Abstract
Background. The longitudinal relationship between coffee use and hypertension is not well known.
Aim. We did a prospective study to investigate if there is a temporal relationship between coffee consumption and development of sustained hypertension.
Method. We assessed 1107 white subjects with elevated blood pressure who were followed up for 6.4 years. Coffee intake and other life‐style factors were ascertained from regularly administered questionnaires. Incident physician‐diagnosed hypertension was the outcome measure.
Results. During the follow‐up, 561 subjects developed sustained hypertension, whereas 546 subjects did not meet the criteria for treatment. Coffee drinkers developed sustained hypertension more frequently than abstainers (53.1% versus 43.9%, P = 0.007). The incidence of hypertension did not differ between moderate and heavy coffee drinkers. Kaplan‐Meier analysis confirmed that sustained hypertension was developed more frequently by coffee drinkers compared with nondrinkers (P<0.001). The adjusted relative risk of hypertension was greater in both categories of coffee drinking than in abstainers (hazard ratio, 95% confidence limit (CL) = 1.24, 1.06–1.44). The risk of hypertension associated with coffee drinking increased gradually with increasing level of alcohol use (adjusted P for interaction = 0.005).
Conclusions. In subjects screened for stage 1 hypertension a nonlinear association was found between coffee consumption and development of sustained hypertension.
Introduction
Coffee is a widely consumed beverage, and even small effects on blood pressure (BP) could have an important impact on public health. Acute intake of coffee has been demonstrated to raise BP Citation1,2 but adaptation to the cardiovascular effects of coffee drinking occurs quickly, and during regular use tolerance to the cardiovascular responses seems to develop Citation3. Epidemiologic studies have produced contradictory findings regarding the cross‐sectional association between BP and coffee consumption Citation4–8. Two meta‐analyses of randomized controlled trials demonstrated a small BP increase for regular coffee or caffeine intake, but the study duration ranged from 1 to 12 weeks, and the BP effect of coffee and caffeine intake in hypertensive subjects could not be sufficiently explored Citation9,10. To determine if the pressor effect of coffee drinking seen in clinical trials is maintained over time and whether it translates into an increased risk of developing hypertension over the long term, prospective studies are needed. However, only two large prospective studies of coffee drinking and risk of developing hypertension have been performed, in subjects who had normal BP at baseline evaluation. In 1017 young white US males, drinking coffee was positively associated with BP and risk of hypertension, although findings were weak and the association was no longer significant after adjustment for confounders Citation11. In a prospective cohort study conducted in the Nurses’ Health Studies I and II of 155,594 US normotensive women, habitual coffee consumption was not associated with an increased risk of hypertension Citation12. In a recent analysis of the Doetinchem Cohort Study, coffee abstinence was associated with a lower hypertension risk than was low coffee consumption, and an inverse U‐shaped relation between coffee intake and risk of hypertension was observed in women Citation13. No data are available on the long‐term effects of coffee drinking in hypertensive subjects. Clinical trials conducted in persons with established hypertension indicate that cessation of coffee drinking lowers blood pressure Citation14, but results from long‐term prospective studies in hypertensive individuals are still lacking. That is why reduction of coffee intake has not been included by international guidelines among the life‐style measures suitable to the hypertensive patients Citation15,16. The aim of the present study was to examine the long‐term effect of coffee drinking on the risk of developing sustained hypertension in the participants of the HARVEST (Hypertension and Ambulatory Recording VEnetia Study), a prospective longitudinal study of young subjects screened for stage 1 hypertension Citation17. As coffee drinking is often related to cigarette smoking and alcohol consumption, and these habits may act synergistically on BP Citation8,Citation18, another purpose of the present analysis was to ascertain the effect of regular coffee intake on incident hypertension within strata of smoking status and alcohol use.
Key messages
In the early stage of hypertension there is a nonlinear association between coffee consumption and development of sustained hypertension.
The risk of hypertension associated with coffee drinking increases with increasing level of alcohol use.
Abstinence from caffeinated coffee should be considered among the dietary changes for hypertensive patients. However, further intervention studies are needed to really establish whether cessation of coffee consumption should be included among the nonpharmacological measures for every patient with hypertension.
Materials and methods
Study population
The HARVEST study is a long‐term prospective study of 18–45‐year‐old individuals, initiated in April 1990, investigating the origin of hypertension with regard to clinical Citation19, physiological Citation17, and genetic Citation20 characteristics. Never‐treated subjects screened for stage 1 hypertension (systolic BP between 140 and 159 mmHg and/or diastolic BP between 90 and 99 mmHg) were enrolled. Patients with diabetes mellitus, nephropathy, and cardiovascular disease were excluded Citation17,Citation19,20. Patients’ clinical characteristics are reported in . The higher prevalence of men among our study participants confirms previous observations of a much higher frequency of male subjects in the young, stage 1 segment of the hypertensive population Citation21. The HARVEST study is conducted in 17 hypertension units in Italy. Patients’ recruitment was obtained with the collaboration of the local general practitioners who were instructed during local meetings. Consecutive patients with the above‐mentioned clinical characteristics seen in the offices of the general practitioners and willing to participate in the study were eligible for recruitment and were sent to the referral centers. Patient files, blood and urine samples are periodically collected by five monitors and taken to the coordinating office in Padova, where they are processed.
Table I. Clinical characteristics of the study subjects by coffee intake.
Procedures
The procedures followed were in accordance with institutional guidelines. At baseline, all subjects underwent physical examination, anthropometry, blood chemistry, and urine analysis. Participants completed questionnaires about their medical history, family history of hypertension, physical activity, and dietary habits including coffee intake, alcohol use, and cigarette smoking. Coffee consumption was defined according to the number of caffeine‐containing coffees drunk per day. Decaffeinated coffee was not taken into account. The caffeine content per cup of ‘expresso’ Italian coffee, which was the most abundantly consumed type of coffee by the HARVEST participants, averages 100 mg Citation22,23. Tea and other caffeinated drinks were not taken into account in the present study, being unusual and irregular in this area of Italy (Venetia). A positive family history of hypertension was defined as one or two parents having hypertension and/or taking antihypertensive treatment Citation20. Duration of hypertension was defined as number of months from the first detection of high BP to the baseline assessment. Details about the interview, life‐style assessment, and criteria used for subjects’ classification according to life‐style have been reported elsewhere Citation17,Citation19,20. The study was approved by the HARVEST Ethics Committee, and written informed consent was given by the participants. BP was measured following the recommendations of the British Society of Hypertension Citation24,25, three times after a 5‐minute rest in the supine position. Subjects were instructed to refrain from smoking and drinking coffee prior to the BP measurement. Baseline BP was the mean of six readings obtained during two visits performed 2 weeks apart Citation17. Body mass index (BMI) was considered as an index of adiposity (weight divided by height squared). In 647 participants, urine was collected over 24 hours for catecholamine assessment. Immediately after completion volumes were measured and urine specimens were frozen (−20 C°) and sent to the Coordinating Office at the University of Padova, where epinephrine and norepinephrine were measured by a high‐performance liquid chromatography method Citation17.
Follow‐up and study end points
In the HARVEST study, office BP and life‐style habits are assessed monthly during the first 3 months of follow‐up, then after 6 months, and every 6 months thereafter. After baseline examination, subjects are given general information about nonpharmacological measures by the HARVEST investigators, following the suggestions of current guidelines on the management of hypertensive patients Citation15,16,Citation24–26. To ensure homogeneous counseling by doctors participating in the study, training in current international guidelines was provided to them throughout the study duration. HARVEST participants are followed until they develop sustained hypertension requiring antihypertensive treatment according to the guidelines available at the time. Subjects who do not meet the criteria for treatment are checked at 6‐month intervals unless they drop out. To identify the subjects with sustained hypertension, we followed the guidelines of the British Hypertension Society until 1999 Citation24,25 and then the 1999 World Health Organization–International Society of Hypertension guidelines Citation26, the 2003 European Society of Hypertension–European Society of Cardiology guidelines Citation15, and the 2004 British Hypertension Society–IV guidelines Citation27. The definition of sustained hypertension is based on at least six clinic BP readings taken on two subsequent visits within 1 month Citation19,20. The second end point visit is performed immediately before starting antihypertensive treatment. In the present study, mean follow‐up for the whole cohort was 6.4±3.7 years. Other details on follow‐up procedures have been reported elsewhere Citation19,20.
Data analysis
The present study was performed in the 1185 subjects for whom BP and information on life‐style habits were available both at baseline and final assessments and who had at least 6 months of follow‐up. Seventy‐eight subjects who were past coffee drinkers or drank less than 1 cup/day were excluded, leaving a total of 1107 participants available for analysis. For those subjects who were lost to follow‐up (n = 352), the last available BP values were taken into account. Distribution of coffee drinking was similar among the subjects who remained in the study and those who were lost to follow‐up (P = 0.29). Subjects were categorized according to their habitual consumption of coffee. As we did not find significant differences in the cross‐sectional or longitudinal relationships of BP with coffee intake parameterized as a continuous variable, we classified the participants as nondrinkers (none), moderate drinkers (1–3 cups daily) and heavy drinkers (4 or more cups daily), a classification used in a previous cross‐sectional analysis Citation8. Subjects were divided into four categories of alcohol use (0 g, <50 g, 50–100 g, >100 g of alcohol/day) Citation8. As there were only seven subjects in the >100 g/day alcohol class, the two upper classes of alcohol were subsequently analyzed together. Current smokers were those who reported smoking one or more cigarettes per day. The distribution of clinical variables was compared across classes of coffee consumption by analysis of covariance adjusting for age and sex. The significance of differences in categorical variables was assessed with the chi‐square test. The significance of the effects of coffee consumption and alcohol use on urinary catecholamines was assessed in a two‐way analysis of covariance after adjustment for age and sex. Due to the small size of some subgroups, for this analysis subjects were grouped into two classes (users versus abstainers for both coffee and alcohol). The cumulative incidence of subsequent hypertension associated with coffee consumption at baseline was calculated using Kaplan‐Meier analysis. The difference in hypertension incidence between coffee drinking levels was tested using the log‐rank test. Coffee intake was also modeled as a time‐dependent categorical variable in Cox proportional hazards analysis. No violations to the proportional hazards assumption were detected by inspection of survival curves. Multivariate Cox proportional hazards models were developed to adjust for possible confounding variables. The variables found to be associated with outcome at univariable survival analysis and/or believed to be of prognostic importance were sex, age, BMI, family history for hypertension, duration of hypertension, physical activity, coffee intake, smoking status, alcohol consumption, and baseline BP. Other explanatory variables included in the models were baseline urinary catecholamines (n = 647) and change in body weight at the end of the follow‐up. Because coffee drinking has been suggested to interact with other life‐style factors to increase BP Citation8, Citation18, analyses were also performed within strata of alcohol use and smoking status. In these analyses coffee was treated as a two‐category factor (nondrinkers = 0, drinkers = 1), as the incidence of hypertension did not differ among classes of coffee drinkers. Estimates of relative risk and corresponding two‐sided 95% confidence intervals (CIs) relating coffee consumption to risk of hypertension were computed from the Cox models. A two‐tailed probability value<0.05 was considered significant. Data are presented as mean±SD unless specified. For statistics, epinephrine and norepinephrine were logarithmically (base 10) transformed owing to their skewed distribution. Analyses were performed using Statistica version 6 (Stat Soft, Inc., Tulsa, OK, USA) and Systat version 10 (SPSS Inc., Evanston, IL, USA).
Results
Seventy‐three percent of our subjects drank coffee (Table I). Among the coffee drinkers, 86.6% drank 1–3 cups/day, and 14.4% drank over 3 cups/day. Coffee drinkers were older and heavier than abstainers, had higher level or urinary epinephrine, were more sedentary, and were more likely to smoke cigarettes and drink alcohol. Smoking and alcohol use were more common among heavy coffee drinkers than moderate drinkers. Coffee intake was not related to gender, baseline BP, and biochemical data.
Follow‐up
During the follow‐up only 42 subjects (3.8%) changed their habits. Of these, 20 subjects started to drink coffee or increased coffee consumption, whereas 22 subjects quitted or reduced coffee use. During the first few months of follow‐up there was a decline in BP in the group as a whole. After 3 months, the decline was slightly smaller in the coffee drinkers than the subjects who abstained (). During the follow‐up, 561 subjects developed sustained hypertension needing antihypertensive treatment (mean follow‐up 5.6±3.5 years), whereas 546 subjects did not meet the criteria for treatment (mean follow‐up 7.0±3.7 years). Coffee drinkers developed sustained hypertension more frequently than abstainers (53.1% versus 43.9%, P = 0.007). In gender‐specific analyses, the difference was significant among the men (n = 800, 53.5% versus 42.7%, respectively, P = 0.007) but not among the women (n = 307, 52.2% versus 46.9%, respectively, P = non significant (NS)). Kaplan‐Meier analysis confirmed that sustained hypertension was developed more frequently by coffee drinkers compared with noncoffee‐drinkers (log‐rank P<0.001) (), and showed that the incidence of hypertension did not differ between moderate and heavy coffee drinkers. Results of Cox proportional hazards analysis assessing the risk of hypertension associated with coffee drinking at baseline and during follow‐up are given in . In bivariate analysis, the risk of hypertension was statistically significantly greater in the subjects drinking coffee compared with those who abstained. After taking into account age, sex, parental hypertension, hypertension duration, physical activity, smoking status, alcohol intake, and BP at baseline, the association of coffee drinking with hypertension incidence remained statistically significant. When BMI at baseline was added to the model, a marginal decline in the risk of future hypertension was observed. Inclusion of change in body weight during the follow‐up did not materially change these findings. The relative risk of hypertension was greater in both categories of coffee drinking than in subjects who did not drink coffee for both unadjusted (moderate drinkers, hazard ratio (HR), 95% confidence limit (CL) = 1.43, 1.17–1.71; heavy drinkers, HR, 95% CL = 1.30, 0.98–1.68) and fully adjusted data (HR, 95% CL = 1.27, 1.04–1.56, versus 1.24, 0.94–1.66, respectively). In the subset of patients in whom urinary catecholamines were measured (n = 647), coffee intake was still an independent predictor of hypertension incidence (P = 0.02). Epinephrine and norepinephrine did not show an independent significant effect on the rate of development of sustained hypertension. When coffee intake during follow‐up was included in the model as a time‐dependent covariate, results were similar to those seen for baseline coffee drinking ). In analyses stratified by smoking status at baseline, the relative risk of hypertension associated with drinking coffee was similar for smokers and nonsmokers. Likewise, risk of hypertension associated with coffee intake did not differ by gender. In gender‐specific analyses, the fully adjusted risk of hypertension was 1.27 (95% CL = 1.06–1.53, P = 0.01) among the men and 1.25 (95% CL = 0.94–1.67, P = NS) among the women.
Table II. Relative risks for incident hypertension according to coffee intake. Results of Cox regression analyses.
Figure 1. Kaplan‐Meier plots of incident hypertension by coffee intake during a mean follow‐up of 6.4 years. P value<0.000 from log‐rank test.
Subjects stratified by coffee consumption and alcohol use
The incidence of sustained hypertension by coffee intake (treated as a two‐class category) and alcohol consumption is reported in . The effect of coffee drinking on the incidence of hypertension progressively increased with increasing category of alcohol use (P = 0.02). Alcohol was a significant predictor of incident hypertension in the bivariate (P = 0.01) but not multivariate Cox model (P = 0.35). However, in both bivariate and multivariate models the risk of hypertension associated with coffee drinking differed according to baseline alcohol consumption, increasing gradually with increasing level of alcohol use (unadjusted P for interaction = 0.01, fully adjusted P for interaction = 0.005). Two‐way ANCOVA revealed that the difference in urinary epinephrine between coffee drinkers and nondrinkers was significant among the subjects who drank alcohol but not in abstainers and that alcohol had not a direct effect on epinephrine (). No significant differences were found for urinary norepinephrine.
Figure 2. Incidence of sustained hypertension by coffee intake and level of alcohol consumption at baseline in 1107 white subjects screened for stage 1 hypertension during a mean follow‐up of 6.4 years. Unadjusted P for coffee x alcohol interaction at Cox analysis = 0.01. P adjusted for sex, age, body mass index, family history for hypertension, duration of hypertension, smoking status, baseline blood pressure, and change in body weight at the end of the follow‐up = 0.005.
Figure 3. Urinary epinephrine by coffee consumption(drinkers versus nondrinkers) and alcohol use (drinkers versus abstainers) at baseline in 647 white subjects screened for stage 1 hypertension. P‐values were calculated for log‐transformed data.
Discussion
In this prospective study of the association of coffee consumption with the development of sustained hypertension needing antihypertensive treatment in subjects screened for stage 1 hypertension, coffee intake was a significant predictor of incident hypertension irrespective of the number of cups drunk per day. After adjustment for a number of factors potentially associated with hypertension incidence, coffee drinkers had a 24% increased chance of developing sustained hypertension compared to nondrinkers. Information on coffee intake was updated during the follow‐up to take into account changes in individual behavior. When most recent rather than baseline coffee intake was considered, a similar increase in the risk of hypertension was observed to that for baseline evaluation. This is probably due to the fact that only a few participants changed their habits during the follow‐up. All guidelines consistently recommend smoking cessation, reduction of alcohol use, increased physical activity, and several dietary changes for preventing development of sustained hypertension Citation15,16. However, coffee consumption is not included among the life‐style measures which should be instituted. Thus, doctors involved in the management of HARVEST study participants did not put much emphasis on the necessity to reduce or quit coffee intake.
To our knowledge, this study is the first to prospectively evaluate the putative effect of coffee consumption on the long‐term risk of sustained hypertension in subjects screened for stage 1 hypertension. The adverse effects of coffee on hypertension have constituted a controversial subject for several decades and are based mainly on the results of short‐term clinical trials Citation9,10. In normotensive individuals, two prospective studies failed to demonstrate an association between coffee intake and incidence of hypertension Citation11,12. In a cohort of 1017 white male former medical students, Klag et al. found a greater relative risk of hypertension in all categories of coffee drinking compared with men who did not drink coffee at baseline Citation11. However, after taking into account differences among coffee intake categories in incidence of hypertension in parents and the number of cigarettes smoked, alcohol intake, physical activity, and body mass index during follow‐up, the association of coffee drinking with hypertension incidence was not statistically significant. In a prospective cohort study conducted in the Nurses’ Health Studies I and II of 155,594 US women free from hypertension, a positive association was found between frequency of caffeinated soft drink consumption and the risk of hypertension Citation12. However, neither caffeinated nor decaffeinated coffee demonstrated a positive association with incident hypertension in either cohort. At variance with the above results, in a recent analysis of the Doetinchem Cohort Study, abstainers from coffee and, in women only, heavy consumers (>6 cups/day) showed lower risks of hypertension than did low coffee consumers (1–3 cups/day) Citation13. In a study by Funatsu et al. Citation28, coffee intake of more than 3 cups per day for 4 weeks lowered blood pressure in a small group of prehypertensive men (mean BP ∼130/80 mmHg). The above data were obtained from normotensive individuals Citation11–13,Citation28. However, some controlled studies suggest that the association between coffee drinking and increased BP is peculiar to hypertensive individuals Citation29,30 and that the effect of coffee drinking on systolic and diastolic blood pressure is greater in younger participants. According to Mazurek et al. Citation29, drinking one cup of coffee caused after 60 min to 2 hours elevated systolic BP and after 60 min diastolic BP, only in hypertensive patients. In a study by Rakic et al. Citation30, the effects of regular coffee intake on BP over 2 weeks differed according to whether subjects were normotensive or hypertensive, as defined by raised BP or treatment with antihypertensive agents. In hypertensive subjects, ambulatory systolic BP and diastolic BP over a 24‐hour period showed significant differences related to coffee drinking, with a pattern of a decrease in BP in abstainers and increase in BP in coffee drinkers Citation30. This differential effect in hypertensive individuals, detected with a controlled study design, may explain the negative results reported in the two cohort studies which were performed in normotensive individuals Citation11,12. In addition, in both the Klag et al. Citation11 and the Winkelmayer et al. Citation12 studies the participants’ BP was not directly measured, and the diagnosis of hypertension was self‐reported. In the HARVEST study, the diagnosis of sustained hypertension was made on the basis of several visits encompassing an average of over 50 BP measurements per person. Obviously, the rate of incident hypertension was much greater than that observed in the two aforementioned longitudinal studies Citation11,12 because the HARVEST participants started from higher BP levels. The risk of hypertension was similar among our male and female participants (HR = 1.27 and 1.25, respectively). However, the association between coffee intake and risk of hypertension did not reach the level of statistical significance among the women, probably due to the much smaller number of female subjects enrolled in the HARVEST study. This is suggested also by the results of Cox analysis in the whole group in which no interactive effect was found between coffee and gender on the risk of hypertension.
In the HARVEST study, the relation between caffeine intake and risk of hypertension was nonlinear, as the risk of hypertension did not increase with increasing consumption of coffee. This finding may appear surprising but is in agreement with the results of the Klag et al. study Citation11, in which the relative risk estimates increased only slightly with successive levels of coffee drinking, and decreased somewhat in the heaviest drinkers. In the women of both Nurses’ Health Studies cohorts Citation12 and those of the Doetinchem Cohort Study Citation13, even a modest inverse U‐shaped relation was found between caffeine intake and the incidence of hypertension. The nonlinearity of the association between coffee consumption and hypertension incidence may suggest that the risk of hypertension was influenced by something about the health habits of the coffee drinkers rather than by a pure biologic effect of coffee. In agreement with other reports Citation11,12,Citation31–34, in the present study coffee intake was positively related to alcohol consumption and smoking status and was more common among sedentary than active subjects. These life‐style factors might have contributed to the difference in longitudinal BP effects that we observed for coffee. However, body weight rose to the same extent in the coffee categories suggesting that the increased rate of hypertension observed among the coffee drinkers was not due to dietary factors or differences in physical activity habits. In the present study, alcohol use affected the magnitude of the difference in incident hypertension that we observed for coffee drinkers versus nondrinkers. In fact, the risk of hypertension related to coffee use progressively increased across the classes of alcohol consumption. Unfortunately, the majority of previous studies on the BP effects of coffee did not report the concurrent level of alcohol use and, thus, the interactive effect of these two life‐style factors could not be studied Citation9,10. In a recent study in prehypertensive subjects, Funatsu et al. observed a decrease in BP after coffee drinking in habitual alcohol drinkers, but that study lasted only 4 weeks and a comparison with heavy alcohol drinkers or abstainers was not made Citation28.
Caffeine‐induced pressor effects may involve several mechanisms. Some authors stressed the importance of the caffeine‐related antagonism of endogenous adenosine, leading to vasoconstriction and increased total peripheral resistance Citation35. Caffeine may exaggerate sympathetic adrenal medullary responses to the stressful events of normal daily life Citation36,37. Indeed, caffeine has been reported to increase BP and heart rate associated with higher levels of self‐reported stress during the activities of the day Citation38. Thus, when combined with mental stress coffee may produce undesirable BP in subjects at risk for hypertension. Urinary epinephrine, norepinephrine, and vanillylmandelic acid have been shown to increase after caffeine administration in humans Citation39,40. Also in the present study, coffee drinking showed a linear relationship with epinephrine level. In addition, the effect of caffeine on epinephrine appeared to be greater in the subjects who drank alcohol. Acute increases in plasma alcohol increase sympathetic nerve activity, and some studies have suggested that alcohol promotes hypertension through sympathetic activation Citation41,42. The present results suggest that this effect of alcohol may facilitate the effect of caffeine on epinephrine release. The detrimental effect on aortic stiffness and wave reflections described after acute Citation43 and chronic Citation44 coffee intake could be related to both the antagonism of adenosine and the release of catecholamines promoted by caffeine. The HARVEST participants who drank coffee were heavier than those who abstained from drinking. However, when baseline BMI and changes in body weight during the follow‐up were considered in the Cox regression, the association of coffee drinking with hypertension incidence changed only marginally indicating that this relationship was not explained by an effect of coffee on body weight.
Conclusions
Nonpharmacological measures are widely agreed to lower BP and prevent hypertension in subjects at risk. The present data show that subjects screened for stage 1 hypertension who abstain from drinking coffee have a lower risk of developing sustained hypertension than coffee drinkers. According to our findings, abstinence from caffeinated coffee should be considered among the dietary changes that should be instituted in hypertensive patients, especially in male individuals and subjects who drink alcohol. Further research is warranted to establish whether coffee use is a risk factor for hypertension also in women and whether cessation of coffee consumption is really beneficial for hypertensive patients.
Acknowledgements
Sources of funding. The study was funded by the University of Padova, Padova, Italy, and by the Associazione ‘18 Maggio 1370’, San Daniele del Friuli, Italy.
Conflict of interest. The sources of funding had no role in the design, conduct, analysis, or reporting of the study, or in the decision to submit the manuscript for publication. The authors have no financial interest in the subject matter or materials discussed in the manuscript.
References
- Smits P., Thien T., Van 'T Laar A. The cardiovascular effects of regular and decaffeinated coffee. Br J Clin Pharmacol 1985; 19: 852–4
- Pincomb G. A., Lovallo W. R., Passey R. B., Whitsett T. L., Silverstein S. M., Wilson M. F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men. Am J Cardiol 1985; 56: 119–22
- Robertson D., Wade D., Workman R., Woosley R. L. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest 1981; 67: 1111–7
- Stensvold I., Tverdal A., Foss O. P. The effect of coffee on blood lipids and blood pressure: results from the Norwegian cross‐sectional study, men and women, 40–42 years. J Clin Epidemiol 1989; 42: 877–84
- Salvaggio A., Periti M., Miano L., Zambelli C. Association between habitual coffee consumption and blood pressure levels. J Hypertens 1990; 8: 585–90
- Burke V., Beilin L. J., German R., Grosskorpf S., Ritchie J., Puddey I. B., et al. Association of lifestyle and personality characteristics with blood pressure and hypertension: a cross‐sectional study in the elderly. J Clin Epidemiol 1992; 45: 1061–70
- Kirchhoff M., Torp‐Pedersen C., Hougaard K., Jacobsen T. J., Sjol A., Munch M., et al. Casual blood pressure in a general Danish population: relation to age, sex, weight, height, diabetes, serum lipids and consumption of coffee, tobacco and alcohol. J Clin Epidemiol 1994; 47: 469–74
- Narkiewicz K., Maraglino G., Biasion T., Rossi G., Sanzuol F., Palatini P., on behalf of the HARVEST Study Group (Italy). Interactive effect of cigarettes and coffee on daytime systolic blood pressure in patients with mild essential hypertension. J Hypertens 1995; 13: 965–70
- Jee S. H., He J., Whelton P. K., Suh I., Klag M. J. The effect of chronic coffee drinking on blood pressure: a meta‐analysis of controlled clinical trials. Hypertension 1999; 33: 647–52
- Noordzij M., Uiterwaal C. S., Arends L. R., Kok F. J., Grobbee D. E., Geleijnse J. M. Blood pressure response to chronic intake of coffee and caffeine: a meta‐analysis of randomized controlled trials. J Hypertens 2005; 23: 921–8
- Klag M. J., Wang N. Y., Meoni L. A., Brancati F. L., Cooper L. A., Liang K. Y., et al. Coffee intake and risk of hypertension: the Johns Hopkins precursors study. Arch Intern Med 2002; 162: 657–62
- Winkelmayer W. C., Stampfer M. J., Willett W. C., Curhan G. C. Habitual caffeine intake and the risk of hypertension in women. JAMA 2005; 294: 2330–5
- Uiterwaal C. S. P. M., Verschuren M. W. M., Bueno‐de‐Mesquita H. B., Ocké M., Geleijnse J. M., Boshuizen H. C., et al. Coffee intake and incidence of hypertension. Am J Clin Nutr 2007; 85: 718–23
- Superko H. R., Myll J., DiRicco C., Williams P. T., Bortz W. M., Wood P. D. Effects of cessation of caffeinated‐coffee consumption on ambulatory and resting blood pressure in men. Am J Cardiol 1994; 73: 780–4
- 2003 European Society of Hypertension‐European Society of Cardiology guidelines for the management of arterial hypertension,. J Hypertens 2003; 21: 1011–53
- Chobanian A. V., Bakris G. L., Black H. R., Cushman W. C., Green L. A., Izzo J. L., et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–72
- Palatini P., Graniero G., Mormino P., Nicolosi L., Mos L., Visentin P., et al. Relation between physical training and ambulatory blood pressure in stage I hypertensive subjects. Results of the HARVEST trial. Circulation 1994; 90: 2870–6
- Freestone S., Yeo W. W., Ramsay L. E. Effect of coffee and cigarette smoking on the blood pressure of patients with accelerated (malignant) hypertension. J Hum Hypertens 1995; 9: 89–91
- Palatini P., Mormino P., Mos L., Mazzer A., Dorigatti F., Zanata G., et al. Microalbuminuria, renal function and development of sustained hypertension: a longitudinal study in the early stage of hypertension. J Hypertens 2005; 23: 175–82
- Sartori M., Semplicini A., Siffert W., Mormino P., Mazzer A., Pegoraro F., et al. G‐protein beta3‐subunit gene 825T allele and hypertension: a longitudinal study in young grade I hypertensives. Hypertension 2003; 42: 909–14
- Wang Y., Wang Q. J. The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines: new challenges of the old problem. Arch Intern Med 2004; 164: 2126–34
- Casiglia E., Paleari C. D., Petucco S., Bongiovì S., Colangeli G., Baccillieri M. S., et al. Haemodynamic effects of coffee and purified caffeine in normal volunteers: A placebo‐controlled clinical study. J Hum Hypertens 1992; 6: 95–9
- Periti M., Salvaggio A., Quaglia G., Di Marzio L. Coffee consumption and blood pressure: An Italian study. Clin Sci 1986; 72: 443–7
- Treating mild hypertension. Report of the British Hypertension Society working party., BMJ. 298. 694–8
- Sever P., Beevers G., Bulpitt C., Lever A., Ramsay L., Reid J., et al. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ 1993; 306: 983–7
- 1999 World Health Organization—International Society of Hypertension Guidelines for the Management of Hypertension, Guidelines Sub‐Committee. Blood Press 1999; 1: 9–43
- Williams B., Poulter N. R., Brown M. J., Davis M., McInnes G. T., Potter J. F., et al. British Hypertension Society guidelines for hypertension management 2004 (BHS‐IV): summary. BMJ 2004; 328: 634–40
- Funatsu K., Yamashita T., Nakamura H. Effect of coffee intake on blood pressure in male habitual alcohol drinkers. Hypertens Res 2005; 28: 521–7
- Mazurek W., Negrusz‐Kawecka M. Effect of coffee on blood pressure and activity renin‐angiotensin‐ aldosterone system and catecholamines concentration in patients with essential hypertension. Pol Merkuriusz Lek 1999; 7: 159–63
- Rakic V., Burke V., Beilin L. J. Effects of Coffee on Ambulatory Blood Pressure in Older Men and Women: A Randomized Controlled Trial. Hypertension 1999; 33: 869–73
- Swanson J. A., Lee J. W., Hopp J. W. Caffeine and nicotine: A review of their joint use and possible interactive effects in tobacco withdrawal. Addict Behav 1994; 3: 229–56
- Klesges R. C., Ray J. W., Klesges L. M. Caffeinated coffee and tea intake and its relationship to cigarette smoking: An analysis of the second national health and nutrition examination survey (NHANES II). J Subst Abuse 1994; 6: 407–18
- Kono S., Shinchi K., Imanishi K., Todoroki I., Hatsuse K. Coffee and serum gamma‐glutamyltransferase—A study of self‐defense officials in Japan. Am J Epidemiol 1994; 139: 723–7
- Kozlowski L. T., Henningfield J. E., Keenan R. M., Lei H., Leigh G., Jelinek J. C., et al. Patterns of alcohol, cigarette, and caffeine and other drug use in two drug abusing populations. J Subst Abuse Treat 1993; 10: 171–9
- Rachima‐Maoz C., Peleg E., Rosenthal T. The effect of caffeine on ambulatory blood pressure in hypertensive patients. Am J Hypertens 1998; 11: 1426–32
- Greenberg W., Shapiro D. The effects of caffeine and stress on blood pressurein individuals with and without a family history of hypertension. Psychophysiology 1987; 24: 151–6
- Lane J. D., Williams R. B., Jr. Caffeine affects cardiovascular response to stress. Psychophysiology 1985; 22: 648–55
- Lane J. D., Pieper C. F., Phillips‐Bute B. G., Bryant J. E., Kuhn C. M. Caffeine affects cardiovascular and neuroendocrine activation at work and home. Psychosom Med 2002; 64: 595–603
- Bellet S., Roman L., Decastro O., Kim K. E., Kershbaum A. Effect of caffeine ingestion on catecholamine release. Metabolism 1969; 18: 288–91
- Levi L. The effect of coffee on the function of the sympatho‐adrenal‐medullary system in men. Acta Medica Scand 1967; 181: 431–8
- Randin D., Vollenweider P., Tappy L., Jequier E., Nicod P., Scherrer U. Suppression of alcohol‐induced hypertension by dexamethasone. N Engl J Med 1995; 332: 1733–7
- van de Borne P., Mark A. L., Montano N., Mion D., Somers V. K. Effects of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity. Hypertension 1997; 29: 1278–83
- Mahmud A., Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform. Hypertension 2001; 38: 227–31
- Vlachopoulos C., Panagiotakos D., Ioakeimidis N., Dima I., Stefanadis C. Chronic coffee consumption has a detrimental effect on aortic stiffness and wave reflections. Am J Clin Nutr 2005; 81: 1307–12
Appendix
List of the centers participating in the HARVEST study
Belluno—Cardiologia: G Catania, R Da Cortà
Cremona—Div. Medica: G Garavelli
Dolo—Div. Medica: F Pegoraro, S Laurini
Mirano—Cardiologia: D D'Este
Padova—Clinica Medica 4: F Dorigatti, V Zaetta, P Frezza, P Bratti, D Perkovic, C Guarnieri, A Zanier
Pordenone—Centro Cardioreumatologico: G Cignacco, G Zanata
Rovereto—Ala—Div. Medica: M Mattarei, T Biasion
Rovigo—Cardiologia: P Zonzin, A Bortolazzi
San Daniele del Friuli—Area di Emergenza: L Mos, S Martina, O Vriz
San Donà di Piave—Cardiologia: L Milani, C Canali
Trento—Div. Medica: P Dal Ri, S Cozzio
Treviso—Div. Nefrologia: G Calconi, P Gatti
Vittorio Veneto—Div. Medica: M Santonastaso, E Cozzutti, R Garbelotto, A Mazzer
Trial Coordinator: P Palatini