reduced the risks of total stroke andof ischemic stroke in a cohort of healthy, predominantly whitephysicians. Although this finding may be important for personswho consume alcoholic beverages with low or moderate frequency,no generalizations about the benefits of a change in lifestyleshould be drawn from the observation. The risk reduction associatedwith such a change is clearly smaller than that associated withmedical interventions, such as treatment for hypertension. Moreover,aside from the serious morbidity and social problems relatedto alcohol use, it has been shown that in a large population,any increase in alcohol consumption is associated with a proportionateincrease in heavy drinking.66 Heavy drinking is a risk factorfor hemorrhagic and ischemic stroke,3,6,17 as well as for morbidityand mortality from other causes; therefore, in the words ofMarmot and Brunner, "Any public health recommendation that emphasizesthe positive aspects of alcohol would be likely . . . to domore harm than good."22
Supported by grants from the National Institutes of Health (CA34944, CA 40360, HL 26490, and HL 34595) and by a grant fromthe German Academic Exchange Service (to Dr. Berger).
We are indebted to the staff of the Physicians' Health Studyand to the dedicated and conscientious physicians who participatedin this trial.
Source Information
From the Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital (K.B., U.A.A., J.M.G., J.E.B., R.J.G.); the Massachusetts Veterans Epidemiology Research and Information Center, Department of Veterans Affairs Boston Healthcare System (J.M.G.); the Department of Ambulatory Care and Prevention, Harvard Medical School (J.E.B.); the Department of Biostatistics, Harvard School of Public Health (R.J.G.); the Department of Neurology, Boston University School of Medicine (C.S.K.) — all in Boston; the Institute of Epidemiology and Social Medicine and the Department of Neurology, University of Muenster, Muenster, Germany (K.B.); and the Department of Epidemiology and Public Health, University of Miami School of Medicine, Miami (C.H.H.).
Address reprint requests to Dr. Ajani at the Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave. E., Boston, MA 02215, or at uajani{at}rics.bwh.harvard.edu.
References
Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349:1436-1442. [CrossRef][Medline]
Renaud S, Criqui MH, Farchi G, Veenstra J. Alcohol drinking and coronary heart disease. In: Verschuren PM, ed. Health issues related to alcohol consumption. Washington, D.C.: International Life Sciences Institute Press, 1993:81-123.
Camargo CA Jr. Moderate alcohol consumption and stroke: the epidemiologic evidence. Stroke 1989;20:1611-1626. [Free Full Text]
Camargo CA Jr. Case-control and cohort studies of moderate alcohol consumption and stroke. Clin Chim Acta 1996;246:107-119. [CrossRef][Medline]
Scherr PA, LaCroix AZ, Wallace RB, et al. Light to moderate alcohol consumption and mortality in the elderly. J Am Geriatr Soc 1992;40:651-657. [Medline]
Sacco RL, Elkind M, Boden-Albala B, et al. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999;281:53-60. [Free Full Text]
Gill JS, Shipley MJ, Tsementzis SA, et al. Alcohol consumption -- a risk factor for hemorrhagic and non-hemorrhagic stroke. Am J Med 1991;90:489-497. [Medline]
Kono S, Ikeda M, Tokudome S, Nishizumi M, Kuratsune M. Alcohol and mortality: a cohort study of male Japanese physicians. Int J Epidemiol 1986;15:527-532. [Free Full Text]
Stampfer MJ, Colditz GA, Willett WC, Speizer FE, Hennekens CH. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 1988;319:267-273. [Abstract]
Donahue RP, Abbott RD, Reed DM, Yano K. Alcohol and hemorrhagic stroke: the Honolulu Heart Program. JAMA 1986;255:2311-2314. [Free Full Text]
Gill JS, Shipley MJ, Hornby RH, Gill SK, Beevers DG. A community case-control study of alcohol consumption in stroke. Int J Epidemiol 1988;17:542-547. [Free Full Text]
Gill JS, Zezulka AV, Shipley MJ, Gill SK, Beevers DG. Stroke and alcohol consumption. N Engl J Med 1986;315:1041-1046. [Abstract]
Rodgers H, Aitken PD, French JM, Curless RH, Bates D, James OF. Alcohol and stroke: a case-control study of drinking habits past and present. Stroke 1993;24:1473-1477. [Free Full Text]
Wolf PA, D'Agostino RB, Odell P, Belanger AJ, Hodges D, Kannel WB. Alcohol consumption as a risk factor for stroke: the Framingham study. Ann Neurol 1988;24:177-177.abstract
Palomäki H, Kaste M. Regular light-to-moderate intake of alcohol and the risk of ischemic stroke: is there a beneficial effect? Stroke 1993;24:1828-1832. [Free Full Text]
Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N Engl J Med 1997;337:1705-1714. [Free Full Text]
Kiyohara Y, Kato I, Iwamoto H, Nakayama K, Fujishima M. The impact of alcohol and hypertension on stroke incidence in a general Japanese population: The Hisayama Study. Stroke 1995;26:368-372. [Free Full Text]
Palmer AJ, Fletcher AE, Bulpitt CJ, et al. Alcohol intake and cardiovascular mortality in hypertensive patients: report from the Department of Health Hypertension Care Computing Project. J Hypertens 1995;13:957-964. [CrossRef][Medline]
Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet 1988;2:1267-1273. [Medline]
Shaper AG. Alcohol and mortality: a review of prospective studies. Br J Addict 1990;85:837-847. [CrossRef][Medline]
Wannamethee SG, Shaper AG. Patterns of alcohol intake and risk of stroke in middle-aged British men. Stroke 1996;27:1033-1039. [Free Full Text]
Marmot M, Brunner E. Alcohol and cardiovascular disease: the status of the U shaped curve. BMJ 1991;303:565-568.
Criqui MH. The reduction of coronary heart disease with light to moderate alcohol consumption: effect or artifact? Br J Addict 1990;85:854-857. [CrossRef]
Boffetta P, Garfinkel L. Alcohol drinking and mortality among men enrolled in an American Cancer Society prospective study. Epidemiology 1990;1:342-348. [Medline]
Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129-135. [Abstract]
Manson JE, Buring JE, Satterfield S, Hennekens CH. Baseline characteristics of participants in the Physicians' Health Study: a randomized trial of aspirin and beta-carotene in U.S. physicians. Am J Prev Med 1991;7:150-154. [Medline]
Camargo CA Jr, Hennekens CH, Gaziano JM, Glynn RJ, Manson JE, Stampfer MJ. Prospective study of moderate alcohol consumption and mortality in US male physicians. Arch Intern Med 1997;157:79-85. [Free Full Text]
Klag MJ, He J, Mead LA, Ford DE, Pearson TA, Levine DM. Validity of physicians' self-reports of cardiovascular disease risk factors. Ann Epidemiol 1993;3:442-447. [Medline]
Berger K, Kase CS, Buring JE. Interobserver agreement in the classification of stroke in the Physicians' Health Study. Stroke 1996;27:238-242. [Free Full Text]
Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220.
Williams GD, Aitken SS, Malin H. Reliability of self-reported alcohol consumption in a general population survey. J Stud Alcohol 1985;46:223-227. [Medline]
Giovannucci E, Colditz G, Stampfer MJ, et al. The assessment of alcohol consumption by a simple self-administered questionnaire. Am J Epidemiol 1991;133:810-817. [Free Full Text]
Ascherio A, Rimm EB, Giovannucci EL, et al. A prospective study of nutritional factors and hypertension among US men. Circulation 1992;86:1475-1484. [Free Full Text]
Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992;339:1523-1526. [CrossRef][Medline]
Ruf JC, Berger JL, Renaud S. Platelet rebound effect of alcohol withdrawal and wine drinking in rats: relation to tannins and lipid peroxidation. Arterioscler Thromb Vasc Biol 1995;15:140-144. [Free Full Text]
Hillbom M, Kaste M. Alcohol intoxication: a risk factor for primary subarachnoid hemorrhage. Neurology 1982;32:706-711. [Free Full Text]
Juvela S, Hillbom M, Numminen H, Koskinen P. Cigarette smoking and alcohol consumption as risk factors for aneurysmal subarachnoid hemorrhage. Stroke 1993;24:639-646. [Free Full Text]
Juvela S, Hillbom M, Palomäki H. Risk factors for spontaneous intracerebral hemorrhage. Stroke 1995;26:1558-1564. [Free Full Text]
Kauhanen J, Kaplan GA, Goldberg DE, Salonen JT. Beer binging and mortality: results from the Kuopio ischaemic heart disease risk factor study, a prospective population based study. BMJ 1997;315:846-851. [Free Full Text]
Kiechl S, Willeit J, Egger G, Oberhollenzer M, Aichner F. Alcohol consumption and carotid atherosclerosis: evidence of dose-dependent atherogenic and antiatherogenic effects: results from the Bruneck Study. Stroke 1994;25:1593-1598. [Abstract]
Kiechl S, Willeit J, Rungger G, Egger G, Oberhollenzer F, Bonora E. Alcohol consumption and atherosclerosis: what is the relation? Prospective results from the Bruneck Study. Stroke 1998;29:900-907. [Free Full Text]
Reed DM, Resch JA, Hayashi T, MacLean CJ, Yano K. A prospective study of cerebral artery atherosclerosis. Stroke 1988;19:820-825. [Free Full Text]
Watts GF, Mazurkiewicz JC, Tonge K, Nelson V, Warburton FG, Slavin BM. Lipoprotein(a) as a determinant of the severity of angiographically defined carotid atherosclerosis. QJM 1995;88:321-326.
Gordon T, Kannel WB, Castelli WP, Dawber TR. Lipoproteins, cardiovascular disease, and death: the Framingham Study. Arch Intern Med 1981;141:1128-1131. [Free Full Text]
Langer RD, Criqui MH, Reed DM. Lipoproteins and blood pressure as biological pathways for effect of moderate alcohol consumption on coronary heart disease. Circulation 1992;85:910-915. [Free Full Text]
Rath M, Niendorf A, Reblin T, Dietel M, Krebber HJ, Beisiegel U. Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients. Arteriosclerosis 1989;9:579-592. [Erratum, Arteriosclerosis 1990;10:1147.] [Free Full Text]
Jurgens G, Koltringer P. Lipoprotein(a) in ischemic cerebrovascular disease: a new approach to the assessment of risk for stroke. Neurology 1987;37:513-515. [Free Full Text]
Nago N, Kayaba K, Hiraoka J, et al. Lipoprotein(a) levels in the Japanese population: influence of age and sex, and relation to atherosclerotic risk factors: the Jichi Medical School Cohort Study. Am J Epidemiol 1995;141:815-821. [Free Full Text]
Quyyumi AA. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 1998;105:32S-39S. [Medline]
Fields CE, Makhoul RG. Vasomotor tone and the role of nitric oxide. Semin Vasc Surg 1998;11:181-192. [Medline]
Criqui MH, Cowan LD, Tyroler HA, et al. Lipoproteins as mediators for the effects of alcohol consumption and cigarette smoking on cardiovascular mortality: results from the Lipid Research Clinics Follow-up Study. Am J Epidemiol 1987;126:629-637. [Free Full Text]
Flegal KM, Cauley JA. Alcohol consumption and cardiovascular risk factors. Recent Dev Alcohol 1985;3:165-180. [Medline]
Kasturi R, Yatsu FM, Alam R, Rogers S. Restriction fragment length polymorphism of the apoprotein A-I-C-III gene cluster in control and stroke-prone white and black subjects: racial differences. Stroke 1992;23:1257-1264. [Free Full Text]
Bihari-Varga M, Szekely J, Gruber E. Plasma high density lipoproteins in coronary, cerebral and peripheral vascular disease: the influence of various risk factors. Atherosclerosis 1981;40:337-345. [CrossRef][Medline]
Adams RJ, Carroll RM, Nichols FT, et al. Plasma lipoproteins in cortical versus lacunar infarction. Stroke 1989;20:448-452. [Free Full Text]
Glueck CJ, Rorick MH, Schmerler M, et al. Hypofibrinolytic and atherogenic risk factors for stroke. J Lab Clin Med 1995;125:319-325. [Medline]
Torres Duarte AP, Dong QS, Young J, Abi-Younes S, Myers AK. Inhibition of platelet aggregation in whole blood by alcohol. Thromb Res 1995;78:107-115. [CrossRef][Medline]
Landolfi R, Steiner M. Ethanol raises prostacyclin in vivo and in vitro. Blood 1984;64:679-682. [Free Full Text]
Altura BM, Altura BT. Role of magnesium and calcium in alcohol-induced hypertension and strokes as probed by in vivo television microscopy, digital image microscopy, optical spectroscopy, 31P-NMR, spectroscopy and a unique magnesium ion-selective electrode. Alcohol Clin Exp Res 1994;18:1057-1068. [CrossRef][Medline]
Ridker PM, Vaughan DE, Stampfer MJ, Sacks FM, Hennekens CH. A cross-sectional study of endogenous tissue plasminogen activator, total cholesterol, HDL cholesterol, and apolipoproteins A-I, A-II, and B-100. Arterioscler Thromb 1993;13:1587-1592. [Free Full Text]
Ridker PM, Vaughan DE, Stampfer MJ, Glynn RJ, Hennekens CH. Association of moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator. JAMA 1994;272:929-933. [Free Full Text]
Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993;118:956-963. [Free Full Text]
Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994;343:940-943. [CrossRef][Medline]
Rose G, Day S. The population mean predicts the number of deviant individuals. BMJ 1990;301:1031-1034.
Streppel, M T, Ocke, M C, Boshuizen, H C, Kok, F J, Kromhout, D
(2009). Long-term wine consumption is related to cardiovascular mortality and life expectancy independently of moderate alcohol intake: the Zutphen Study. J. Epidemiol. Community Health
63: 534-540
[Abstract][Full Text]
Laonigro, I., Correale, M., Di Biase, M., Altomare, E.
(2009). Alcohol abuse and heart failure. Eur J Heart Fail
11: 453-462
[Abstract][Full Text]
Zhou, K., Zhang, L., Xi, J., Tian, W., Xu, Z.
(2009). Ethanol Prevents Oxidant-Induced Mitochondrial Permeability Transition Pore Opening in Cardiac Cells. Alcohol Alcohol
44: 20-24
[Abstract][Full Text]
Ikehara, S., Iso, H., Toyoshima, H., Date, C., Yamamoto, A., Kikuchi, S., Kondo, T., Watanabe, Y., Koizumi, A., Wada, Y., Inaba, Y., Tamakoshi, A., Japan Collaborative Cohort Study Group,
(2008). Alcohol Consumption and Mortality From Stroke and Coronary Heart Disease Among Japanese Men and Women: The Japan Collaborative Cohort Study. Stroke
39: 2936-2942
[Abstract][Full Text]
Athyros, V. G., Liberopoulos, E. N., Mikhailidis, D. P., Papageorgiou, A. A., Ganotakis, E. S., Tziomalos, K., Kakafika, A. I., Karagiannis, A., Lambropoulos, S., Elisaf, M.
(2008). Association of Drinking Pattern and Alcohol Beverage Type With the Prevalence of Metabolic Syndrome, Diabetes, Coronary Heart Disease, Stroke, and Peripheral Arterial Disease in a Mediterranean Cohort. ANGIOLOGY
58: 689-697
[Abstract]
Kloner, R. A., Rezkalla, S. H.
(2007). To Drink or Not to Drink? That Is the Question. Circulation
116: 1306-1317
[Abstract][Full Text]
Jonsen, A., Gullstrand, B., Guner, N., Bengtsson, A.A., Nived, O., Truedsson, L., Sturfelt, G.
(2007). Genetically determined mannan-binding lectin deficiency is of minor importance in determining susceptibility to severe infections and vascular organ damage in systemic lupus erythematosus. Lupus
16: 245-253
[Abstract]
Wong, D. R., Willett, W. C., Rimm, E. B.
(2007). Smoking, Hypertension, Alcohol Consumption, and Risk of Abdominal Aortic Aneurysm in Men. Am J Epidemiol
165: 838-845
[Abstract][Full Text]
Gueye, A. S., Chelamcharla, M., Baird, B. C., Nguyen, C., Tang, H., Barenbaum, A. L., Koford, J. K., Shihab, F., Goldfarb-Rumyantzev, A. S.
(2007). The association between recipient alcohol dependency and long-term graft and recipient survival. Nephrol Dial Transplant
22: 891-898
[Abstract][Full Text]
Everett, B. M., Kurth, T., Buring, J. E., Ridker, P. M.
(2006). The Relative Strength of C-Reactive Protein and Lipid Levels as Determinants of Ischemic Stroke Compared With Coronary Heart Disease in Women. J Am Coll Cardiol
48: 2235-2242
[Abstract][Full Text]
Kurth, T., Moore, S. C., Gaziano, J. M., Kase, C. S., Stampfer, M. J., Berger, K., Buring, J. E.
(2006). Healthy lifestyle and the risk of stroke in women.. Arch Intern Med
166: 1403-1409
[Abstract][Full Text]
Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Circulation
113: e873-e923
[Abstract][Full Text]
Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Stroke
37: 1583-1633
[Abstract][Full Text]
Sacco, R. L., Adams, R., Albers, G., Alberts, M. J., Benavente, O., Furie, K., Goldstein, L. B., Gorelick, P., Halperin, J., Harbaugh, R., Johnston, S. C., Katzan, I., Kelly-Hayes, M., Kenton, E. J., Marks, M., Schwamm, L. H., Tomsick, T.
(2006). Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.. Circulation
113: e409-e449
[Abstract][Full Text]
Sacco, R. L., Adams, R., Albers, G., Alberts, M. J., Benavente, O., Furie, K., Goldstein, L. B., Gorelick, P., Halperin, J., Harbaugh, R., Johnston, S. C., Katzan, I., Kelly-Hayes, M., Kenton, E. J., Marks, M., Schwamm, L. H., Tomsick, T.
(2006). Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.. Stroke
37: 577-617
[Abstract][Full Text]
Fukushima, S., Kinoshita, A., Puatanachokchai, R., Kushida, M., Wanibuchi, H., Morimura, K.
(2005). Hormesis and dose-response-mediated mechanisms in carcinogenesis: evidence for a threshold in carcinogenicity of non-genotoxic carcinogens. Carcinogenesis
26: 1835-1845
[Abstract][Full Text]
Paraskevas, K. I., Daskalopoulou, S. S., Daskalopoulos, M. E., Liapis, C. D.
(2005). Secondary Prevention of Ischemic Cerebrovascular Disease. What Is the Evidence?. ANGIOLOGY
56: 539-552
[Abstract]
Klatsky, A. L.
(2005). Editorial Comment--Alcohol and Stroke: An Epidemiological Labyrinth. Stroke
36: 1835-1836
[Full Text]
Schaeffner, E. S., Kurth, T., de Jong, P. E., Glynn, R. J., Buring, J. E., Gaziano, J. M.
(2005). Alcohol Consumption and the Risk of Renal Dysfunction in Apparently Healthy Men. Arch Intern Med
165: 1048-1053
[Abstract][Full Text]
Szmitko, P. E., Verma, S.
(2005). Antiatherogenic potential of red wine: clinician update. Am. J. Physiol. Heart Circ. Physiol.
288: H2023-H2030
[Abstract][Full Text]
Mukamal, K. J., Ascherio, A., Mittleman, M. A., Conigrave, K. M., Camargo, C. A. Jr, Kawachi, I., Stampfer, M. J., Willett, W. C., Rimm, E. B.
(2005). Alcohol and Risk for Ischemic Stroke in Men: The Role of Drinking Patterns and Usual Beverage. ANN INTERN MED
142: 11-19
[Abstract][Full Text]
Iso, H., Baba, S., Mannami, T., Sasaki, S., Okada, K., Konishi, M., Tsugane, S., for the JPHC Study Group,
(2004). Alcohol Consumption and Risk of Stroke Among Middle-Aged Men: The JPHC Study Cohort I. Stroke
35: 1124-1129
[Abstract][Full Text]
Zee, R. Y.L., Ridker, P. M., Cook, N. R.
(2004). Prospective Evaluation of the Alcohol Dehydrogenase {gamma}1/{gamma}2 Gene Polymorphism and Risk of Stroke. Stroke
35
: e39-e42
[Abstract][Full Text]
Ding, J., Eigenbrodt, M. L., Mosley, T. H. Jr, Hutchinson, R. G., Folsom, A. R., Harris, T. B., Nieto, F. J.
(2004). Alcohol Intake and Cerebral Abnormalities on Magnetic Resonance Imaging in a Community-Based Population of Middle-Aged Adults: The Atherosclerosis Risk in Communities (ARIC) Study. Stroke
35: 16-21
[Abstract][Full Text]
Engstad, T., Viitanen, M., Arnesen, E.
(2003). Predictors of Death Among Long-Term Stroke Survivors. Stroke
34: 2876-2880
[Abstract][Full Text]
Jackson, V. A., Sesso, H. D., Buring, J. E., Gaziano, J. M.
(2003). Alcohol Consumption and Mortality in Men With Preexisting Cerebrovascular Disease. Arch Intern Med
163: 1189-1193
[Abstract][Full Text]
Reynolds, K., Lewis, L. B., Nolen, J. D. L., Kinney, G. L., Sathya, B., He, J.
(2003). Alcohol Consumption and Risk of Stroke: A Meta-analysis. JAMA
289: 579-588
[Abstract][Full Text]
Agarwal, D. P.
(2002). CARDIOPROTECTIVE EFFECTS OF LIGHT-MODERATE CONSUMPTION OF ALCOHOL: A REVIEW OF PUTATIVE MECHANISMS. Alcohol Alcohol
37: 409-415
[Abstract][Full Text]
Woo, D., Sauerbeck, L. R., Kissela, B. M., Khoury, J. C., Szaflarski, J. P., Gebel, J., Shukla, R., Pancioli, A. M., Jauch, E. C., Menon, A. G., Deka, R., Carrozzella, J. A., Moomaw, C. J., Fontaine, R. N., Broderick, J. P., Rosand, J., Greenberg, S. M.
(2002). Genetic and Environmental Risk Factors for Intracerebral Hemorrhage: Preliminary Results of a Population-Based Study * Editorial Comment: Preliminary Results of a Population-Based Study. Stroke
33: 1190-1196
[Abstract][Full Text]
Djousse, L., Myers, R. H., Province, M. A., Hunt, S. C., Eckfeldt, J. H., Evans, G., Peacock, J. M., Ellison, R. C.
(2002). Influence of Apolipoprotein E, Smoking, and Alcohol Intake on Carotid Atherosclerosis: National Heart, Lung, and Blood Institute Family Heart Study. Stroke
33: 1357-1361
[Abstract][Full Text]
Dulli, D. A.
(2002). Alcohol, Ischemic Stroke, and Lessons From a Negative Study. Stroke
33: 890-891
[Full Text]
Djousse, L., Ellison, R. C., Beiser, A., Scaramucci, A., D'Agostino, R. B., Wolf, P. A.
(2002). Alcohol Consumption and Risk of Ischemic Stroke: The Framingham Study. Stroke
33: 907-912
[Abstract][Full Text]
Wiebe, S., Nicolle, M. W
(2002). Recent developments: Recent developments in neurology. BMJ
324: 656-660
[Full Text]
Gavin, T. P., Wagner, P. D.
(2002). Acute ethanol increases angiogenic growth factor gene expression in rat skeletal muscle. J. Appl. Physiol.
92: 1176-1182
[Abstract][Full Text]
Xin, X., He, J., Frontini, M. G., Ogden, L. G., Motsamai, O. I., Whelton, P. K.
(2001). Effects of Alcohol Reduction on Blood Pressure: A Meta-Analysis of Randomized Controlled Trials. Hypertension
38: 1112-1117
[Abstract][Full Text]
Mukamal, K. J., Longstreth, W. T. Jr, Mittleman, M. A., Crum, R. M., Siscovick, D. S., Bereczki, D.
(2001). Alcohol Consumption and Subclinical Findings on Magnetic Resonance Imaging of the Brain in Older Adults: The Cardiovascular Health Study Editorial Comment: The Cardiovascular Health Study. Stroke
32: 1939-1946
[Abstract][Full Text]
Ostir, G. V., Markides, K. S., Peek, M. K., Goodwin, J. S.
(2001). The Association Between Emotional Well-Being and the Incidence of Stroke in Older Adults. Psychosom. Med.
63: 210-215
[Abstract][Full Text]
Hines, L. M., Stampfer, M. J., Ma, J., Gaziano, J. M., Ridker, P. M., Hankinson, S. E., Sacks, F., Rimm, E. B., Hunter, D. J.
(2001). Genetic Variation in Alcohol Dehydrogenase and the Beneficial Effect of Moderate Alcohol Consumption on Myocardial Infarction. NEJM
344: 549-555
[Abstract][Full Text]
Yang, Z.-w., Wang, J., Zheng, T., Altura, B. T., Altura, B. M., Hurn, P. D.
(2001). Ethanol-Induced Contractions in Cerebral Arteries : Role of Tyrosine and Mitogen-Activated Protein Kinases Editorial Comment: Role of Tyrosine and Mitogen-Activated Protein Kinases. Stroke
32: 249-257
[Abstract][Full Text]
Regan, T. J.
(2000). Moderate Alcohol Consumption and Risk of Coronary Heart Disease Among Women With Type 2 Diabetes Mellitus. Circulation
102: 487-488
[Full Text]
Lowenfels, A. B., Maisonneuve, P., Longstreth, W.T., Psaty, B. M., Berger, K., Kase, C. S., Ajani, U. A.
(2000). Alcohol Consumption and the Risk of Stroke. NEJM
342: 1137-1138
[Full Text]
27.8) decreased with increasing alcohol intake. 
