Alcohol Consumption and Risk of Peripheral Arterial Disease

The Rotterdam Study

Rozemarijn Vliegenthart1,2, Johanna M. Geleijnse1,3, Albert Hofman1, Wouter T. Meijer1, Frank J. A. van Rooij1, Diederick E. Grobbee4 and Jacqueline C. M. Witteman1

1 Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam, the Netherlands.
2 Department of Radiology, State University Groningen/University Hospital Groningen, Groningen, the Netherlands.
3 Department of Human Nutrition and Epidemiology, Agricultural University, Wageningen, the Netherlands.
4 Julius Center for Patient Oriented Research, University Medical Center, Utrecht, the Netherlands.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Moderate alcohol consumption is associated with a reduced risk of cardiovascular disease. Data on alcohol consumption and atherosclerosis are scarce. To determine the association between alcohol consumption and risk of peripheral arterial disease, the authors carried out a cross-sectional study (1990–1993) in the population-based Rotterdam Study among men and women aged 55 years or over. Data on alcohol consumption and peripheral arterial disease, as measured by the ankle/brachial blood pressure index, were available for 3,975 participants without symptomatic cardiovascular disease. Male drinkers consumed beer, wine, and liquor, while female drinkers consumed predominantly wine and fortified wine types. An inverse relation between moderate alcohol consumption and peripheral arterial disease was found in women but not in men. Because of residual confounding by smoking, analyses were repeated in nonsmokers. In nonsmoking men, odds ratios were 0.86 (95% confidence interval (CI): 0.46, 1.63) for daily alcohol consumption up to and including 10 g, 0.75 (95% CI: 0.37, 1.55) for 11–20 g, and 0.68 (95% CI: 0.35, 1.34) for more than 20 g, compared with nondrinking. In nonsmoking women, corresponding odds ratios were 0.65 (95% CI: 0.48, 0.87), 0.66 (95% CI: 0.42, 1.05), and 0.41 (95% CI: 0.21, 0.77), respectively. In conclusion, an inverse association between alcohol consumption and peripheral arterial disease was found in nonsmoking men and women.

aged; alcohol drinking; alcoholic beverages; atherosclerosis

Abbreviations: CI, confidence interval; OR, odds ratio


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Alcohol drinking affects the occurrence of ischemic heart disease. The association of alcohol with coronary morbidity and mortality is U or J shaped (1GoGoGoGo–5Go). The underlying mechanism of the reduced risk associated with moderate levels of alcohol is not known. One of the potential mechanisms is the effect of alcohol on atherosclerosis (3Go). The presence of peripheral arterial disease, which is largely asymptomatic, is an indicator of a long-term atherogenic process in the peripheral blood vessels. Peripheral arterial disease is considered present below a certain cutoff point of the ankle/brachial blood pressure index (6Go), and it is associated with atherosclerotic diseases in other vessel beds (7Go) and with cardiovascular morbidity and mortality (8GoGoGoGo–12Go). Only a few studies have investigated the relation between alcohol consumption and peripheral arterial disease. Among the 1,592 participants of the Edinburgh Artery Study, a positive linear association of alcohol consumption with the ankle/brachial blood pressure index was found in men but not in women (13Go). The protective effect was attributable to wine drinking in particular, but it was no longer significant after additional adjustment for social class. A recent study in 4,549 American Indian men and women showed a significant inverse association of alcohol consumption with peripheral arterial disease (14Go). However, the level of alcohol intake and the type of beverages consumed were not taken into account. The prospective Physicians' Health Study demonstrated an inverse association of moderate alcohol use with symptomatic peripheral arterial disease (15Go), although the range of alcohol intake in the study population was small and this population comprised relatively healthy men. In the Framingham Heart Study an inverse association was found between moderate alcohol consumption and the occurrence of intermittent claudication (16Go). However, only a small proportion of subjects with peripheral arterial disease were symptomatic. Furthermore, alcohol might have influenced the clinical symptoms of peripheral arterial disease (17Go).

The population-based Rotterdam Study of 7,983 people aged 55 years or over provides the opportunity to investigate in detail the association of alcohol consumption with peripheral arterial disease. In 3,975 subjects free from cardiovascular disease at baseline, we studied the consumption of different levels and types of alcohol in relation to peripheral arterial disease, taking into account important confounders.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The Rotterdam Study
The Rotterdam Study is a prospective study designed to investigate the occurrence and determinants of chronic and disabling cardiovascular, neurogeriatric, locomotor, and ophthalmologic diseases in an aging population. The rationale and design of the study have been described previously (18Go). The cohort includes 7,983 men and women aged 55 years or over (78 percent of the eligible population), living in a suburb of Rotterdam, the Netherlands. Of these, 879 subjects lived in nursing homes. From August 1990 until June 1993, baseline data were collected during a home interview by a trained research assistant and at two visits to the study center for clinical examination and assessment of diet.

Assessment of alcohol intake and diet
Alcohol consumption was assessed as part of a dietary interview. A trained dietician interviewed the participants at the study center, using a validated, semiquantitative food frequency questionnaire (19Go). The interview was based on a checklist on which the subjects had indicated the foods and beverages consumed more than once a month during the preceding year. The dietary interviews were performed using a computer program that simultaneously checked the data. Participants reported the number of alcoholic beverages they consumed on a weekly basis, in each of four categories: beer, wine, liquor, and moderately strong alcohol types. The latter category contained predominantly fortified wines, namely, sherry and port. Nondrinkers were considered abstainers. The subjects were asked whether their level of alcohol use had changed during the last 5 years and, if so, whether the amount had increased or decreased. For each of the different beverages, the number of drinks was multiplied by the average amount of ethanol in one drink of the alcoholic beverage. A "drink" was defined as 200 ml of beer that contained 8.0 g of ethanol, 100 ml of wine that contained 10.0 g of ethanol, 50 ml of liquor that contained 14.0 g of ethanol, or 75 ml of moderately strong alcohol types that contained 10.5 g of ethanol. By adding the amounts of ethanol in the four groups, we calculated the total amount of alcohol in grams per day. A validation study that compared the nutrient intake derived from the food frequency questionnaire with that from a 15-day food record showed a correlation coefficient of 0.89 for the intake of alcohol (19Go). Because most of the moderately strong alcoholic drinks were wine types, this category was combined with the wine category in the analyses. The alcohol consumption was divided into nondrinking, use of <=10 g, >10–<=20 g, and >20 g/day.

Study interview
Smoking status was assessed, and subjects were categorized as current, former, or never smokers. In ever smokers, we asked for the average number of cigarettes smoked, as well as the number of smoking years. From this information, the number of cigarette pack-years was computed. We used information about the highest attained level of education as an indicator of socioeconomic status. This variable was categorized as low (primary education), intermediate (secondary general or vocational education), and higher (higher vocational education or university). Intermittent claudication was diagnosed according to the criteria of the World Health Organization by means of the Rose questionnaire (20Go). Information on myocardial infarction and stroke in the subjects' history was obtained by direct questioning and considered positive when confirmed by physicians' records. Data on previous coronary artery bypass graft surgery or percutaneous transluminal coronary angiography were collected during the interview.

Clinical examination
Clinical examinations were performed during a visit at the research center. Height and weight were measured with participants in light clothes and without shoes. Body mass index was calculated as the weight (kg)/height (m)2. Serum total cholesterol was determined by an enzymatic procedure. High density lipoprotein cholesterol was measured similarly after precipitation of the non-high density lipoprotein cholesterol fraction (21Go). Diabetes mellitus was considered present with current use of antidiabetes medication, or when nonfasting random or postload glucose levels exceeded 11.0 mmol/liter (22Go, 23Go).

Blood pressure was measured at the right brachial artery using a random-zero sphygmomanometer with the participant in a sitting position. The mean of two consecutive measurements was used in the analysis. Hypertension was defined as a systolic blood pressure of 160 mmHg or higher, a diastolic blood pressure of 95 mmHg or higher, or current use of antihypertensive drugs for the indication of hypertension. An 8-MHz continuous wave Doppler probe (Huntleigh 500 D; Huntleigh Technology, Bedfordshire, United Kingdom) and a random-zero sphygmomanometer were used to measure the systolic blood pressure level of the posterior tibial artery in both legs (6Go). The blood pressure was measured once for each leg, with the participant in supine position. The ratio of the ankle systolic blood pressure to the brachial systolic blood pressure, the ankle/brachial blood pressure index, was calculated for each leg. Peripheral arterial disease was considered present when the ankle/brachial index was <0.9 in at least one leg (24Go).

Population for analysis
Noninstitutionalized participants who visited the study center were eligible for a dietary interview (n = 6,521). Of these, diet could not be assessed in 271 subjects of the pilot phase and in 122 subjects suspected of dementia. Furthermore, a random group of 481 participants was not interviewed because of logistic reasons. Of the dietary reports, 212 were considered unreliable by the dietician and were excluded. Thus, dietary data were available for 5,435 subjects. Of these 5,435, data on the ankle/brachial blood pressure index were missing for 535 participants. Additionally, subjects with an ankle/brachial blood pressure index of more than 1.5 (n = 272) were excluded because this index usually results from arterial rigidity that prevents compression of the ankle artery. Subjects with complete data on diet and the ankle/brachial blood pressure index (n = 4,900) differed from excluded subjects (n = 1,621) only in mean age and in diabetes status. The mean age was higher in those excluded because of exclusion of subjects suspected for dementia, while the percentage of diabetes mellitus was higher in subjects excluded because of missing data, probably from nonassessable arteries on both sides. To avoid a spurious association due to a change in alcohol consumption as a result of symptomatic cardiovascular disease, subjects with a history of myocardial infarction, stroke, coronary artery bypass graft surgery, or percutaneous transluminal coronary angiography were excluded from the analysis (n = 653). Ultimately, 3,975 subjects were included in the present analysis.

Data analysis
Levels of potential confounders were compared between categories of alcohol consumption, using a general linear model. In this model, age and sex were included as covariates. Risk estimates were obtained for men and women separately. The relation between alcohol consumption and peripheral arterial disease was assessed using logistic regression analysis that adjusted for age. The risk of peripheral arterial disease in each category of alcohol consumption was compared with the risk among nondrinkers. The associations were expressed as odds ratios with 95 percent confidence intervals. A second model additionally adjusted for possible confounding factors, namely, cigarette pack-years, body mass index, and diabetes mellitus. Another model also adjusted for education as a measure of socioeconomic status. The first two logistic models were also conducted after exclusion of subjects who had reduced their alcohol consumption in the last 5 years. Because of potential residual confounding by smoking, we stratified according to smoking status and repeated the logistic regression analysis, adjusting for age and cigarette pack-years. To study the association of drinking (yes/no) specific types of alcohol, we used the two aforementioned logistic regression models but simultaneously took into account the amount of consumption of other types of alcohol. The data were analyzed using SPSS 7.5 for Windows (SPSS, Inc., Chicago, Illinois).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
General characteristics of the study population are presented in table 1. Of the participants, 62.5 percent were female. The percentage of drinkers among men (88.5 percent) was higher than that among women (74.7 percent). Furthermore, the average daily amount of alcohol consumed by drinkers was much higher for men than for women (16.4 (standard deviation, 18.8) g and 6.2 (standard deviation, 10.2) g, respectively). The prevalence of peripheral arterial disease was slightly lower in men (13.4 percent) than in women (14.4 percent). Of those with peripheral arterial disease, only a few subjects reported intermittent claudication as assessed by the Rose questionnaire (7.5 percent of male cases, 3.9 percent of female cases). In a general linear model adjusted for sex, the mean level of alcohol intake decreased with an increase in age category (p for trend <0.001). After adjustment for age and sex, the level of alcohol intake was associated with cigarette pack-years (p < 0.001), diabetes mellitus (p = 0.12), and attained level of education (p = 0.02) (data not shown). The level of high density lipoprotein cholesterol was significantly higher in male and female drinkers compared with nondrinkers. In addition, women who consumed alcohol were on average older, more often diabetic, more likely smokers, and more highly educated compared with nondrinking women.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Baseline characteristics of 3,975 men and women aged 55 years or over without cardiovascular disease, The Rotterdam Study, 1990–1993*

 
Table 2 shows the distribution of consumption of various alcoholic beverages. Among men, beer, liquor, and wines were consumed by almost equal percentages (46.6, 40.1, and 41.4 percent, respectively). The average daily amount consumed by drinkers of the specific beverages was higher for beer and liquor (1.2 drinks) than for wine and fortified wine (0.74 drink). The percentage of women who drank wine and fortified wine was much higher (66.4 percent) than the percentages of women who drank beer and liquor (5.2 and 17.5 percent, respectively). Wine-, beer-, or liquor-drinking women drank less than men who drank the same alcoholic beverages.


View this table:
[in this window]
[in a new window]
 
TABLE 2. Consumption of alcoholic beverages in 3,975 men and women without cardiovascular disease, The Rotterdam Study, 1990–1993

 
Table 3 presents odds ratios of peripheral arterial disease for various levels of alcohol consumption adjusted for age and in multivariate analyses additionally adjusted for cigarette pack-years, body mass index, and diabetes mellitus. In men, there was no inverse association between alcohol consumption and the risk of peripheral arterial disease. In the age-adjusted model, a slightly protective, but statistically nonsignificant association with peripheral arterial disease was observed for men who consumed up to 10 g of alcohol daily compared with nondrinkers (odds ratio (OR) = 0.84, 95 percent confidence interval (CI): 0.51, 1.38). However, this association disappeared in multivariate analysis. In women, a risk reduction of 22–36 percent was observed for alcohol drinkers compared with nondrinkers. This reduced risk among women was significant for daily consumption of up to 10 g of alcohol and in multivariate analysis for up to 20 g of alcohol daily. Additional adjustment for socioeconomic status did not change the results for either sex (data not shown). There was no significant interaction between alcohol consumption and sex (data not shown). Exclusion of subjects who had reduced their alcohol consumption in the last 5 years (190 subjects, 4.0 percent of the women and 6.1 percent of the men) did not affect the associations (data not shown).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Risk of peripheral arterial disease according to level of alcohol consumption among 3,975 men and women without cardiovascular disease, The Rotterdam Study, 1990–1993

 

View this table:
[in this window]
[in a new window]
 
TABLE 4. Risk of peripheral arterial disease by level of alcohol consumption according to smoking status among 3,975 men and women without cardiovascular disease, The Rotterdam Study, 1990–1993

 
Stratified analysis according to smoking status revealed different odds ratios of peripheral arterial disease by category of alcohol consumption in smokers and nonsmokers (table 4). In logistic regression analysis adjusted for age and cigarette pack-years, odds ratios of peripheral arterial disease in increasing categories of alcohol consumption were lower among past and never smokers than among current smokers. In past and never smokers, an inverse association was found between alcohol consumption and peripheral arterial disease. In nonsmoking men, the odds ratios were 0.86 (95 percent CI: 0.46, 1.63) for daily alcohol consumption up to 10 g, 0.75 (95 percent CI: 0.37, 1.55) for 11–20 g, and 0.68 (95 percent CI: 0.35, 1.34) for more than 20 g compared with nondrinking (test for trend: p = 0.21). In nonsmoking women, corresponding odds ratios were 0.65 (95 percent CI: 0.48, 0.87), 0.66 (95 percent CI: 0.42, 1.05), and 0.41 (95 percent CI: 0.21, 0.77), respectively (test for trend: p < 0.001). The lowest odds ratio was found in never smoking women with a daily alcohol consumption of more than 20 g (OR = 0.32, 95 percent CI: 0.11, 0.91). In smoking subjects there was no inverse association between alcohol consumption and peripheral arterial disease.

The risk of peripheral arterial disease associated with the use of the separate alcoholic beverages was computed, adjusted for age and the use of other alcoholic beverages, and in a second model adjusted also for cigarette pack-years, body mass index, and diabetes mellitus. The association was stronger for the consumption of wine and fortified wine than for the consumption of beer or liquor. In women, the risk of peripheral arterial disease associated with the use of wine types was statistically significant (first model: OR = 0.72, 95 percent CI: 0.57, 0.91; second model: OR = 0.74, 95 percent CI: 0.58, 0.95). In men, the odds ratios for wine were 0.81 (95 percent CI: 0.59, 1.13) and 0.88 (95 percent CI: 0.63, 1.24), respectively. The estimates of the risk of peripheral arterial disease associated with beer and liquor consumption for both men and women ranged from 0.86 to 1.14 and were not statistically significant. In logistic regression analysis of data from nonsmokers, no consistent association between an alcoholic beverage and peripheral arterial disease was found, except for wine and fortified wine in women (OR = 0.67, 95 percent CI: 0.51, 0.88). There was no significant inverse association between any type of alcoholic beverage and peripheral arterial disease in current smokers (odds ratios ranging from 0.92 to 1.17).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the large population-based Rotterdam Study, we found an inverse association of alcohol consumption with peripheral arterial disease in women. The association was present already at low levels of alcohol use and was still present for levels of moderate alcohol consumption. In men, there was virtually no association of alcohol intake with peripheral arterial disease. Among nonsmoking subjects, an inverse association was found between alcohol consumption and peripheral arterial disease in both men and women. The largest risk reduction, 59 percent, was found in women who consumed over 20 g of ethanol per day. The strengths of the present study include a large and well-described cohort of elderly men and women, classification of consumption of alcohol and the types of beverages based on a validated food checklist, and a relatively large number of mostly asymptomatic peripheral arterial disease cases (558 subjects).

In the present study, drinking habits were self reported. This might have caused underreporting of alcohol use, especially among heavy drinkers. This is more likely to have occurred for men than for women, since more men were heavy drinkers. Imprecision in the reporting of alcohol consumption would tend to weaken the associations found. Shaper et al. (4Go) have argued that nondrinkers might not be suitable for use as reference group in an examination of the effects of alcohol on peripheral arterial disease. The group of nondrinkers could be less healthy than expected, because of inclusion of former heavy drinkers and people who have stopped drinking because of ill health, particularly ischemic heart disease. Furthermore, it is probable that lifelong nondrinkers have reasons for being abstainers that introduce other biases and have an adverse risk profile. This is most likely for men, for whom abstaining from alcohol is rather uncommon in society, at least in the age category of our cohort. However, additional exclusion of subjects who had reduced their alcohol consumption in the last 5 years did not change our results. Furthermore, participants with prevalent symptomatic cardiovascular disease were excluded from the analysis. In addition, drinking patterns may influence the risk of cardiovascular diseases (25Go). In our study, there was no information about the regularity of alcohol consumption.

Using peripheral arterial disease as an indicator of atherosclerosis has the advantage that most subjects with peripheral arterial disease are asymptomatic (6Go). Thus, spurious associations between alcohol and peripheral arterial disease, resulting from symptoms that cause a change in alcohol consumption, are not likely to occur. Possible misclassification of peripheral arterial disease cases was probably nondifferential and would only weaken the real associations. In the Rotterdam Study, subjects did not report their physical activity, one of the confounders of the relation between alcohol consumption and peripheral arterial disease. Because measurement of the ankle/brachial blood pressure index was performed only on noninstitutionalized subjects who visited the research center and because participants with dementia were not interviewed about their diet, our subjects were relatively healthy and mobile. They may not be a representative sample of the whole elderly population without prevalent symptomatic cardiovascular disease.

Only a few other studies have investigated the association of alcohol consumption with the presence of peripheral atherosclerosis. Jepson et al. (13Go) found in the Edinburgh Artery Study a higher ankle/brachial blood pressure index (thus less peripheral arterial disease) in men with high alcohol consumption but no association in women. The ankle/brachial blood pressure index was associated with wine consumption but not with beer or liquor consumption. After additional adjustment for social class the positive associations disappeared, possibly indicating confounding by social class. The findings for women in this study were considered the result of the relatively low consumption of alcohol in this group (median consumption of one drink per week). In the prospective Physicians' Health Study, the relative risk of symptomatic peripheral arterial disease associated with moderate alcohol use was 0.74 in multivariate analysis (15Go). This cohort comprised subjects who were on average 10 years younger and had a higher average educational level than the men in our study. Furthermore, the overall alcohol consumption was very low in comparison with our study and other studies: 97 percent of the men reported use of less than two drinks a day. The consumption of different types of alcoholic beverages was not taken into account in this study. The Framingham Heart Study found the lowest risk of intermittent claudication at levels of 13–24 g of alcohol per day in men (hazard ratio = 0.67, 95 percent CI: 0.42, 0.99) and 7–12 g in women (hazard ratio = 0.44, 95 percent CI: 0.23, 0.80), compared with nondrinkers (16Go). Beer and wine especially were negatively associated with the occurrence of intermittent claudication. The study population, although younger than our population, had a distribution of alcohol consumption similar to ours. In this study and the Physicians' Health study, only subjects with an onset of intermittent claudication or peripheral arterial surgery were considered peripheral arterial disease cases. Alcohol may influence the clinical symptoms of peripheral arterial disease by preferentially dilating diseased arteries (16Go). In a study among American Indians, a study population with fewer cases of peripheral arterial disease than ours, a statistically significant inverse association between alcohol drinking and peripheral arterial disease was found in multiple logistic regression analysis. However, there was no information on the types and amount of alcohol consumed (14Go).

We found an inverse association between alcohol consumption and peripheral arterial disease for women but not for men. Because of the small range of alcohol intake among women, with only 10 percent consuming over 20 g of alcohol daily, it was not possible to examine the risk of peripheral arterial disease in heavy-drinking women. Although the range of alcohol consumption among men was wider, the odds ratio of peripheral arterial disease was not significantly different from one for any of the alcohol consumption categories compared with nondrinking. Part of the gender difference may be explained by a strong confounding effect of smoking. In nonsmoking subjects, an inverse association between alcohol consumption and peripheral arterial disease was present in both men and women. The inverse association was strongest in never-smoking women. Unfortunately, we were not able to study the association between alcohol consumption and peripheral arterial disease in never-smoking men because of small numbers. In our population, only 8 percent of men had never smoked. The percentage of never-smoking men was higher in the Edinburgh Artery Study (25 percent) and in the Physicians' Health Study (50 percent). The effect of smoking may have been less distorting in these studies. Furthermore, the discrepancy concerning the observed associations for men and women can possibly be explained in part by differences in the distribution of the beverage types consumed. In our study population women consumed mainly wine and fortified wine types, and we found the association to be strongest for these alcoholic beverages. The inverse association of wine consumption and peripheral arterial disease is in concordance with results from the Edinburgh Artery Study (13Go). Contrary to their results, the associations we found remained after additional adjusting for social class. Although our data for men are not incompatible with an effect of wine, the association was weak and not significant. Furthermore, because of small numbers of cases among beer drinkers and liquor drinkers in women, possible inverse associations between these beverages and peripheral arterial disease cannot be excluded.

An extensive review on alcohol and risk of coronary heart disease concluded that there is strong evidence that beer, liquor, and wine are all three associated with a lower risk of coronary heart disease (26Go). The review focused primarily on the acute events of coronary atherosclerotic disease, in which clotting and fibrinolysis are also thought to play a major role. We studied the long-term process of atherogenesis, in which the effect of alcoholic beverages on atherosclerosis is more important. Alcohol itself affects hemostasis (27Go) and affects atherosclerosis through its effect on the lipid profile (28Go). Possibly additional effects on atherosclerosis may be mediated by substances present only in wines. Wine and fortified wines contain phenolic substances, which have been shown to have antioxidant effects on low-density lipoproteins, thus decelerating atherogenesis (29Go, 30Go).

In summary, in this large population-based study moderate alcohol consumption was inversely associated with peripheral arterial disease in women but not in men. Residual confounding by smoking may have influenced the results. Among nonsmokers an inverse association was found between alcohol consumption and peripheral arterial disease in both men and women.


    ACKNOWLEDGMENTS
 
The Rotterdam Study is supported in part by the NESTOR program for geriatric research (Ministry of Health and Ministry of Education), the Netherlands Heart Foundation, the Netherlands Organization for Scientific Research (NWO), the Health Research and Development Council (ZON), and the Municipality of Rotterdam.

The authors thank all field workers, computer assistants, and laboratory technicians of the Ommoord research center for their enthusiastic and skilful contributions to the data collection. They also thank Hanneke den Breeijen for coordinating the collection of dietary data.


    NOTES
 
Correspondence to Dr. J. C. M. Witteman, Department of Epidemiology and Biostatistics, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands (e-mail: witteman{at}epib.fgg.eur.nl).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Goldberg RJ, Burchfiel CM, Reed DM, et al. A prospective study of the health effects of alcohol consumption in middle-aged and elderly men. The Honolulu Heart Program. Circulation 1994;89:651–9.[Abstract]
  2. Hein HO, Suadicani P, Gyntelberg F. Alcohol consumption, serum low density lipoprotein cholesterol concentration, and risk of ischaemic heart disease: six year follow up in the Copenhagen male study. BMJ 1996;312:736–41.[Abstract/Free Full Text]
  3. Gaziano JM, Gaziano TA, Glynn RF, et al. Light-to-moderate alcohol consumption and mortality in the Physicians' Health Study enrollment cohort. J Am Coll Cardiol 2000;35:96–105.[ISI][Medline]
  4. Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet 1988;2:1267–73.[ISI][Medline]
  5. Rehm JT, Bondy SJ, Sempos CT, et al. Alcohol consumption and coronary heart disease morbidity and mortality. Am J Epidemiol 1997;146:495–501.[Abstract]
  6. Meijer WT, Hoes AW, Rutgers D, et al. Peripheral arterial disease in the elderly: The Rotterdam Study. Arterioscler Thromb Biol 1998;18:185–92.[Abstract/Free Full Text]
  7. Shinozake T, Hasegawa T, Yano E. Ankle-arm index as an indicator of atherosclerosis: its application as a screening method. J Clin Epidemiol 1998;51:1263–9.[ISI][Medline]
  8. Criqui MH, Denenberg JO, Langer RD, et al. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med 1997;2:221–6.[Medline]
  9. Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996;25:1172–81.[Abstract]
  10. von Kemp K, van den Brande P, Peterson T, et al. Screening for concomitant diseases in peripheral vascular patients. Results of a systematic approach. Int Angiol 1997;16:114–22.[ISI][Medline]
  11. Vogt MT, Cauley JA, Newman AB, et al. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA 1993;270:465–9.[Abstract]
  12. Sikkink CJ, van Asten WN, van 't Hof MA, et al. Decreased ankle/brachial indices in relation to morbidity and mortality in patients with peripheral arterial disease. Vasc Med 1997;2:169–73.[Medline]
  13. Jepson RG, Fowkes FG, Donnan PT, et al. Alcohol intake as a risk factor for peripheral arterial disease in the general population in the Edinburgh Artery Study. Eur J Epidemiol 1995;11:9–14.[ISI][Medline]
  14. Fabsitz RR, Sidawy AN, Go O, et al. Prevalence of peripheral arterial disease and associated risk factors in American Indians. Am J Epidemiol 1999;149:330–8.[Abstract]
  15. Camargo CA, Stampfer MJ, Glynn RJ, et al. Prospective study of moderate alcohol consumption and risk of peripheral arterial disease in US male physicians. Circulation 1997;95:577–80.[Abstract/Free Full Text]
  16. Djoussé L, Levy D, Murabito JM, et al. Alcohol consumption and risk of intermittent claudication in the Framingham Heart Study. Circulation 2000;102:3092–7.[Abstract/Free Full Text]
  17. Diehm C, Mörl H, Müller-Bühl U, et al. Acute effects of alcohol on peripheral circulation in normal persons and patients with peripheral occlusive diseases. (In German). Vasa 1983;12:166–71.[ISI][Medline]
  18. Hofman A, Grobbee DE, de Jong PT, et al. Determinants of disease and disability in the elderly: the Rotterdam Study. Eur J Epidemiol 1991;7:403–22.[ISI][Medline]
  19. Klipstein-Grobusch K, den Breeijen JH, Goldbohm RA, et al. Dietary assessment in the elderly: validation of a semiquantitative food frequency questionnaire. Eur J Clin Nutr 1998;52:588–96.[ISI][Medline]
  20. Rose GA, Blackburn H, Gillum RF, et al. Cardiovascular survey methods. Geneva, Switzerland: World Health Organization, 1982.
  21. van Gent CM, van der Voort HA, de Bruyn AM. Cholesterol determinants. A comparative study of methods with special reference to enzymatic procedures. Clin Chim Acta 1977;75:243–51.[ISI][Medline]
  22. Diabetes mellitus. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1985;727:1–113.[Medline]
  23. Stolk RP, Pols HA, Lamberts SW, et al. Diabetes mellitus, impaired glucose tolerance, and hyperinsulinemia in an elderly population. The Rotterdam Study. Am J Epidemiol 1997;145:24–32.[Abstract]
  24. Fowkes FGR, Housley E, Cawood EHH, et al. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 1991;20:384–92.[Abstract]
  25. Kauhanen J, Kaplan GA, Goldberg DE, et al. Beer binging and mortality: results from the Kuopio ischaemic heart disease risk factor study, a prospective population based study. BMJ 1997;315:846–51.[Abstract/Free Full Text]
  26. Rimm EB, Klatsky A, Grobbee D, et al. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits. BMJ 1996;312:731–6.[Abstract/Free Full Text]
  27. Lowe GD, Fowkes FG, Dawes J, et al. Blood viscosity, fi-brinogen, and activation of coagulation and leukocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993;87:1915–20.[Abstract]
  28. Rimm EB, Williams P, Fosher K, et al. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523–8.[Abstract/Free Full Text]
  29. Frankel EN, Kanner J, German JB, et al. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993;341:454–7.[ISI][Medline]
  30. Stein JH, Keevil JG, Wiebe DA, et al. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation 1999;100:1050–5.[Abstract/Free Full Text]
Received for publication August 28, 2000. Accepted for publication August 20, 2001.