The effects of coffee drinking on the cardiovascular system: Experimental and epidemiological research

PREVENTIVE MEDICINE 6, 106 119 (1977)

The Effects of Coffee System: Experimental

Drinking on the Cardiovascular and Epidemiological Research

FREDERICK Department

A. MACCORNACK

of Epidemiology, American Health Foundation, I370 Avenue of the Americas, New York, New York 10019

The controversy over heavy coffee drink& and its possible role in the etiology of myocardial infarction is discussed. Relevant pharmacological information is presented and interpreted in context of the most substantial epidemiologic data. A review of the pharmacologic literature on caffeine suggests no permanent detrimental effects of its use under “normal” circumstances as it is typically ingested in coffee, cola beverages, and aspirin. Conflicting epidemiologic data are analyzed and reinterpreted. It is noted that unless cigarette smoking is controlled when analyzing coffee consumption, a confounding of information occurs, i.e., as cigarette smoking increases, coffee consumption increases. Since heavy cigarette smoking has been shown to be a risk factor in the etiology of cardiovascular diseases, coffee consumption data is therefore confounded by it. Data from the American Health Foundation on 1,014 male patients documents a strong association between these two variables. It is concluded that, in view of these data, “heavy” coffee consumption plays no significant role in the etiology of cardiovascular diseases in general and myocardial infarction in particular.

INTRODUCTION

The debate over the possible association between heavy coffee consumption and myocardial infarction has now been in the literature for over 25 years. The discussion has been kept alive because of contradictory evidence found both in laboratory research on caffeine and in epidemiological studies on heart disease. This review will examine the relevant research on both caffeine and coffee as they pertain to the etiology of heart disease. Concern over coffee as a potentially harmful beverage came about because of its prevalent use. Statistics on daily consumption of both regular and instant brews in the U.S. showed that the per capita total in 1974was 2.25 cups a day, a decrease from 1962when consumption was calculated at 3.12 cups (44). With an estimated average of 95 mg of caffeine per cup (range of 50 to 120 mg), some researchers suspected that these average doses could have a potential influence on the development of some types of heart disease. Data from both 1962 and 1974 showed that heaviest consumption of this beverage occurred between the ages of 40-59, the ages of high risk for heart attack among males. Not only was coffee implicated in the role of increased incidence of heart disease, but the associated additives-sugar and whole milk or cream-were thought to play a part as well. Regular additions of dairy products could affect blood lipid values, a link in heart disease etiology. This review will treat laboratory research on caffeine and coffee as separate entities because the biochemical properties of each are different. Dose-response measurements on the two sources of caffeine are not always identical. Thus, generalizations about caffeine studies will be made for the effects of coffee drinking where appropriate. 104 Copyright 0 1977 by Academic Press, Inc. All rights of reproduction in any form resewed.

ISSN 0091-7435

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ANALYSIS

A complete chemical analysis of the unroasted coffee bean is done only with great difficulty because of the complex nature of the molecular structure of its many components. Discrete chemical substances such as caffeine, trigonelline and chlorogenic acid are the most easily definable compounds of the bean, while other major components are more difficult to identify, except as belonging to particular chemical functional groups. There are two major coffee bean varieties-Arabica and Robusta-with 1 and 2% caffeine, respectively. Other than the caffeine differences, their content is generally comparable. The principal constituents of the green bean are carbohydrates, oils, proteins, ash, nonvolatile acids, trigonelline and caffeine. The roasted bean includes those elements plus the important phenolica and volatiles. Volatiles are chemically classed as acids, amines, sulfides, carbonyls (aldehydes and ketones); nonvolatiles are comprised of acids, carbohydrates, proteins, oils, phospholipids and minerals. The major nonvolatile acid in green coffee is chlorogenic acid, from which certain phenolics are derived upon pyrolysis. The effect that roasting has upon the green bean varies according to the botanical variety, natural origin and amount of roasting involved. Coffee has both water soluble and insoluble parts. Roasting changes the chemical consistency of over 90% of the water soluble substances and renders other products very volatile in the brewing process. In addition, most of the proteins are denatured and certain pyrolysis products, such as fiu-an and furfural, appear. Those substances most responsible for coffee flavor and aroma are the volatiles and phenols, which are evolved upon roasting, and the browning products, pyrolized carbohydrates. The majority of the volatiles are aldehydes (50%) and ketones (20%). Esters and heterocyclics are also present. These volatiles are subject to oxidation, polymerization, precipitation and resinification, all of which can destroy good coffee aroma and produce “staling”. There seems to be great controversy over exactly how much caffeine is contained in a cup of coffee or in any xanthine-containing beverage. Depending on the particular botanical origin of the bean, figures ranging from extremes of 0.62% to 3.21% caffeine have been given (7), although commercial blending of coffee beans considerably narrows the range of caffeine content. Problems in assessing caffeine content per cup are encountered when considering exactly how much coffee (or tea) is in each cup and how much water is used in brewing. There apparently is no uniform definition of “average cup size”. Estimated caffeine content (U.S., 1974) measured in mglcup for brewed coffee is 90- 120 mg, and is 66-74 mg for instant coffee, l-6 mg for decaffeinated coffee, 70 mg for leaf tea and 30 mg for cola beverages (7). Although there are vitamins present in coffee (riboflavin, pantothenic acid, choline, niacin, and B,), they are of no dietary import, with the possible exception of niacin. Each cup of coffee contains approximately 2% of the minimum daily human requirement of this vitamin. Calories in one cup of coffee are low, about 2-4 per cup (56). CAFFEINE

PHARMACOLOGY

Caffeine, the most active ingredient in the popular drink coffee, has a well-

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documented history as a mild stimulant and euphoriant. Caffeine, (1’,3’,7’trimethylxanthine) theophylline, and theobromine are the three major xanthine derivatives and are commonly known as xanthines. All three are structurally related to uric acid, a purine; and likewise, all three affect similar parts of the body. The differences in their pharmacological effects lie principally in their relative potencies. These xanthines generally produce CNS stimulation, cardiac and skeletal muscle stimulation, smooth muscle relaxation, and diuresis. Besides coffee, beverages containing caffeine and other xanthine derivatives include tea, cocoa, and cola drinks. There is widespread agreement that the popularity of these drinks is due, in part, to their mild antidepressant action. Caffeine and other xanthines have other valuable therapeutic properties, as well. Their pharmaceutical value, however, cannot generally be equated with their action as mediated by caffeine-containing drinks. Small amounts of caffeine (50-200 mg) have long been known to overcome fatigue and drowsiness, increase one’s ability to do strenuous work, and improve concentration for extended time periods, through stimulation of the CNS. Motor activities are also improved and a keener perception of sensory stimuli is generally evidenced. However, the stimulatory effects of larger amounts of caffeine may impair motor functions where great and delicate coordination is required and may also induce irritability, tremor, insomnia, nervousness, and headache. While caffeine does increase mental alertness, it has never been known to increase intelligence. Large doses of caffeine will affect not only the cerebral cortex and the medulla, but the spinal cord as well. In addition, the stimulation of the CNS by xanthines is sometimes followed by physiological depression (20). Of the three major xanthines, caffeine is the least potent with respect to the positive inotropic and chronotropic effects exerted on cardiac muscle. While all parts of the cardiovascular system are in some way affected by xanthines, some of these actions are antagonistic. Thus, looking at a single function is often deceptive because it may remain unchanged while other functions are being positively or negatively affected. Xanthines stimulate the myocardium directly, although some of these effects might be hidden because of simultaneous stimulation of the medullary vagal nuclei. Small doses of caffeine (5&200 mg) generally cause bradycardia due to vagal stimulation. When large doses of caffeine are given (200-500 mg), however, stimulation of the myocardium prevails with resultant tachycardia. Occasionally, sensitive individuals react to small doses of caffine with tachycardia (56). This direct myocardial stimulation by xanthines, especially theophylline, causes an increase in cardiac output, with an accompanying decrease in venous blood pressure (bp), due to the more efficient emptying of the heart. While the direct myocardial and central vasomotor stimulation increases systemic bp, the central vagal stimulation and peripheral vasodilation decrease bp. The end result is usually a slight rise of no more than 10 mm Hg (20). Xanthines exert a relaxing influence on smooth muscle, especially on bronchiolar tissue. This is particularly the case when such muscles are constricted experimentally with histamines, or as a result of bronchial asthma. A likely biochemical mechanism underlying certain of the metabolic and physiological effects of the xanthines has been attributed to the adenyl cyclase-

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cyclic AMP-phosphodiesterase chain. Xanthines inhibit phosphodiesterase breakdown of CAMP, thus prolonging and increasing the stimulatory action of CAMP on many tissues and enabling interactions on the parameters of lipolysis and glycogenolysis with other hormones. Xanthines may also produce their effects-particularly with regard to cardiac and skeletal muscle stimulation-by causing a change in Ca+2 fluxes in these tissues. Alternatively, a combination of increase of influx and efflux of Ca2+ and the prolongation of CAMP levels may form the resultant stimulation. It is from this mechanism that the well-known hyperglycemic effect and increase of free fatty acid (FFA) mobilization caused by the introduction of xanthines can be explained. The accumulation of CAMP, caused by inhibition of PDE, increases phosphorylase activity, yielding glycogenolysis and, finally, glucose production. Xanthines have an analagous effect on lipid production. Cyclic AMP activates the triglyceride lipases, hydrolizing triglycerides in adipose tissue and increasing the level of FFA in the blood. Many theories about blood FFA levels and cardiovascular disease implications have been suggested, but so far nothing has been proven (3,4,24,35,41-43,60). In fact, it is imperative that a certain level of FFA be maintained through the enzymatic splitting of neutral fat into nonesterified fatty acids and glycerol in order to cover the energy needs of those tissues that take up and oxidize nonesterified fatty acids (40). Although lipolysis is a necessity for the healthy and proper functioning of the body, there is concern over what are “normal” levels of FFA. Some feel that the elevation of FFA levels is responsible for a shortened prothrombin time and increase in blood coagulability (56). Xanthines can be of particular therapeutic value by their action on the myocardium, smooth muscle, CNS, and kidneys. Caffeine is used only as a CNS stimulant, counteracting CNS poisoning by depressants such as morphine. Theobromine and theophylline are employed to stimulate cardiovascular circulation and can also mollify the severity and frequency of angina pectoris. Xanthines aid in relieving pulmonary edema and dyspnea. Theophylline is used in the treatment of bronchial asthma; xanthines are also effective in overcoming spasm of the biliary tract. In addition, more common use of xanthines is as a caffeine-salicylate combination used to relieve headaches. Although caffeine and other xanthines as contained in beverages are nontoxic within the range of normal human consumption, pharmaceutical xanthines, particularly theophyllines, can sometimes lead to fatal events. The toxic effects of these drugs are generally extensions of their pharmacological actions to a detrimental degree. An overdose of caffeine can lead to convulsions with resultant death from respiratory arrest. With a fatal dose of caffeine in man being more than 10 gm, death from caffeine is highly unlikely. However, high “normal” doses cause sensory disturbances, such as ringing in the ears and light flashes, restlessness, insomnia, tachycardia, prominent diuresis, and hypertension. Gastric irritation can arise, even from 150 mg of caffeine contained in a cup of coffee. Larger doses of xanthines can cause nausea, vomiting, pain and hematemesis. CAFFEINE

EFFECTS ON THE CARDIOVASCULAR

SYSTEM

Laboratory studies on animals show that I.V. administration of caffeine has

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paradoxical effects on the cardiovascular system. Cardiac tissue is stimulated (or depressed, depending on the dose), producing an increased heart rate, vasodilation through peripheral depression of the vasoconstrictor mechanism, central vasoconstrictor stimulation, and cardiac irregularities (8). The increased heart rate usually has a shorter duration than the vasodilator effect. The use of denervation procedures and blocking drugs in animal laboratory studies has shown that blood pressure fall is due primarily to the peripheral vasodilation effects of caffeine. However, here again, a secondary blood pressure rise is noted, thought to be due to a reflex vasoconstriction and cardiac stimulation. It has been suggested that the secondary pressor response represents a central effect of caffeine (50-52). The decrease in blood pressure and increase in heart rate in animals is a generalization determined by dose and route of administration of caffeine. Intravenous doses up to 10 mg/kg produce a slight to moderate fall in blood pressure. Oral administration of caffeine produces slower drug absorption and diminished cardiovascular effects, dose for dose, than I.V. administration. Thus, compensating circulatory reflexes are better able to keep pace with the initial oral drug stimulation, partially counteracting the caffeine-induced changes. Cardiac arrhythmias, often produced by I.V. administration, can occur because of changes in the refracting period, conduction time, conduction pathway, or combinations of these. High doses of caffeine are generally necessary to alter electrical parameters of cardiac function (1,15,49,58). Generalizing from these studies on intact animals, administration of 10-15 cups of coffee (100-150 mg caffeine/cup) at one time would be necessary to replicate these effects. Differential effects of caffeine on specific vascular beds yield varying results depending on dosage. However, general responses include dilation of peripheral, visceral, and pulmonary vessels; no consistent response in cerebral vessels; and a slight dilation in coronary vessels in animals (52). The belief that caffeine dilates coronary vessels rests primarily on experiments with isolated hearts (22,26,28,30,54). Studies of the effect of caffeine on humans are segregated by therapeutic doses of caffeine and caffeine in coffee. Equating the two sources of caffeine administration is fallacious; cardiovascular effects due to caffeine are duplicated only by heavy doses of coffee ingestion. Other effects due to secondary components of the coffee beverage are largely unknown. Most studies of caffeine dose-response effects indicate that within a dose range of 0.1 to 0.5 g, variations in blood pressure and heart rate were slight with I.V. administration (6,14,18). Intramuscular, subcutaneous, and oral administration of caffeine presented similar results (53). Experimental studies of coffee consumption by humans have shown that blood pressure and pulse changes were slight in healthy young volunteers with administration of 3-4 n&kg of coffee and caffeine. Increases of 10 mm Hg iu pressure and decreases in pulse averaging 5 per minute have been reported (26). These alterations tended to diminish on repeated testing over a period of weeks. Older men (53- 77 years) showed a greater blood pressure rise than young men (2 l-25 years) after coffee consumption, but half the older subjects had very high control blood pressure levels (26).

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Cardiac output as a response to coffee and caffeine ingestion varies according to different studies; however, in one well-designed study, oral caffeine increased cardiac output in young healthy subjects by 15% after 0.65 g and by 1l%after 0.97 g, with a peak output at 10 min and a recovery period of l-2 hr (21). It has been noted that the temperature and/or volume of the ingested beverage will also affect cardiac output. Work by Drettner(16) showed that volume effects (vasoconstriction and vasodilation) are more prominent than temperature effects. Information on cardiac arrhythmias is limited, but one study showed that tachycardia was present in 24 of 113 (21.2%) subjects who were heavy coffee drinkers and bradycardia appeared in 7 (6.2%) of the 113 (39). Cerebral vasoconstriction has been documented (14,19,37), but the effects on coronary circulation are virtually unknown. Thus, the increase in cardiac work probably masks any effect of increased coronary flow. BLOOD LIPIDS AND CAFFEINE

The hypothesized link between caffeine and atherosclerotic heart disease is partially based on studies which have shown that caffeine ingestion tends to elevate levels of human plasma lipids (4,60). The increase in these lipids over a long period of time is known to be associated with the deposition of fatty material in arterial and vessel walls. Experiments on rats have demonstrated that elevated levels of serum lipids occur in proportion to the dose of caffeine added to the diet (11). Results of several experiments yield some discrepancy in lipid response, however, making it difficult to draw significant conclusions from these experiments, especially as they apply to man. Extensive work by Bellet on free fatty acids (FFA) and the effects of caffeine on humans shows a general FFA elevation upon ingestion of caffeine (2-4). Others have shown that this effect is greater in younger subjects (15-40 years) than in older ones (41-70 years), irrespective of sex. Bellet suggests that FFA may be converted through beta-oxidation into cholesterol molecules which in turn become lipoproteins and a part of the hyperlipidemia condition which is associated with atherosclerosis. These elevated levels have been associated with elevation of other lipid fractions, principally triglycerides and cholesterol. Bellet’s work shows that differential responses occur in his trials with coffee, decaffeinated coffee, and water, with coffee producing the highest elevations in FFA within a 4-hr period after ingestion (4). But the fact that the role of FFA and lipoprotein response to caffeine is more complex than Bellet suggests is supported by other research (60) where the role of nicotinic acid, epinephrine and norepinephrine have been shown to affect the mobilization of FFA in blood plasma. CHLOROGENIC

ACID

The presence of chlorogenic acid in roasted coffee beans is estimated to be from 1.6 to 2.7% of the total bean composition (9). It is estimated that 80-90% of the chlorogenic acid present in roasted coffee enters the prepared beverage. The metabolism of chlorogenic acid in the body is complex. Animal studies show that oral applications of 3.75-15 mg/kg produce stimulation of the CNS. Stimulant effects are about six times less than that of caffeine administered in the

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same way (5). Simultaneous administration of caffeine and chlorogenic acid did not produce cumulative response measurements. Successive administrations up to 300 mg/kg cause a drop in blood pressure, pulse rate and pH. These actions are thought to be due to the acid function of chlorogenic acid. An interesting interaction with caffeine was shown to accelerate the resorption of caffeine in the stomach and intestines with an accelerated elimination of caffeine through the kidneys (10). SUCROSE

INTAKE AND CARDIOVASCULAR

DISEASE

Conflicting reports have been made on dietary sucrose intake and the develop ment of ischemic heart disease. Yudkin (1957) proposed that dietary sucrose intake rather than fat was the important variable distinguishing heart disease and nonheart disease patients (59). Sucrose intake was estimated to be twice as high among patients with arterial disease than for control patients. Contradictory evidence for Yudkin’s position that sugar rather than fat consumption is primary to the development of heart disease came from work by Paul et al. (45,46) which studied the diets of nearly 2,000 men in a prospective study. Risk factors corroborated those established by the Framingham study (12,13), i.e., high serum cholesterol, blood pressure, body fatness, and especially cigarette smoking. Regarding diet, Paul found no association between traditionally associated dietary components and the development of heart disease; but he found that heart patients tended to drink more coffee and smoke more than normal control subjects (45,46). However, he noted no significant association between heavy intake of sucrose and coronary diseaseFurther contradictory evidence for the dietary sugar hypothesis was found by Howell and Wilson (27). Comparison of sugar intake of 1,158 men with no history of ischemic heart disease and 170 men with confirmed or possible heart disease failed to show any significant correlations between sugar intake and traditional blood parameters. EPIDEMIOLOGIC

STUDIES

Clinical laboratory studies on the cardiovascular effects of caffeine and coffee produced an interest in testing a possible association between heavy coffee consumption and selected diseases of the heart and circulatory system. Several epidemiologic studies were conducted over a period of 20 years to test the hypothesized association. These studies used several different methodological approaches and varied in their comprehensiveness as to which related factors were included in the analysis. Basically, retrospective, cross-sectional, and prospective designs were used and population sizes ranged from 50 to over 5,000 persons. Results ranged from no association between heavy coffee consumption and the increased risk of heart disease to a significantly higher risk attributed to heavy coffee consumption. The contradictory evidence of these studies as it relates to the hypothesized association has been discussed elsewhere (13,23,25,29,34). Much of the interest in a possible association between heavy coffee consumption and heart disease developed as a result of a prospective study of 1,989 Western Electric employees in Chicago by Paul in 1963 (45). Men aged 40-55 and

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employed for at least 2 years at the Hawthorne works of Western Electric were subjects in the g-year study. All were free from clinical coronary disease at the outset. Yearly health exams were given for the term of the study. Coffee consumption was determined at the time of the exam, along with family history, dietary data, physical activity, and a complete lab work-up. A bimodal distribution of coffee consumption was found in the data from coronary heart disease (CHD). People either drank no coffee or they drank 150cups or more per month (*5/day). Data were inconclusive about an association with MI. The author suggested that more work was needed before a judgement was passed regarding this study’s finding. A later report, published by the same author in 1968, discussed the earlier findings in a different light, stating that when smoking habits were controlled, the “true” effects of heavy coffee drinking were reduced to no association with an increased risk for developing CHD (46). Cumulative data from the Framingham Heart Disease study corroborated the findings Paul had later reported (12,13). The Framingham data came from a cohort of 5,209 males and females, aged 30-62, selected between 1949-1952. The determination of coffee drinking habits was not made until 6 years after the study began. At that time, 1,992 males and females had their coffee drinking status measured (ages 35-69) by the examining doctor and their clinical status evaluated. Reevaluations occurred every second year. The most recent exam (12th) showed no change in coffee drinking habits during that period. Coffee consumption was determined by asking how many cups of coffee the subject drank in a 24-hr period. Cigarette smoking, alcohol consumption, serum cholesterol level, and relative weight and blood pressure were recorded at each exam. Follow-up over the total series of exams was 85% with a 2% loss of subjects. Estimates of heart disease (HD) risk were determined by the computation of a morbidity ratio-the ratio of the number of subjects in whom clinical manifestations of the disease actually developed (in particular subgroups) to the number of subjects without disease, grouped by the coffee consumption status, Data from this study showed that after cigarette smoking was held constant, the association of coffee drinking with coronary heart disease ceased to exist. Using a different study design, Hennekens et al. obtained similar results (23). Information on a large number of variables, including coffee consumption, was obtained from wives of 649 male patients, aged 40-69, who died from CHD within 24 hours of onset of symptoms. Wives of neighborhood controls matched for age and SES also gave information. Analysis on the matched pairs was performed using stratification based on multivariate risk scores. This score was created by using all variables used in the study, deriving the actual score for each subject from a linear discriminant function separating patients and controls. In cases of overlap, subjects were divided into five equal strata. Within each quintile a risk ratio was computed. A summary risk ratio for matched-pair risk estimates was that developed by Miettinen. The proportion of coffee drinkers between cases and controls was almost identical (77.0% and 74.8%, respectively). The crude risk ratio estimate was 1.1 for coffee drinkers who died of heart attack. The overall maximum likeli-

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hood estimate of the risk ratio for “any” versus “no” coffee drinking was 1.1 (95% two-sided C.I. = 0.8-1.6). Repeating the analysis with coffee drinkers grouped by l-5 cups/day and 6+ cups/day gave a summary risk ratio estimate of 1.2 and 1.0, respectively. Using a step-up multiple regression analysis with case-controls as the dependent variable led the authors to conclude that the principle variables of diabetes, history of MI, cigarette smoking, history of angina, congestive heart failure, physical activity, relative weight, and history of hypertension were not a result of coffee drinking. Overall, the findings suggested that for “low” and “middle” risk patients the risk of death due to CHD associated with coffee drinking was small, regardless of amount of coffee drunk, if it existed at all. The maximum increased risk estimated by this analysis for coffee consumption was 10%. Klatsky et al. (34) and Jick et al. (29) found no association and a significant association, respectively, when they used retrospective studies to test the coffee-CHD association. The population in the Klatsky study was comprised of 464 Black and White (88% White) persons who had undergone a health exam at Kaiser-Permanente facilities in California between 1964- 1970. Each subject in the study had been selected because he subsequently suffered his first MI. At the time of the health exam, one question on daily coffee consumption was asked. Controls were selected via computer search from the health exam population. Controls were matched 2 : 1 to cases by age, sex, race, and exam date. Control 1 was designated Ordinary, and matched for age, sex, race, and exam date. Control 2 was the same except for exam date, blood pressure, or the absence of an ECG abnormality, and for current cigarette smoking, Matching was also done by systolic and diastolic blood pressure, serum cholesterol level, and serum glucose level. The control group was culled from 25,000 records. Results of the data analysis showed that once smoking habits were controlled, no significant association was found between the level of coffee consumption and the presence or development of heart disease. The retrospective study by Jick et al. contradicted these findings. The study of coffee and myocardial infarction (MI) from the Boston Collaborative Drug Surveillance Program was based on a hospital population of 440 surviving MI patients (cases) who were being treated in 24 Boston-area hospitals. These patients were selected as consecutive admissions to general medical and surgical wards less than 72 hr after admission. A small fraction were missed due to time lags between patient and admission interviews. All subjects who were White, aged 40-69, with no history of a discharge diagnosis of acute MI, and admitted to a surgical ward were excluded. The selection of cases was based on an MI diagnosis in the routine discharge write-up. Controls were all patients without acute MI. Those with a history of coronary artery disease were taken into account in the data analysis. Two controls were selected for each case. In the analysis, cases and controls were matched by age, sex, history of MI, smoking habits (smoker, nonsmoker, other), season of the year, and hospital. Data were collected by trained nurses. The questionnaire grouped coffee consumption into three categories: none; 1-S/day; 6+/day. Patients were asked in the interview if they ever had a heart attack, high blood pressure, or diabetes. The analysis of data from this study found a higher consumption of coffee among cases

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than among controls. No relationship was found between smoking and heart disease when compared with controls. Smoking exerted no influence on the association between coffee and heart disease. A sixth study using a cross-sectional study design was conducted by Heyden et al. in Evans County, Georgia (25). In l%O a biracial adult population of 3,102 aged 40-75 was medically examined over a 2-year period. In addition, a 50% sample of adolescents aged 15-39 was examined and included in the study. This diseaseprevalence study consisted of history-taking for heart disease and stroke, a physical exam, ECG, and urine and blood analyses. A second survey was done on the same individuals between 1967 and 1969. The re-exam rate was 90.9%. Coffee consumption was an average taken between summer and winter consumption rates. Data were collected by the examining physician. In this study population there were 2,530 coffee drinkers, 12% (N = 300) of whom drank 5 or more cups per day. The majority drank l-2 cups per day. High consumers were primarily White males. Coffee drinking varied considerably between Blacks and Whites. Crude frequency distributions on the coffee data showed no significant differences between White male “no” and “low” coffee drinkers and White male “high” coffee drinkers with a history of coronary heart disease. (In this study, CHD included angina, a history of MI, and sudden death.) The study’s author concluded that no association existed between coffee consumption and cardiovascular diseases. A small-scale study considered under the topic of epidemiologic investigation was conducted by Thiel(55) in Oklahoma. Of all seven studies, this was the only one which measured psychological characteristics of subjects along with data on life habits. Fifty MI patients consecutively screened upon entry to a hospital were matched by age and sex with healthy volunteers seen for routine physical exams at the same hospital. Any person with a history of heart disease, diabetes, pathologic Q waves and ST and T wave changes on ECG was excluded. Cases and controls were from all SES levels. Matching was not perfect by SES. More controls were among higher SES groups. Cases and controls were divided into groups of 25, aged 40 to 50 and 51 to 60. All individuals were interviewed by the principal investigator, who covered behavior, job, home life, a measure of depression and anxiety, as well as data on life habits. Interviews were recorded and judged by a “blind” panel who rated the interviewee along the lines of type “A” or “B” behavior patterns as developed by Friedman and Rosenman (17). A significant difference was found between cases and controls on the following variables for both age groups, with the direction being higher among cases: smoking, nervousness, sleep disturbances, night eating, working hours per week, sports involvement, number of divorces, anxiety and depression scale scores, and serum glucose abnormalities. In each age group, there were strong correlations between anxiety-scale ratings and excessive behavior patterns, and between smoking and nervousness. To clarify the apparent smoking and coffee-drinking association which appeared in several studies already discussed, an analysis was done on data from the American Health Foundation on 1,014 White males who were interviewed be-

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tween 1973 and 1975 in eight cities across the U.S. It showed that heavy coffee consumption (>4 cups/day) was directly associated with moderate to heavy cigarette smoking (>I 1 cigarettes/day). Figure 1 shows that in each smoking category, coffee consumption becomes greater as cigarette consumption increases. It is interesting to note the opposite pattern of coffee-drinking habits among nonsmokers and cigar and pipe smokers. The salient feature of this sample’s analysis is that the highest coffee consumption for any group (7+ cups/day) occurred among those who smoked 21+ cigarettes per day, a group defined by the Framingham Study as a high-risk heart-disease group (31). In a subanalysis of the data on 295 males and 83 females, it was found that among 72 nonsmokers, none was a heavy coffee drinker, whereas among 13 heavy smokers (~2 packs per day) none was a “none” or “occasional” coffee drinker. Among those who had once smoked but had successfully quit smoking at least 12 months prior to the interview, heavy coffee drinking (7+ cups/day) was less frequent than among the current-smokers group. Present and ex-smokers also differed in that ex-smokers were twice as likely to be “none” or “occasional” coffee drinkers (14.9% vs 10%) and present smokers were more frequently heavy coffee drinkers (14.9% vs 1.6%). BY age group, the proportion of daily coffee drinkers showed a peak among NON-SMOKERS

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FIG. 1. Coffee consumption by smoking habit for 1,014 white male hospital patients, United States, 1973-1975.

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those aged 50-59 (87%) with a steady decline with older ages (Fig. 2). Coffee and cigarette use showed similar declines with increasing age. DISCUSSION

The most robust epidemiologic tool by design is the prospective study because it eliminates the potentially powerful bias of case and control classification. It is also the most sensitive design to test a possible association between a personal habit and the subsequent development of disease. The Western Electric (1968) and Framingham studies, which utilized this study design, found little or no attributable risk of coffee consumption on heart-attack occurrence once the effects of cigarette smoking were controlled. Despite voluminous laboratory and epidemiologic research over the past few decades on the possible association between caffeinated coffee consumption and heart disease, sufficient and convincing evidence on the subject has not as yet appeared. One major setback to conclusive investigative research on the pharmacology of beverage caffeine is the nonequivalence of caffeine as a therapeutic drug and caffeine as contained in coffee and other beverages. Because of the large difference in potencies of these two “caffeines”, inferences made about one from the other are questionable. Research is generally conducted on pure, therapeutic caffeine; thus, results are valid only for that substance and can only be considered comparable to large overdoses of beverage caffeine-generally much more than any human is capable of consuming at one time. Another problem in approaching certainty about beverage caffeine effects is the difficulty either in measuring the effects of such caffeine or knowing their permanence. Although coffee has been shown to produce slight gastric irritation, temporary arrythmia, or bp changes, the influence and permanence of these effects is unknown; direct association with CHD is difficult to maintain. Likewise, possi-

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FIG. 2. Coffee and cigarette consumption by age group for 295 male hospital patients, 1973-1975

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ble harmful, long-term effects of the FFA elevations caused by caffeine consumption need further elucidation before any causal connection is made. Great difficulties are met in measuring plasma lipid levels; moreover, some studies have shown that both animal and human subjects are not affected in this way and exhibit no rise in FFA. A recent study hypothesized that accumulations of cyclic AMP are linked to the onset of ventricular fibrillation and subsequent MI (48). This theory could have bearing on the association some claim between beverage caffeine, particularly coffee, and heart disease, since caffeine is known to inhibit CAMP breakdown. However, the conditions under which this event takes place are not yet fully understood. Moreover, laboratory research has yet to show that beverage caffeine and drug caffeine are comparable in effect. Much as theories on FFA levels have to be further quantified and documented before a correlation is proven, so does this link between CAMP levels, fibrillation, and the role that beverage caffeine might play in this occurrence. Many epidemiologic studies concerned with determining a possible association between heavy coffee consumption and the development of heart disease are subject to common biasing factors such as sampling errors, poor matching in case-control designs, and interview biasing, all of which have been extensively discussed elsewhere (31-33,38,47,56). Incompletely defined variables, such as occur with the amount of cigarettes smoked and amount and strength of coffee consumed, are a problem in most of the studies cited here. For example, variations in the strength of commercially prepared brews are considerable; estimated averages vary as well by geographic location in the U.S. (44). A logical argument to be leveled against arbitrary grouping of cups of coffee consumed per day is that total caffeine in milligrams is not dependent on the number of cups consumed, given variations in preferred coffee strength and cup size among individuals. Lack of control over this essential defining aspect of caffeine consumption would obviously weaken attempts to compare numbers of cups per day with the incidence of MI. It is, after all, caffeine, not liquid consumption, which is of interest. The replication of negative findings for the association between MI occurrence and heavy coffee drinking by all except one retrospective study might suggest that either there is no association between heavy caffeine consumption and MI or the epidemiologic techniques are too gross in their level of measurement to determine an association. The dose-response problem is formidable, as was suggested by the variable results obtained by laboratory research on caffeine and the measurement problem present in all epidemiologic studies. This review has suggested that the strong positive association reported in several epidemiologic surveys between cigarette smoking and coffee consumption is a critical factor when considering the relative effects of selected variables in the etiology of heart disease. As was noted by Dawber (12,13), Hennekens (23), and Paul (46), once the effects of heavy cigarette smoking were controlled, the contributory effect of heavy coffee consumption (>4 cups/day) for elevating the risk of heart disease was insignificant. We conclude, therefore, that these predominantly negative epidemiologic results suggest a “negative causal association” between heavy caffeine intake and the incidence of cardiovascular diseases.

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ACKNOWLEDGEMENT Grateful appreciation is extended to Joan C. Spivak, whose knowledge and critical evaluation of this paper aided in its writing.

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