Coffee and coronary heart disease: A review

Coffee and Coronary Heart Disease: A Review Phillip C. Rosmarin

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OR CENTURIES, the Western world has enjoyed coffee for the stimulant properties of its caffeine content. Its use is commonplace and widespread; in fact, a social gathering is incomplete without the serving of coffee. Few other commodities exist where the “free refill” is not only accepted but rather is the norm. However, along with its widespread use, coffee has also been the object of scrutiny as a potential etiologic agent in various human maladies from fibrocystic breast disease to malignant neoplasms. Perhaps it is because of its common usage that these associations have been made, but few have withstood critical review by the scientific community. In recent decades, much attention has focused on a possiblerole for coffee in increasing coronary heart disease(CHD) and CHD risk factors. The studies have focused on three major CHD risks: cholesterol and lipids, hypertension, and arrythmogenicity. This article will serve asa review of the more pertinent works published in theseareas. BACKGROUND

Coffee, as a beverage made from the extract of coffee beans, is available in a variety of forms: instant, filtered drip-brewed, boiled, and percolated. It is known to contain hundreds of chemicals, few of which have been studied in any detail with the exception of caffeine.’ A cup of coffee might contain between 29 to 176 mg of caffeine with a median amount of 74 mg.2 Caffeine is known to be responsiblefor the stimulant properties of the drink which has led to its popularity and use; it has naturally also been blamed for all of the purported adverse effects of coffee. This has led researchers to use purified caffeine in some studies and brewed coffee in others. Whether it is necessary to distinguish between these methodologic differences remains to be seen as the other chemical constituents in the effluent of the coffee brew are further delineated and studied for their pharmacologic properties. Since at least one study reported another potentially bioactive substance in coffee,3 for the purpose of this review that distinction will be maintained whenever possible. Another confounding variable through the Progress

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years has been the now well recognized association of cigarette smoking with coffee consumption.4*5Earlier reports were unaware of the association of smoking with CHD. Cigarette smoking is recognized as a major correctable risk factor for CHD as well as having adverseeffects on high density lipoprotein cholesterol which is protective for CHD.6 COFFEE AND TOTAL

CHD

Epidemiologic work examining the possible association of coffee consumption to total CHD and CHD mortality spans more than two decades. One of the earliest studies was by Paul et al in 1963 which was a prospective cohort study of nearly 2,000 men in which a positive correlation was found between coffee intake and CHD.’ Apparently, the authors did not adjust for cigarette smoking among the coffee drinkers. In 1974, Dawber reported the experience of the Framingham study in which multivariant analysesshowedthat no increasein total CHD, angina pectoris, myocardial infarction (MI) or sudden death could be correlated to coffee consumption4 The only correlation with coffee intake was death from all causeswhich was no longer significant when adjustments for cigarette smoking were made. Yano et al reported in 19775and again in 1987* on their cohort of Japanesemen living in Hawaii that no associationexisted betweencoffee intake and CHD after adjusting for cigarette use. Later, in a cross-sectionalstudy of a large cohort in Evans County, Georgia, Heyden et al found no association between coffee use and total mortality or CHD mortality.’ However, they did note a positive correlation in the subgroup of white men but admit they did not adjust for cigarette smoking becauseof the lack of association in the cohort overall. They also stated that the lack of systematic differences in vascular mortality among the four race-sex groups led to the concluFrom the Department of Medicine, the University of Tennessee, Memphis. Address reprint requests to Phillip C. Rosmarin, MD, Assistant Professor of Medicine, University of Tennessee. Memphis, 800 Madison Ave, Memphis, TN 38103. up 1989 by W.B. Saunders Company. OOU-0620/89/3203-0004%5,00/O

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sion of no association. Most recently, LaCroix et al found a dose response association between coffee consumption and clinical CHD in a prospective observational series.” This study has been criticized for failing to control adequately for dietary changes,“,” emotional stress,” and cholesterol levels,11~12although cigarette smoking was measured and controlled for in the analysis. Case-control studies examining the association of coffee consumption with CHD likewise have been conflicting. The Boston Collaborative Drug Surveillance Program found that persons drinking more than five cups of coffee per day have twice the risk of MI than nondrinkers.13 Their entry history queried the patients’ normal coffee consumption. Jick et al found drinking one to five and six or more cups of coffee per day to increase the risk of Ml by 60% and 120%, respectively.14 Their coffee consumption histories were concerned with recent intake over the previous 3 months and not with long-term habitual intake. The Klatsky et al review of the Kaiser-Permanente program found no association between coffee consumption and acute MI.” Their coffee consumption history was likewise obtained by recall questionnaire at an office interview an indeterminate amount of time before the index MI. Finally, Hennekens et al found no increased risk of death from CHD and coffee consumption.16 By design, information concerning coffee consumption, other coronary risk factors, and habits were obtained from wives of both cases and controls, and covered the 3 months before the index event. All of these studies recorded recent coffee intake that may not reflect long-term use. Therefore, it is unclear whether these associations were due to acute effects of coffee or due to its chronic ingestion and pathologic effects thereof. While these results may raise more questions than they answer, the overall conclusions support previous findings of no association between coffee consumption and CHD. The divergence of findings in these studies underscore a problem with epidemiologic studies. While they are most useful in establishing associations of various factors with disease, they cannot by nature of their design establish cause and effect.” This can best be done with a prospective clinical trial.” Unfortunately, with a multifactorial disease process such as CHD that may take decades to become

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manifest, a clinical trial is not feasible, and epidemiologic studies are the only practical tools with which one is left to work. This has led many investigators to look specifically at the effect of coffee on some of the established risk factors for CHD such as serum lipids and arterial BP. COFFEE AND SERUM LIPIDS

Since Bellet et al showed caffeine and coffee intake could increase serum levels of free fatty acids,” a wealth of data hascome forth exploring the possibleconnection between coffee consumption and atherogenic lipids. The early work was, again, epidemiologic in nature. In a case-control analysis published in 1966, Little et al found a positive correlation between coffee consumption and serum cholesterol levels in a cohort of patients surviving a Ml compared with agematched controls,20but no adjustments for smoking were made. Positive correlations between coffee and cholesterol were made by Bjelke in 197421 and Sacks et al in 1975,22 but these findings were incidental to the primary research questions. In a cross-sectional study of nearly 5,000 Australians, Shirlow and Mathers found that total caffeine consumption (ie, coffee and tea) was positively correlated with serum cholesterol levels in women, while the useof caffeinated coffee but not total caffeine intake, was positively correlated with serum cholesterol levels in men.23 They also noted an interaction between smoking and caffeine intake in the effect on serum cholesterol in the women. Klatsky et al in the analysis of data from a cross-sectionalevaluation of over 42,000 men and women noted a positive correlation between coffee intake level and serum cholesterol.24While the association was statistically highly significant, the actual mean differences were ~5%. which is about the expected error of variance for routine automated cholesterol testing. Recently, Williams et al published a cross-sectional study of 7.7 middle-aged American men which showed a positive correlation between coffee intake and serum apolipoprotein B, low density lipoprotein cholesterol, and total cholesterol.2s The authors point out that although coffee drinking is associated with higher CHD risk lipid profiles, the causality remains to be determined. Finally, in yet another crosssectional study, Heyden et al found that coffee drinking and smoking appeared to have a syner-

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gistic effect on raising serum levels of atherogenie lipids, but that coffee alone did not.26 It should be noted that none of the above studies is definitive in establishing a cause and effect relationship between coffee consumption and atherogenic serum lipids by nature of their design. Neither can they vindicate coffee of a possible role. It is also noteworthy that none of these studies methodically ascertained the brewing method used in the preparation of the coffee consumed, a point that may be very important and that will be developed later. The confusion created by these divergent results created the need for clinical trials to establish causality, including differentiating between the effects of coffee v the caffeine content of coffee. The most interesting data to date have come from the Tromso, Norway group. In their first report in 1983 on a cross-sectional study of over 14,000 subjects, they found a positive correlation between coffee intake and serum cholesterol.27 This led them to study in a prospective, crossover clinical trial 17 healthy volunteers drinking six or more cups of coffee per day v total abstention from coffee, using tea as a substitute. They found that coffee consumption did indeed cause an increase in serum cholesterol levels.28 At this point, it should be noted that the predominant method of brewing coffee in Norway is by boiling. This differs from American techniques that formerly were instant or percolated coffee and, more recently, filtered drip-brewed. This difference in brewing methods as well as amount of coffee consumed has been used to criticize these results. Undaunted by the critics, the Tromso group released data on yet another clinical trial in which the effect of coffee on the cholesterol levels of 33 men with hypercholesterolemia was examined.29 Four groups were studied. One group continued usual coffee use, one totally abstained for 10 weeks, two groups abstained for 5 weeks and then resumed drinking coffee-one group drinking boiled and the other drinking filtered coffee for the final 5 weeks. When off coffee, the serum cholesterol levels in these latter three groups decreased. Upon resumption of coffee intake, the group drinking boiled coffee had a marked increase in serum cholesterol, whereas the group drinking filtered coffee did not. While the small number of subjects in each group did not permit subgroup analysis on the effect of

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brewing method, these results are most provocative and perhaps indicative of the reason for the differences in results over the years. In fact, in response to this last report, Martin and Woo described the finding of a possible surfactant coffee factor that could be precipitated by hard water and removed by filtration.3 They speculated that this surfactant might be the factor responsible for the changes observed in the Norwegian studies, and that changes in surfactant availability depending on the use of hard or soft water might explain the differences in results from different localities. This idea was further supported by another cross-sectional survey by the Tromso group, which found a positive correlation between consumption of boiled coffee and serum total cholesterol but no correlation between filtered coffee use and serum cholesterol.30 This led our group at the University of Tennessee, Memphis to perform a prospective crossover clinical trial of the effect of moderate coffee consumption on serum lipids. Study participants used filtered coffee only, and no effect was found on any of the lipid fractions (unpublished data). It should be noted that all other forms of caffeine were eliminated during this trial, and normal healthy volunteer men were used. Further confirmation of the importance of the method of brewing was supplied by Aro et al in a randomized crossover trial comparing boiled coffee, filtered coffee, and tea consumed for 4-week intervals.31 They found that consuming boiled coffee resulted in a significant increase in serum total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B, whereas filtered coffee and tea consumption did not increase these lipids. These results support the idea that filtered coffee, at least in moderate amounts, does not increase serum cholesterol. Although the early data are conflicting, this may be attributed to the problems of the study designs, as well as perhaps the differences in the hardness of water and brewing methods in various localities. The more recent clinical trials seem to support the fact that in moderation, filter-brewed coffee does not increase CHD risk by adversely affecting serum levels of atherogenie lipids. To be sure, more work is required on different methods of brewing, hard versus soft water, and the presence of other bioactive substances such as this surfactant coffee factor that

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may be responsible for the adverse effects noted previously. Until more clearly defined, it cannot be uniformly recommended that coffee intake be curtailed, although it may be reasonable for those with hypercholesterolemia to undergo a trial of abstention at best, or at a minimum change to drinking filter-brewed coffee in low to moderate amounts. COFFEE AND HYPERTENSION

The story concerning the effect of coffee on blood pressure(BP) is even lessclear, as much of the work in this field has been done with purified caffeine in either a placebo beverage or added to decaffeinated coffee. Because of this it becomes even more difficult to separate coffee from caffeine. Early pharmacologic experiments with caffeine in the 1930s found no change32or small increases33 in BP after administration. Similarly, experiments with coffee compared with decaffeinated coffee found a small increase in BP with coffee ingestion.34These short-term experiments contrasted with a longer-term study that showed a diminution of coffee’s pressor activity over ensuing weeks.35 In 1945, Hadley reported a definite tendency toward hypertension, with decreased heart rate, in coffee and tea users in a cross-sectional evaluation of 10,000 consecutive office patients.36 However, he did not report his standard deviations or control for any other factors in the analysis. More recent work has shown a definite ability of caffeine to increase BP in an acute, short-term study. Several studies examining the interaction of coffee or caffeine with stresson increasing BP have shown that after drinking coffee or caffeine37-39 and before subjugation to mental stress, both normal and hypertensive subjects will experience an increase in BP, which is further augmented by stress.Likewise, Robertson hasshown an acute pressor effect of caffeine in young, healthy, caffeine-naive subjects.40Interestingly, in this three-hour experiment, the increase in BP was no longer statistically significant after two hours. Freestone and Ramsay, in comparing coffee with an orange squash placebo, found an increase in BP after drinking coffee in hypertensive subjects.41Cigarette smoking had an effect on BP additive to that of coffee alone.

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To confound matters, several epidemiologic studies have found no correlation between coffee consumption and the risk of hypertension. Data from the Framingham study show no correlation between increasing coffee intake and BP.4 Bertrand et al reported their results compiled from 5 1,000 corporate physicals showing no relationship between coffee consumption and elevated BP.42 Likewise, the data from the KaiserPermanente program showed no association between coffee intake and elevation of BP.43 Recently, Periti et al reported the results of a large cross-sectional study of Italians and actually demonstrated a decreasein BP ascoffee consumption increased.44 This apparent discrepancy has been resolved by the finding of tolerance to the pressor effects of caffeine as alluded to by Horst et a1.35In longer-term studies where caffeine was consumed regularly for a week, Robertson et al found the pressor effect of caffeine to be gone after one to four days in both normal45 and borderline hypertensive46 subjects. They also found a loss of the increase in serum catecholamines after 1 week of regular caffeine consumption that had been noted at the beginning of the study.45This was further confirmed by our group at the University of Tennessee,which found no effect of regular coffee consumption on BP in a crossover clinical trial in which no other caffeine intake was permitted (unpublished data). It has been proposed that the acute pressor effects of coffee and caffeine can be explained, at least in part, by the increase in circulating catecholamines resulting in increased cardiac output.47 This explains the short-term increase in BP aswell as the rapid development of tolerance, as tachyphylaxis to the effects of catecholamines is known to develop within a few hours.48 It would seem, then, that coffee and caffeine are not etiologic in inducing hypertension. Rather, they are cardiac stimulants whosepressoreffects are indirectly mediated and to which tolerance develops rapidly. COFFEE, CAFFEINE, AND ARRHYTHMIAS

The least understood potential connection between coffee and CHD is the arrhythmogenic effect of caffeine. Anecdotal reports indicate that

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coffee may cause palpitations, but scientific data on caffeine’s arrhythmogenic properties are sparse. While caffeine’s toxic effects at high doses are known to include cardiac dysrhythmiaq4’ the effects of more moderate doses have not been well explored. In animal models, caffeine has been shown to increase the duration of the action potential of myocardial cells” and increase the rate of spontaneous discharge and initiate spontaneous repetitive activity in Purkinje fibers,5’ both of which may predispose to arrhythmias. On the other hand. caffeine has also been shown to have antiarrhythmic properties in acute myocardial ischemia in a rat mode1.52 The data that are available from human subjects is likewise contradictory. In a randomized nondrug intervention, DeBacker et al found no decrease in ventricular ectopic activity (VEA) in normal men by stopping coffee consumption.53 In a prospective study of coffee’s acute effects on hemodynamics, Gould’s group found no abnormalities of rhythm in either normal or cardiac patients after ingestion of coffee.54 The Myers et al report on coffee’s effect in post myocardial infarction patients revealed no increase in VEA in those patients given caffeine compared with those given placebos.55 On the other hand, ventricular ectopy was shown to have a positive correlation with coffee and tea used in a cross-sectional

studyS6 and was noted to increase with coffee ingestion in certain individuals with underlying idiopathic VEA in a prospective tria1.57 In one clinical trial from the early 1950s coffee was found to increase VEA, an effect not related to caffeine content but rather to the degree of roasting of the coffee beans.58 Finally, with the newer technology of the electrophysiology laboratory, Dobmeyer et al have shown that coffee and caffeine can shorten the effective refractory period of the right atrium and ventricle as well as the atrioventricular node, while the refractory period of the left atrium is prolonged.5g In response to programmed stimulation, they showed that coffee and caffeine produced atria1 tachyarrhythmias in both patients and controls, and ventricular tachycardia in two patients. They concluded that these rhythms therefore may occur spontaneously, and thus supported the possibility that in certain susceptible individuals

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caffeine may be arrhythmogenic and may even induce potentially lethal arrhythmias. Given the mixed results in this area, it would seem that further investigation is warranted into the possible link between coffee and cardiac arrhythmias. In particular, what are the factors or underlying conditions that predispose to VEA with caffeine ingestion? Can this arrhythmogenic effect of caffeine account for the increases in total CHD mortality associated with coffee as observed in some studies? Until this issue is further defined, it would seem unwarranted to make widespread uniform recommendations concerning coffee use. However, those individuals with underlying heart disease or with history of cardiac symptoms following coffee ingestion would be prudent to abstain or at least minimize their coffee and caffeine intake. SUMMARY

Since the early 1900s coffee has been implicated as having adverse effects on human health. Recent attention has focused on coffee’s relation to CHD, but because of conflicting results of epidemiologic studies on coffee and CHD mortality, attention has turned to the effects of coffee and caffeine on individual CHD risk factors. Coffee’s effect on serum lipids does not appear to be due to caffeine. If in fact an adverse effect on lipids exists, it may be related to other factors including biochemical constituents other than caffeine, hardness of the water used in preparation, and the method of preparation, filtered coffee having no effect. The data are fairly convincing that chronic coffee ingestion does not induce hypertension, although acute consumption produces a small, short-lived increase in BP. The least well understood effect of coffee is its potential to induce cardiac arrhythmias, including potentially lethal ventricular ectopy in certain individuals. More work is needed in this area of arrhythmias before any concrete recommendations can be made. Until more convincing evidence against coffee is compiled, it appears that, at least in moderate amounts in otherwise healthy persons, coffee is a safe beverage. ACKNOWLEDGMENT Many thanks to Kathon Kelly preparation of the manuscript.

for her assistance

in the

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