COFFEE AND HEART DISEASE
MYOCARDIAL INFARCTION AND OVERALL CORONARY HEART DISEASE
The scientific evidence for a link between coffee drinking or caffeine intake and coronary heart disease risk is entirely derived from observational epidemiological studies. Such studies can only show associations and not cause effect relationships. There are no intervention trials on the relationship between coffee drinking or caffeine intake and coronary heart disease risk and hence no cause effect studies although there are intervention trials on risk factors for disease such as blood pressure, blood lipids and blood homocysteine. Two types of observational epidemiological study have been published. The case control study has the weakest design as exposure, in this case to caffeine or coffee, is measured at the same time as coronary heart disease risk making it impossible to decide which is cause and which effect. The cohort study has a stronger design as exposure is measured prospectively in a group of initially healthy subjects and the appearance of coronary heart disease over time monitored.
Case control studies and cohort studies are subject to confounding and the best studies adjust the data for other known risk factors for coronary heart disease. However, even after adjustment it is still possible that coffee drinking or caffeine intake are acting as markers for some other aspect of lifestyle which is the true cause of the disease. A good example of this is the finding of the Olivetti Heart Study that after multivariate adjustment coffee consumption was significantly associated with cigarette smoking, a well-established risk factor for heart disease (1). The idea that coffee drinking is a marker for a lifestyle characterised by known risk factors for heart disease including smoking, lack of physical activity and consumption of saturated fat is supported by data from three other cohort studies (2, 3, 4).
Observational epidemiological studies of associations between coffee consumption and risk of cardiovascular disease were reviewed in the early 1990s (5, 6, 7). Greenland (6), for example, published a meta-analysis of 8 case control studies and 14 cohort studies and noted a fairly homogeneous increased risk in case control studies and a very heterogeneous and much smaller increased risk in cohort studies. It was concluded that “the evidence thus remains ambiguous regarding both the existence and size of a coffee effect”.
A number of case control studies have been published since the early 1990s. An Italian case control study carried out within the framework of the GISSI-2 trial on therapy for heart attack survivors found that after adjustment for other risk factors coffee consumption may indicate an increase in the risk of heart attack (8). A second Italian case control study indicated that the consumption of decaffeinated coffee was significantly associated with risk of heart attack in women although this association was no longer significant after adjustment for diabetes, hypertension and hyperlipidaemia (9). However, a case control study from the USA was unable to find any significant associations between consumption of either caffeinated or decaffeinated coffee and risk of heart attack (10). By contrast, a third Italian case control study found a significant association between the consumption of 6 or more cups of coffee per day and risk of heart attack after adjustment for confounders (19). Finally, a Swedish case control study showed that consumption of boiled coffee rather than filtered coffee was associated with increased risk of a first nonfatal heart attack (20). However, this result could be interpreted as suggesting that boiled coffee consumption helps people survive a heart attack.
A number of cohort studies have also been published since the early 1990s. In a cross-sectional study of 10,359 subjects in the Scottish Heart Health Study, it was found that non coffee drinkers had a significantly higher risk of coronary heart disease than the three categories of coffee drinkers (11). After 7.7 years of follow-up of this cohort, coffee consumption was associated with reduced risk of coronary morbidity and mortality although the statistical significance of these associations was marginal (12).
By contrast, a recent publication from the John Hopkins Precursors Study found that most categories of coffee consumption were significantly associated with increased risk of coronary heart disease, particularly heart attack, in smokers and non-smokers (13). However, in an editorial Willett argued that the author’s conclusions were not supported by their data and concluded that the results must have been due to chance (14).
Four subsequent cohort studies have not established any strong associations between coffee drinking and risk of coronary heart disease. A Norwegian cohort study of 38,500 subjects over 12 years found that coffee consumption was associated with increased risk of death from coronary heart disease but only when nine or more cups of strong Scandinavian coffee were drunk (15). In addition, if the first six years of follow-up were excluded, the association disappeared. A publication from the Nurses Health Study in the USA in which 712 cases of coronary heart disease were diagnosed in a cohort of 85,747 women over a period of ten years were unable to find any associations between coffee consumption or caffeine intake and risk of coronary heart disease (16). In a cohort of 5,766 Scottish men followed up for 21 years there were no associations between coffee consumption and coronary heart disease mortality (17). In a Finnish cohort of 20,179 subjects followed up for 10 years, there were no significant associations between coffee consumption and the risk of nonfatal heart attack, coronary heart disease mortality or total mortality in men or women (18). Although not significant, the highest risks were found in the non-coffee drinkers.
The strongest evidence for the idea that coffee consumption is associated with increased risk of coronary heart disease comes from the case control studies. Such studies have a weaker design than cohort studies and suffer from bias introduced by the choice of controls and differential recall of food and beverage consumption over extended periods by cases and controls. By contrast, the results of cohort studies do not support the idea that coffee consumption increases risk of coronary heart disease and one study even suggests that coffee consumption might protect against coronary heart disease. The single study showing an increased risk of coronary heart disease with coffee consumption was dismissed by the editor of the journal it was published in who is himself a well known epidemiologist (14).
Overall the evidence does not support the proposition that coffee consumption causes heart disease.
CARDIAC ARRHYTHMIAS
There is little experimental evidence for the idea that caffeine causes cardiac arrhythmias. In intervention trials neither 300 nor 450 mg doses of caffeine increased the occurrence or severity of ventricular arrhythmias in patients recovering from a heart attack (1, 2). In addition 200 mg caffeine had no effect on patients with malignant ventricular arrhythmia (3) and 275 mg caffeine had no effect on patients with clinical ventricular tachycardia (4). Caffeine restriction had no effect on patients with symptomatic idiopathic ventricular beats (5). In a prospective cohort study of 128,934 adults over 8 years there was no association between consumption of coffee and risk of death attributed to cardiac arrhythmia without specified cause (6). A review of intervention trials and epidemiological studies concluded that “moderate ingestion of caffeine does not increase the frequency or severity of cardiac arrhythmia’s in normal persons, patients with ischaemic heart disease, or those with pre-existing serious ventricular ectopy (7)”.
BLOOD PRESSURE
Confusion surrounding caffeine’s effect on blood pressure is long-standing. It was originally thought to lower blood pressure but subsequently believed to raise it. In 1988 Myers reviewed seventeen intervention trials and cross-sectional studies (1). He concluded that “…caffeine does not produce a persistent increase in blood pressure. Individuals who do not regularly consume caffeine may experience a slight increase in blood pressure when they are exposed to caffeine, but tolerance develops rapidly and blood pressure returns to baseline”.
The results of studies on subjects with normal blood pressure published since this review confirm its conclusions. An intervention trial in moderate coffee drinkers showed that moderate daily consumption of coffee does not elevate blood pressure measured in an outpatient clinic (2). A second intervention trial in habitual coffee drinkers showed that caffeine supplements produced a small increase in ambulatory blood pressure which returned to normal after three days (3). A third intervention trial in habitual coffee drinkers showed that abstaining from caffeine for 9 weeks had no effect on blood pressure (4).
Similar effects of caffeine have been observed in hypertensive subjects. In an intervention trial, caffeine administration to hypertensive subjects raised systolic blood pressure but this effect was no longer observed after the first 24 hours (5). In a second intervention trial there were no effects on blood pressure of drinking caffeinated coffee or abstaining in patients with borderline or mild hypertension (6). In a cohort study of hypertensive subjects, there were no associations between caffeine consumption and all-cause or cardiovascular disease mortality (7, 8). Hence there is no evidence in hypertensive subjects of a sustained effect of caffeine consumption on blood pressure nor increased death rates from cardiovascular disease.
However, some studies have demonstrated potential negative effects of caffeine on blood pressure. It has been shown that intake of caffeine during behavioural stress in subjects with borderline hypertension elevates blood pressure (9). Subjects with hypertension and subjects with normal blood pressure may respond differently to caffeine. Thus diastolic blood pressure returned to normal more quickly in subjects with normal blood pressure than in subjects with hypertension after caffeine ingestion (10). It has also been claimed that 24 hour monitoring of blood pressure is necessary to reveal all the effects of caffeine on blood pressure (11).
Prospective epidemiological studies have given contradictory results. Results from the Multiple Risk Factor Intervention Trial (MRFIT) on 11,000 men for 6 years indicated a statistically significant inverse association between caffeine consumption and systolic or diastolic blood pressure (12). By contrast, a study of 1017 men for 33 years demonstrated an increased risk of hypertension associated with drinking 5 or more cups of coffee per day (13). However, this association was not significant.
In the light of the results of subsequent studies, the conclusions of Myers in his 1988 review are still valid. A more recent critical review of over 100 published studies concluded that coffee or caffeine may only be harmful to hypertension prone subjects and then only in large doses although the authors did not specify these doses (14).
Research into the effects of coffee drinking on blood pressure has continued and it can be concluded that coffee drinking is generally not considered to be an important risk factor for hypertension. The effect of caffeine from all drinks, including coffee, on blood pressure was found to be in the range of 2.0 - 2.4 mm Hg for systolic blood pressure and 0.73 - 0.80 for diastolic blood pressure (15,16,17). Blood pressure levels return to baseline/control levels within a few hours following ingestion, with a fading of the mild hypertensive effect of caffeine taking place over a few days or weeks. A recently published meta-analysis of 16 studies reported that blood pressure elevations are larger with caffeine (systolic 4.16 mm Hg, diastolic 2.41 mm Hg) than with coffee (systolic 1.22 mm Hg, diastolic 0.49 mm Hg). This reflects that when ingested from coffee, caffeine has a small effect on blood pressure (17). Further, Geliejnse et al in 2004 (18) reported that hypertension, the prevalence of which is increasing in Western societies, is mainly caused by being overweight, physical inactivity, high sodium intake, and low potassium intake with the impact of coffee being quite small by comparison. It is also relevant to point out that the slight increase in blood pressure levels attributable to coffee is not larger than that experienced during common activities such as taking part in a conversation (19). A recent study (20) examined the association between caffeine intake and incident hypertension in a cohort of 155,594 women in the United States. Caffeine intake and possible confounders were ascertained from regularly administered questionnaires. In this large cohort habitual coffee consumption WAS NOT associated with an increased risk of hypertension, but consumption of sugared or diet cola was associated with it.
BLOOD CHOLESTEROL
The effects of drinking different types of coffee on blood lipid levels including total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol have been reviewed (1). The authors summarised the evidence that the diterpenes cafestol and kahweol are the cholesterol-raising factors in coffee and classified coffee brews as containing low, moderate or high levels of diterpenes.
Filtered coffee and instant coffee contain low levels of diterpenes. In some intervention trials, neither filtered coffee (2) nor instant coffee (3) had any effect on blood lipid levels. In one intervention trial, however, filtered coffee elevated both LDL- and HDL-cholesterol levels so that the ratio of LDL to HDL and hence the risk of cardiovascular disease did not change (4). Mocha coffee, common in Italy and Spain, and Espresso coffee contain moderate levels of diterpenes. Intervention trials have demonstrated that neither Mocha coffee (5) nor Espresso coffee (6) had any effect on total, LDL or HDL cholesterol levels. Boiled coffee and cafetiere coffee contain high levels of diterpenes. Intervention trials have demonstrated that both boiled coffee (2) and cafetiere coffee (7) raise total and LDL-cholesterol levels. However, the second of these studies has been criticised (8, 9) because the effect was small and within the normal diurnal and seasonal variation in cholesterol levels, the effect was of marginal statistical significance and there was evidence at the end of the 24-week study that cholesterol levels were falling again implying adaptation to coffee intake.
The caffeine content of coffee does not appear to have any influence on blood lipid levels. An intervention trial has shown that consumption of decaffeinated coffee did not lower total or LDL-cholesterol levels (10) and a cross-sectional study was unable to show any association between caffeine intake and total, LDL- or HDL-cholesterol (11).
A meta-analysis of intervention trials published prior to December 1998 on the effects of coffee on blood lipid levels was published in 2001 (12). The authors identified twenty- three papers but excluded nine from their analysis due to design faults. A significant dose response relationship between consumption of all types of coffee and total or LDL cholesterol levels was shown. They observed greater effects in subjects with hyperlipidaemia or when either caffeinated and decaffeinated coffee or boiled and filtered coffee were compared.
It can be concluded that heavy consumption of boiled coffee but not filtered coffee elevates blood total and LDL cholesterol levels. This effect is more obvious in hyperlipidaemic subjects. However, the clinical, statistical and long-term significance of the effects of boiled coffee on blood lipid levels has been questioned. Although more common in Scandinavia and the Middle East, drinking boiled coffee is comparatively rare in most countries
BLOOD HOMOCYSTEINE
Homocysteine is a naturally occurring amino acid found in the blood and tissues. However, it is not among the twenty amino acids which are the building blocks of proteins and hence is not found in dietary protein. Homocysteine is formed from the amino acid methionine which is a constituent of dietary protein. Homocysteine can also be converted back to methionine by two pathways. One of these pathways requires cobalamin (vitamin B12) and tetrahydrofolate (derived from dietary folic acid) as cofactors. An alternative route for the metabolism of homocysteine is conversion to cystathionine and then to the amino acid cysteine. This conversion requires pyridoxal phosphate (derived from vitamin B6) as a cofactor. Hence, efficient disposal of homocysteine requires three dietary vitamins namely folic acid, vitamin B12 and vitamin B6. Green vegetables and citrus fruits are excellent sources of folic acid, and vitamins B6 and B12 are found in a wide range of plant and animal foods including whole grain products, bananas, fatty fish, nuts, poultry and red meats. A balanced diet will, therefore, provide adequate intakes of all three vitamins and hence ensure efficient disposal of homocysteine.
Over thirty years have gone by since it was first suggested that elevated levels of homocysteine in the blood are associated with a high risk of cardiovascular disease (1). However, not all studies have been able to demonstrate this association. After correction for other risk factors, a study of cases and controls from the Atherosclerosis Risk in Communities (ARIC) study was unable to find any association between blood homocysteine levels and risk of coronary heart disease (2). Similarly, after correction for other risk factors, a study of cases and controls from the Caerphilly cohort was unable to show that coronary heart disease risk was associated with serum homocysteine levels (3).
The crucial question is whether the elevated blood homocysteine level causes cardiovascular disease or whether cardiovascular disease causes the elevated blood homocysteine level. A review of 43 studies found that most cross-sectional and case control studies were able to find an association between blood homocysteine levels and cardiovascular disease risk whereas most prospective studies were not (4). The authors noted that the few prospective studies showing an association included subjects with pre-existing cardiovascular disease. They concluded that elevated homocysteine levels were a consequence of cardiovascular disease and not a cause of it. By contrast, a more recent meta-analysis of 72 studies of subjects with a genetically determined elevated homocysteine level and 20 prospective studies of normal subjects concluded that there was “strong evidence that the association between homocysteine and cardiovascular disease is causal” (5). The authors concluded that lowering homocysteine levels by 3 μmol/l would reduce the risk of heart disease by 16%.
It has been suggested that coffee consumption elevates homocysteine levels and that abstention from coffee lowers them. While seven cross-sectional studies (6, 7, 8, 9, 10, 11, 12) have shown that coffee consumption is positively associated with plasma total homocysteine concentrations in both men and women, three other cross-sectional studies (13, 14, 15) failed to show any association.
Although these associations do not prove that coffee consumption raises the blood level of homocysteine they are supported by the results of four out of five intervention trials. Plasma total levels of homocysteine were elevated by 1.2 μmol/l by drinking a litre of unfiltered coffee per day for 2 weeks (16) or increased by 1.5 μmol/l by drinking a litre of paper-filtered coffee per day for 4 weeks (17). It has also been shown that abstention from filtered coffee for 6 weeks is associated with a decrease in total homocysteine levels of 1.08 μmol/l (18). Plasma levels of homocysteine were elevated by 0.4 μmol/l by 870 mg caffeine per day and by 0.9 μmol/l by 0.9 l filtered coffee (containing 870 mg caffeine) per day for two weeks suggesting that caffeine is partly responsible for the homocysteine raising effect of coffee (19). By contrast, a fifth intervention trial was unable to demonstrate any effect of five cups of coffee per day for 1 week on plasma homocysteine levels although this study was not well controlled (20).
It has been suggested that caffeine might be the factor in coffee that elevates plasma total levels of homocysteine because it may inhibit the conversion of homocysteine to cysteine by acting as a vitamin B6 antagonist (6, 11, 16). However, direct evidence for this proposal is lacking. Chlorogenic acid may also be partly responsible for this effect as an intake of 2 g per day for a week increased plasma total homocysteine (21).
Hence there is still disagreement over whether the blood homocysteine level is a risk factor for cardiovascular disease. In addition, it is not clear whether even high intakes of coffee are sufficient to raise blood homocysteine levels enough to influence cardiovascular disease risk nor is it clear whether abstention from coffee will lower levels enough to reduce risk. An effect of coffee consumption on cardiovascular disease risk mediated by homocysteine levels is unlikely.
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