Coffee Consumption and Cardiovascular Health Coffee is the most widely consumed beverage worldwide and is only second to water drinking and is consumed by 83% of adults in the United States. The long-held controversy regarding the association of coffee consumption with an increased incidence of cardiovascular diseases (CVDs) and hypertension has been reversed by several recent prospective cohort studies and meta-analyses, which have demonstrated that coffee consumption is not associated with increased incidence of CVDs and hypertension and instead it could have a beneficial effect. To get a better understanding of the effects of coffee consumption on cardiovascular health, a Medline search of the English language literature was conducted from 2010 to early 2015 and 25 pertinent reports with information on the effects of coffee drinking, the incidence of CVDs, and hypertension and its mechanism of action were selected for inclusion in this commentary. These studies have shown either a neutral or beneficial effect of coffee on cardiovascular health. In conclusion, coffee is safe to drink by both normal subjects and by those with preexisting CVDs and hypertension. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;116:818e821)
Coffee is the most widely consumed beverage, second only to water, and in the United States, it is consumed by 83% of adults.1 There has been a long-standing controversy regarding the association of coffee consumption with the incidence of cardiovascular diseases (CVDs) and hypertension. This controversy was primarily because of older, not well-controlled studies, which demonstrated a positive association of coffee drinking with the incidence of CVDs, hypertension, and type 2 diabetes mellitus. However, according to a major meta-analysis of the older studies, the evidence for the adverse health effects of coffee consumption was based on case-control studies and not on long-term prospective studies, which showed either a neutral or beneficial effect of coffee consumption with CVDs and hypertension.2 This aspect has been strengthened by recent well-controlled studies, which have demonstrated a beneficial effect of chronic coffee drinking on CVDs and hypertension.3e6 To get a better understanding of the beneficial health effects of coffee consumption, a Medline search of the English language literature was conducted from 2010 to early 2015, and of the 93 abstracts reviewed, 25 pertinent reports with data on coffee consumption, its effect on CVDs and hypertension, and the mechanism for this beneficial effect were selected. These articles together with collateral reports will be discussed in this commentary. Studies Demonstrating a Neutral or Beneficial Effect of Coffee Consumption on CVDs and Blood Pressure Several recent studies and reviews of prospective and randomized studies involving a large number of subjects have demonstrated a beneficial or neutral effect of coffee consumption on CVD, hypertension, heart failure (HF), stroke, and all-cause mortality.3e20 The findings from the See page 820 for disclosure information. 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.05.057
most recent studies3,6e20 are summarized in Table 1. Regarding BP control, 5 studies, 3 large reviews involving 1,502.218, 172,567, and 170,734 subjects6,7,9 and 2 smaller studies, 1 cross-sectional of 836 subjects3 and 1 prospective cohort study of 2,442,8 showed either a beneficial or neutral effect of coffee consumption. Of these studies, 1 review and meta-analysis9 showed that caffeine administration acutely and temporarily increases BP in caffeine-naive hypertensive subjects, whereas another prospective cohort study showed an adverse interaction of high coffee intake with weight and age with SBP for male but not female subjects.8 With respect to the incidence of CVD, CHD, stroke, HF, and all-cause mortality, several prospective control studies11e20 and 2 large reviews and meta-analyses of 170,320 and 1,279,804 patients showed either a neutral of beneficial dose-dependent effect of coffee consumption.9,13 Of major significance is a recent prospective cohort study of 402,260 subjects, which showed a beneficial effect of chronic coffee consumption on all-cause and cause-specific mortality after 13 years of follow-up.11 Similarly, 4 other studies, 3 prospective cohort studies and 1 meta-analysis of 479,689 subjects, showed either a beneficial or neutral effect of coffee consumption.16e18 With respect to the incidence of HF, 1 review of 140,220 subjects19 and 1 prospective cohort study of 59,490 subjects20 showed either a decrease or a neutral effect of coffee intake. Pathophysiological Mechanism for the Beneficial Effects of Coffee Consumption Caffeinated coffee: Caffeinated coffee is a complex beverage containing >1,000 compounds among which the most important are caffeine, diterpene alcohols, and chlorogenic acids.5,21 On ingestion, caffeine is rapidly absorbed through the gastrointestinal tract and achieves a Tmax within 30 to 45 minutes. Subsequently, it is metabolized in the liver by the enzyme CYP1A2 into 3 metabolites, www.ajconline.org
Editorial/The Health Effects of Coffee
819
Table 1 Effects of coffee consumption on cardiovascular diseases and hypertension Author Guessous3 Steffen6 Zhang7 Griggey8 Mesas9 Liu*,10 Freedman11 deKoning Gans12 Ding13 Sugiyama14 Lopez-Garcia15 Floegel16 Kokubo17 Larsson18 Mostofsky19 Wang20
Study design
Subjects number
Age years
F-U years
Event type
Change
C-S Rev Rev P-C Rev,Meta Rev,Meta P-C P-C P-C Rev,Meta P-C P-C P-C P-C Rev,Meta Rev P-C
836 1,502,218 172,567 2,442 M 364 170,320 43,727 402,260 37,514 1,279,804 37,742 W 11,697 W 42,659 82,369 479,689 140,220 59,490
47.8 26-55 26-55 52.1 na 30-83 43.4 50-71 46-52 20-83 40-64 62-68 49-63 45-74 20-75 25-83 25-74
na 6-33 6-33 0-41 2-8 wks 4-25 17 13 13 2-32 10 24 9 3 2-3 na 19.2
SBP BP BP SBP BP CVD all-cause death* all-cause death CHD,Death CVD,Death CVD,Death CVD,Death CHD,Stroke CVD,Stroke Stroke HF HF
Y 4 Y 4 4 4 [ Y Y Y Y 4 4 Y Y Y 4
C-S ¼ cross-sectional; F-U ¼ follow-up; Meta ¼ meta-analysis; na ¼ not available; P-C ¼ prospective cohort study, Rev ¼ review, SBP ¼ systolic blood pressure, [ ¼ increased, Y ¼ decreased, 4 ¼ no change * Indicates that CVD and all-cause mortality occurred only in high coffee drinkers.
Figure 1. The most important ingredients of coffee—caffeine, chlorogenic acid, cafestol, and kahweol—are depicted.
paraxanthine, theobromine, and theophylline, with paraxanthine being the most active metabolite.22 Caffeine exerts its hemodynamic effects through a complex interference with the action of adenosine on its receptors A1 and A2a. Adenosine is an adenine nucleoside that is produced from the hydrolysis of adenosine triphosphate and exerts its hemodynamic effects on the heart and other vascular beds through stimulation of its receptors A1 and A2a.23 The effects exerted by the receptors A1 and A2a are opposite. Stimulation of A1 receptor causes vasoconstriction of the afferent renal arterioles leading to decrease in glomerular filtration rate and renal blood flow and an increase in renal sodium reabsorption. In contrast, stimulation of A2a receptors causes vasodilation in most vascular beds including the efferent renal arteriole, but the action on the A1 receptors over-rides the adenosine
action on the A2a receptors, and the net effect is vasoconstriction.23 Blockade by caffeine of the A1 receptors localized in the afferent arteriole, glomerulus, proximal tubule, and collecting ducts improves glomerular filtration rate and renal blood flow and causes diuresis and natriuresis and lowers the BP. These actions of adenosine inhibitors have been shown to improve the condition of patients with HF by improving renal function and enhancing the action of diuretics.24 Besides receptors A1 and A2a, 2 more adenosine receptors, A2b and A3, with vasodilatory properties have been identified, but their significance is not clearly known. Other mechanisms by which coffee could lower the BP are through the caffeine metabolites (Figure 1), among which are the chlorogenic acids contained in the coffee.25 Chlorogenic acids are potent antioxidants and improve endothelial and vascular function through increased availability of nitric oxide. Decaffeinated coffee: The research on decaffeinated coffee has been limited. A few studies have shown that following decaffeinated coffee ingestion, there was an increase in flow-mediated dilation, in contrast to the ingestion of caffeinated coffee, which was associated with a decrease in flow-mediated dilation. This difference in the vascular effect of decaffeinated and caffeinated coffee has been attributed to the beneficial antioxidant effects of chlorogenic acid on the vascular endothelium by caffeinated coffee.24 Another possible explanation for this difference is the action of hydroxyhydroquinone compound produced by the roasting of coffee beans. Hydroxyhydroquinone might interfere with the protective function of chlorogenic acid on the vascular endothelium (Cano-Marquina et al,24 review). However, a recent large review and meta-analysis of 1,279,804 subjects
820
The American Journal of Cardiology (www.ajconline.org)
did not find any significant association between decaffeinated coffee and incidence of CVD.13 A potential explanation could be the much lower consumption of decaffeinated coffee than caffeinated coffee in these studies that diminished the power for a meaningful statistical comparison. Discussion The data from the review of the recent studies indicate that coffee drinking is fairly safe and does not increase the BP or the incidence of CVDs, strokes, and all-cause mortality. However, some studies have indicated a U shape association for the incidence of hypertension and CVDs between low coffee drinkers (0 to 1 cup/day) and high coffee drinkers (10 cups/day). It appears that the safest coffee consumption is 3 to 6 cups/day, which represents the greatest majority of coffee drinkers.4,5,7,10 Acutely, coffee consumption is associated with a small and temporary increase in BP mostly in coffee-naive but not in habitual coffee drinkers.9 The acute effects of coffee consumption could be mediated through several biologic mechanisms that include the binding of caffeine to adenosine receptors (A1 and A2a), stimulation of the central sympathetic nervous system, and increase in catecholamine levels (Zhao et al7,21 and Modlinger and Welch23). Eventually, tolerance to caffeine-induced pressor effects develops with habitual coffee drinking through a complex set of counter-regulatory mechanisms, which maintain BP control. In addition, ingredients other than caffeine participate in BP control like the CGSs, flavonoids, melanoidins, magnesium, and potassium.24 Recent studies have also shown the importance of genetic factors regarding the association of caffeine intake and the incidence of hypertension and CVDs.22,25 In human subjects, the enzyme CYP1A2 is encoded in the CYP1A2 gene and is responsible for w13% of chromosome’s P450 metabolism of caffeine in the liver.25 It has been postulated that high CYP1A2 activity is associated with rapid caffeine metabolism, which decreases the CVD and BP effects of coffee. Cigarette smoking is also an important inducer of enzyme CYP1A2 activity, and quitting smoking leads to rapid decreases in CYP1A2 activity,22 which could potentiate the protective effects of coffee. This could, perhaps, explain the lower incidence of CVD and strokes in nonsmokers compared with smokers in the Nurse’s Health Study of 83,076 women after 24 years of follow-up.15,26 Additionally, recent studies have shown that CYP1A2 enzyme activity is influenced by regional and genetic factors.27 Subjects of South Asian ancestry have lower CYP1A2 activity than those of European ancestry, but the significance of this finding is not known at present. Regarding the overall beneficial health effects of coffee, the current evidence is reassuring. Coffee consumed in reasonable amounts (3 to 4 cups/day) appears to be safe and have favorable health effects. Its cardiovascular protective effects are mediated, besides its antihypertensive effects, also by its antidiabetic and antioxidant actions.24,25,28 The
adverse effects of coffee on serum lipids can be avoided by drinking filtered instead of boiled coffee that contains the diterpenes, cafestol, and kahweol, which increase the serum cholesterol.4,29 The older studies indicating that coffee consumption was associated with increased incidence of CVD were mostly case-control studies, and such studies have methodologic limitations including recall bias, failure to adjust for cofounders, and selection bias. In a metaanalysis comparing the incidence of CHD, the RR was 1.63 (95% CI 1.50 to 1.78) and 1.05 (95% CI 0.99 to 1.12) for case-control and prospective control studies, respectively.30 Only 1 recent prospective study has reported higher incidence of CVD and all-cause mortality.10 However, close examination of the data indicates that this occurred only in high coffee drinkers (>28 cups/week). Therefore, based on the current state of evidence, the traditional admonition that coffee is a risk factor for CVD and HTN seems to vanish, and there is no reason for people to refrain from coffee drinking whether they are healthy or have preexisting HTN or CVD as stated by other authors as well.5,26,28 Disclosures The author declares no conflict of interest and that no funds were received for the preparation of the manuscript. Steven G. Chrysant, MD, PhD Department of Cardiology University of Oklahoma College of Medicine Oklahoma City, Oklahoma 1. National Coffee Association Releases 2013 Coffee Consumption Data [Press Release]. March 22, 2013, San Francisco. Google 2. Sofi F, Conti AA, Gori AM, Luisi ML, Casini A, Abbate R, Gensini GF. Coffee consumption and risk of coronary heart disease: a metaanalysis. Nutr Metab Cardiovasc Dis 2007;17:209e223. 3. Guessous I, Pruijm M, Ponte B, Ackerman D, Ehret G, Ansermot N, Vuistiner P, Staessen J, Gu Y, Paccaud F, Mohaupt M, Vogt B, Pechere-Berstcthi A, Marti PY, Burnier M, Eao CB, Bochud M. Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions. Hypertension 2015;65: 691e696. 4. Rebello SA, van Dam RM. Coffee consumption and cardiovascular health: getting to the heart of the matter. Curr Cardiol Rep 2013;15: 403. 5. O’Keefe JH, Bhatti SK, Patil HR, DiNicolantonio JJ, Lucan SC, Lavie CJ. Effects of habitual coffee consumption and cardiometabolic disease, cardiovascular health, and all-cause mortality. J Am Coll Cardiol 2013;62:1043e1051. 6. Steffen M, Kuhle C, Hensrud D, Erwin PJ, Murad MH. The effect of coffee consumption on blood pressure and the development of hypertension: a systematic review and meta-analysis. J Hypertens 2012;30: 2245e2254. 7. Zhang Z, Hu G, Caballero B, Appel L, Chen L. Habitual coffee consumption and risk of hypertension: a systematic review and metaanalysis of prospective observational studies. Am J Clin Nutr 2011;93:1212e1219. 8. Griggey PP, Wendell CR, Zonderman AB, Waldstein S. Greater coffee intake in men is associated with steeper age-related increases in blood pressure. Am J Hypertens 2011;24:310e315. 9. Mesas AE, Leon-Munoz LM, Rodriguez-Artelejo F, Lopez-Garcia E. The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis. Am J Clin Nutr 2011;94:1113e1126.
Editorial/The Health Effects of Coffee 10. Liu J, Sui X, Lavie CJ, Hebert JR, Earnest CP, Zhang J, Blair SN. Association of coffee consumption with all-cause and cardiovascular disease mortality. Mayo Clin Proc 2013;88:1066e1074. 11. Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med 2012;366:1891e1904. 12. De Koning Gans JM, Uiterwaal CS, van der Schouw YT, Boer JM, Grobbee DE, Vershuren M, Beulens JW. Tea and coffee consumption and cardiovascular morbidity and mortality. Arterioscler Thromb Vasc Biol 2010;30:1665e1671. 13. Ding M, Bhupathiraju SN, Satija A, van Dam RM, Hu FB. Long-term coffee consumption and risk of cardiovascular diseases. A systematic review and dose-response meta-analysis of prospective cohort studies. Circulation 2014;129:643e659. 14. Suriyama K, Kuriyama S, Akhter M, Kakizaki M, Nakaya N, OhmoriMatsuda K, Shimazu T, Nagai M, Sugawara Y, Hozawa A, Fukao A, Tsuji I. Coffee consumption and mortality due to all causes, cardiovascular disease, and cancer in Japanese women. J Nutr 2010;140: 1007e1013. 15. Lopez-Garcia E, Rodriguez-Artalejo F, Li TY, Mukamal KJ, Hu FB. van dam RM. Coffee consumption and mortality in women with cardiovascular disease. Am J Clin Nutr 2011;94:218e224. 16. Floegel A, Pischon T, Bergmann MM, Teucher B, Kaaks R, Boeing H. Coffee consumption and risk of chronic disease in the European Prospective Investigation into Cancer and Nutrition (EPIC)—Germany study. Am J Clin Nutr 2012;95:901e908. 17. Kokubo Y, Iso H, Saito I, Yamagishi K, Yatsuya H, Ishihara J, Inoue M, Tsugane S. The impact of green tea and coffee consumption on the reduced risk of stroke incidence in Japanese population. The Japan Public Health Center-Based Study Cohort. Stroke 2013;44:1369e1374. 18. Larsson SC, Orsini N. Coffee consumption and risk of stroke: a doseresponse meta-analysis. Am J Epidemiol 2011;174:993e1001. 19. Mostofsky E, Rice MS, Levitan EB, Mittleman MA. Habitual coffee consumption and risk of heart failure. A dose-response meta-analysis. Circ Heart Fail 2012;5:401e405.
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20. Wang Y, Tuomilehto J, Jousilahti P, Antikainen R, Mahonen M, Mannisto S, Katzmarzyk P, Hu G. Coffee consumption and the risk of heart failure in Finnish men and women. Heart 2011;97: 44e48. 21. Zhao Y, Wang J, Ballevre O, Luo H, Zhang W. Antihypertensive effects and mechanisms of chlorogenic acids. Hypertens Res 2012;35: 370e374. 22. Guessous I, Dobrinas M, Kutalik Z, Pruijm M, Ehret G, Maillard M, Bergmann S, Beckmann JS, Cusi D, Rizzi F, Cappuccio F, Cornuz J, Paccaud F, Mooser V, Gaspoz JM, Waeber G, Burnier M, Vollenweider P, Eap CB, Bochud M. Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension. Hum Mol Genet 2012;21:3283e3292. 23. Modlinger PS, Welch WJ. Adenosine A1 receptor antagonists and the kidney. Curr Opin Nephrol Hypertens 2003;12:497e502. 24. Cano-Marquina A, Tarin JJ, Cano A. The impact of coffee on health. Maturitas 2013;75:7e21. 25. Guessous I, Eap CB, Bochud M. Blood pressure in relation to coffee and caffeine consumption. Curr Hypertens Rep 2014;16:468. 26. Lopez-Garcia E, Rodriguez-Artalejo F, Rexrode KM, Ligroscino G, Hu FB, van Dam RM. Coffee consumption and risk of stroke in women. Circulation 2009;119:1116e1123. 27. Perera V, Gross AS, Mclachlan AJ. Influence of environmental and genetic factors of CYP1A2 activity in individuals of South Asian and European ancestry. Clin Pharmacol Ther 2012;92:511e519. 28. Yukawa GS, Mune M, Otani H, Tone Y, Liang XM, Iwahashi H, Sakamoto W. Effects of coffee consumption on oxidative susceptibility of low-density lipoproteins and serum lipid levels in humans. Biochemistry 2004;69:70e74. 29. Jee SH, He J, Appel LJ, Whelton PK, Suh I, Klag MJ. Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol 2001;153:353e362. 30. Kawachi I, Colditz GA, Stone CB. Does coffee drinking increase the risk of coronary heart disease? Results from a meta-analysis. Br Heart J 1994;72:269e275.
Coffee is the most widely consumed beverage, second only to water, and in the United States, it is consumed by 83% of adults.1 There has been a long-standing controversy regarding the association of coffee consumption with the incidence of cardiovascular diseases (CVDs) and hypertension. This controversy was primarily because of older, not well-controlled studies, which demonstrated a positive association of coffee drinking with the incidence of CVDs, hypertension, and type 2 diabetes mellitus. However, according to a major meta-analysis of the older studies, the evidence for the adverse health effects of coffee consumption was based on case-control studies and not on long-term prospective studies, which showed either a neutral or beneficial effect of coffee consumption with CVDs and hypertension.2 This aspect has been strengthened by recent well-controlled studies, which have demonstrated a beneficial effect of chronic coffee drinking on CVDs and hypertension.3e6 To get a better understanding of the beneficial health effects of coffee consumption, a Medline search of the English language literature was conducted from 2010 to early 2015, and of the 93 abstracts reviewed, 25 pertinent reports with data on coffee consumption, its effect on CVDs and hypertension, and the mechanism for this beneficial effect were selected. These articles together with collateral reports will be discussed in this commentary. Studies Demonstrating a Neutral or Beneficial Effect of Coffee Consumption on CVDs and Blood Pressure Several recent studies and reviews of prospective and randomized studies involving a large number of subjects have demonstrated a beneficial or neutral effect of coffee consumption on CVD, hypertension, heart failure (HF), stroke, and all-cause mortality.3e20 The findings from the See page 820 for disclosure information. 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.05.057
most recent studies3,6e20 are summarized in Table 1. Regarding BP control, 5 studies, 3 large reviews involving 1,502.218, 172,567, and 170,734 subjects6,7,9 and 2 smaller studies, 1 cross-sectional of 836 subjects3 and 1 prospective cohort study of 2,442,8 showed either a beneficial or neutral effect of coffee consumption. Of these studies, 1 review and meta-analysis9 showed that caffeine administration acutely and temporarily increases BP in caffeine-naive hypertensive subjects, whereas another prospective cohort study showed an adverse interaction of high coffee intake with weight and age with SBP for male but not female subjects.8 With respect to the incidence of CVD, CHD, stroke, HF, and all-cause mortality, several prospective control studies11e20 and 2 large reviews and meta-analyses of 170,320 and 1,279,804 patients showed either a neutral of beneficial dose-dependent effect of coffee consumption.9,13 Of major significance is a recent prospective cohort study of 402,260 subjects, which showed a beneficial effect of chronic coffee consumption on all-cause and cause-specific mortality after 13 years of follow-up.11 Similarly, 4 other studies, 3 prospective cohort studies and 1 meta-analysis of 479,689 subjects, showed either a beneficial or neutral effect of coffee consumption.16e18 With respect to the incidence of HF, 1 review of 140,220 subjects19 and 1 prospective cohort study of 59,490 subjects20 showed either a decrease or a neutral effect of coffee intake. Pathophysiological Mechanism for the Beneficial Effects of Coffee Consumption Caffeinated coffee: Caffeinated coffee is a complex beverage containing >1,000 compounds among which the most important are caffeine, diterpene alcohols, and chlorogenic acids.5,21 On ingestion, caffeine is rapidly absorbed through the gastrointestinal tract and achieves a Tmax within 30 to 45 minutes. Subsequently, it is metabolized in the liver by the enzyme CYP1A2 into 3 metabolites, www.ajconline.org
Editorial/The Health Effects of Coffee
819
Table 1 Effects of coffee consumption on cardiovascular diseases and hypertension Author Guessous3 Steffen6 Zhang7 Griggey8 Mesas9 Liu*,10 Freedman11 deKoning Gans12 Ding13 Sugiyama14 Lopez-Garcia15 Floegel16 Kokubo17 Larsson18 Mostofsky19 Wang20
Study design
Subjects number
Age years
F-U years
Event type
Change
C-S Rev Rev P-C Rev,Meta Rev,Meta P-C P-C P-C Rev,Meta P-C P-C P-C P-C Rev,Meta Rev P-C
836 1,502,218 172,567 2,442 M 364 170,320 43,727 402,260 37,514 1,279,804 37,742 W 11,697 W 42,659 82,369 479,689 140,220 59,490
47.8 26-55 26-55 52.1 na 30-83 43.4 50-71 46-52 20-83 40-64 62-68 49-63 45-74 20-75 25-83 25-74
na 6-33 6-33 0-41 2-8 wks 4-25 17 13 13 2-32 10 24 9 3 2-3 na 19.2
SBP BP BP SBP BP CVD all-cause death* all-cause death CHD,Death CVD,Death CVD,Death CVD,Death CHD,Stroke CVD,Stroke Stroke HF HF
Y 4 Y 4 4 4 [ Y Y Y Y 4 4 Y Y Y 4
C-S ¼ cross-sectional; F-U ¼ follow-up; Meta ¼ meta-analysis; na ¼ not available; P-C ¼ prospective cohort study, Rev ¼ review, SBP ¼ systolic blood pressure, [ ¼ increased, Y ¼ decreased, 4 ¼ no change * Indicates that CVD and all-cause mortality occurred only in high coffee drinkers.
Figure 1. The most important ingredients of coffee—caffeine, chlorogenic acid, cafestol, and kahweol—are depicted.
paraxanthine, theobromine, and theophylline, with paraxanthine being the most active metabolite.22 Caffeine exerts its hemodynamic effects through a complex interference with the action of adenosine on its receptors A1 and A2a. Adenosine is an adenine nucleoside that is produced from the hydrolysis of adenosine triphosphate and exerts its hemodynamic effects on the heart and other vascular beds through stimulation of its receptors A1 and A2a.23 The effects exerted by the receptors A1 and A2a are opposite. Stimulation of A1 receptor causes vasoconstriction of the afferent renal arterioles leading to decrease in glomerular filtration rate and renal blood flow and an increase in renal sodium reabsorption. In contrast, stimulation of A2a receptors causes vasodilation in most vascular beds including the efferent renal arteriole, but the action on the A1 receptors over-rides the adenosine
action on the A2a receptors, and the net effect is vasoconstriction.23 Blockade by caffeine of the A1 receptors localized in the afferent arteriole, glomerulus, proximal tubule, and collecting ducts improves glomerular filtration rate and renal blood flow and causes diuresis and natriuresis and lowers the BP. These actions of adenosine inhibitors have been shown to improve the condition of patients with HF by improving renal function and enhancing the action of diuretics.24 Besides receptors A1 and A2a, 2 more adenosine receptors, A2b and A3, with vasodilatory properties have been identified, but their significance is not clearly known. Other mechanisms by which coffee could lower the BP are through the caffeine metabolites (Figure 1), among which are the chlorogenic acids contained in the coffee.25 Chlorogenic acids are potent antioxidants and improve endothelial and vascular function through increased availability of nitric oxide. Decaffeinated coffee: The research on decaffeinated coffee has been limited. A few studies have shown that following decaffeinated coffee ingestion, there was an increase in flow-mediated dilation, in contrast to the ingestion of caffeinated coffee, which was associated with a decrease in flow-mediated dilation. This difference in the vascular effect of decaffeinated and caffeinated coffee has been attributed to the beneficial antioxidant effects of chlorogenic acid on the vascular endothelium by caffeinated coffee.24 Another possible explanation for this difference is the action of hydroxyhydroquinone compound produced by the roasting of coffee beans. Hydroxyhydroquinone might interfere with the protective function of chlorogenic acid on the vascular endothelium (Cano-Marquina et al,24 review). However, a recent large review and meta-analysis of 1,279,804 subjects
820
The American Journal of Cardiology (www.ajconline.org)
did not find any significant association between decaffeinated coffee and incidence of CVD.13 A potential explanation could be the much lower consumption of decaffeinated coffee than caffeinated coffee in these studies that diminished the power for a meaningful statistical comparison. Discussion The data from the review of the recent studies indicate that coffee drinking is fairly safe and does not increase the BP or the incidence of CVDs, strokes, and all-cause mortality. However, some studies have indicated a U shape association for the incidence of hypertension and CVDs between low coffee drinkers (0 to 1 cup/day) and high coffee drinkers (10 cups/day). It appears that the safest coffee consumption is 3 to 6 cups/day, which represents the greatest majority of coffee drinkers.4,5,7,10 Acutely, coffee consumption is associated with a small and temporary increase in BP mostly in coffee-naive but not in habitual coffee drinkers.9 The acute effects of coffee consumption could be mediated through several biologic mechanisms that include the binding of caffeine to adenosine receptors (A1 and A2a), stimulation of the central sympathetic nervous system, and increase in catecholamine levels (Zhao et al7,21 and Modlinger and Welch23). Eventually, tolerance to caffeine-induced pressor effects develops with habitual coffee drinking through a complex set of counter-regulatory mechanisms, which maintain BP control. In addition, ingredients other than caffeine participate in BP control like the CGSs, flavonoids, melanoidins, magnesium, and potassium.24 Recent studies have also shown the importance of genetic factors regarding the association of caffeine intake and the incidence of hypertension and CVDs.22,25 In human subjects, the enzyme CYP1A2 is encoded in the CYP1A2 gene and is responsible for w13% of chromosome’s P450 metabolism of caffeine in the liver.25 It has been postulated that high CYP1A2 activity is associated with rapid caffeine metabolism, which decreases the CVD and BP effects of coffee. Cigarette smoking is also an important inducer of enzyme CYP1A2 activity, and quitting smoking leads to rapid decreases in CYP1A2 activity,22 which could potentiate the protective effects of coffee. This could, perhaps, explain the lower incidence of CVD and strokes in nonsmokers compared with smokers in the Nurse’s Health Study of 83,076 women after 24 years of follow-up.15,26 Additionally, recent studies have shown that CYP1A2 enzyme activity is influenced by regional and genetic factors.27 Subjects of South Asian ancestry have lower CYP1A2 activity than those of European ancestry, but the significance of this finding is not known at present. Regarding the overall beneficial health effects of coffee, the current evidence is reassuring. Coffee consumed in reasonable amounts (3 to 4 cups/day) appears to be safe and have favorable health effects. Its cardiovascular protective effects are mediated, besides its antihypertensive effects, also by its antidiabetic and antioxidant actions.24,25,28 The
adverse effects of coffee on serum lipids can be avoided by drinking filtered instead of boiled coffee that contains the diterpenes, cafestol, and kahweol, which increase the serum cholesterol.4,29 The older studies indicating that coffee consumption was associated with increased incidence of CVD were mostly case-control studies, and such studies have methodologic limitations including recall bias, failure to adjust for cofounders, and selection bias. In a metaanalysis comparing the incidence of CHD, the RR was 1.63 (95% CI 1.50 to 1.78) and 1.05 (95% CI 0.99 to 1.12) for case-control and prospective control studies, respectively.30 Only 1 recent prospective study has reported higher incidence of CVD and all-cause mortality.10 However, close examination of the data indicates that this occurred only in high coffee drinkers (>28 cups/week). Therefore, based on the current state of evidence, the traditional admonition that coffee is a risk factor for CVD and HTN seems to vanish, and there is no reason for people to refrain from coffee drinking whether they are healthy or have preexisting HTN or CVD as stated by other authors as well.5,26,28 Disclosures The author declares no conflict of interest and that no funds were received for the preparation of the manuscript. Steven G. Chrysant, MD, PhD Department of Cardiology University of Oklahoma College of Medicine Oklahoma City, Oklahoma 1. National Coffee Association Releases 2013 Coffee Consumption Data [Press Release]. March 22, 2013, San Francisco. Google 2. Sofi F, Conti AA, Gori AM, Luisi ML, Casini A, Abbate R, Gensini GF. Coffee consumption and risk of coronary heart disease: a metaanalysis. Nutr Metab Cardiovasc Dis 2007;17:209e223. 3. Guessous I, Pruijm M, Ponte B, Ackerman D, Ehret G, Ansermot N, Vuistiner P, Staessen J, Gu Y, Paccaud F, Mohaupt M, Vogt B, Pechere-Berstcthi A, Marti PY, Burnier M, Eao CB, Bochud M. Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions. Hypertension 2015;65: 691e696. 4. Rebello SA, van Dam RM. Coffee consumption and cardiovascular health: getting to the heart of the matter. Curr Cardiol Rep 2013;15: 403. 5. O’Keefe JH, Bhatti SK, Patil HR, DiNicolantonio JJ, Lucan SC, Lavie CJ. Effects of habitual coffee consumption and cardiometabolic disease, cardiovascular health, and all-cause mortality. J Am Coll Cardiol 2013;62:1043e1051. 6. Steffen M, Kuhle C, Hensrud D, Erwin PJ, Murad MH. The effect of coffee consumption on blood pressure and the development of hypertension: a systematic review and meta-analysis. J Hypertens 2012;30: 2245e2254. 7. Zhang Z, Hu G, Caballero B, Appel L, Chen L. Habitual coffee consumption and risk of hypertension: a systematic review and metaanalysis of prospective observational studies. Am J Clin Nutr 2011;93:1212e1219. 8. Griggey PP, Wendell CR, Zonderman AB, Waldstein S. Greater coffee intake in men is associated with steeper age-related increases in blood pressure. Am J Hypertens 2011;24:310e315. 9. Mesas AE, Leon-Munoz LM, Rodriguez-Artelejo F, Lopez-Garcia E. The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis. Am J Clin Nutr 2011;94:1113e1126.
Editorial/The Health Effects of Coffee 10. Liu J, Sui X, Lavie CJ, Hebert JR, Earnest CP, Zhang J, Blair SN. Association of coffee consumption with all-cause and cardiovascular disease mortality. Mayo Clin Proc 2013;88:1066e1074. 11. Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med 2012;366:1891e1904. 12. De Koning Gans JM, Uiterwaal CS, van der Schouw YT, Boer JM, Grobbee DE, Vershuren M, Beulens JW. Tea and coffee consumption and cardiovascular morbidity and mortality. Arterioscler Thromb Vasc Biol 2010;30:1665e1671. 13. Ding M, Bhupathiraju SN, Satija A, van Dam RM, Hu FB. Long-term coffee consumption and risk of cardiovascular diseases. A systematic review and dose-response meta-analysis of prospective cohort studies. Circulation 2014;129:643e659. 14. Suriyama K, Kuriyama S, Akhter M, Kakizaki M, Nakaya N, OhmoriMatsuda K, Shimazu T, Nagai M, Sugawara Y, Hozawa A, Fukao A, Tsuji I. Coffee consumption and mortality due to all causes, cardiovascular disease, and cancer in Japanese women. J Nutr 2010;140: 1007e1013. 15. Lopez-Garcia E, Rodriguez-Artalejo F, Li TY, Mukamal KJ, Hu FB. van dam RM. Coffee consumption and mortality in women with cardiovascular disease. Am J Clin Nutr 2011;94:218e224. 16. Floegel A, Pischon T, Bergmann MM, Teucher B, Kaaks R, Boeing H. Coffee consumption and risk of chronic disease in the European Prospective Investigation into Cancer and Nutrition (EPIC)—Germany study. Am J Clin Nutr 2012;95:901e908. 17. Kokubo Y, Iso H, Saito I, Yamagishi K, Yatsuya H, Ishihara J, Inoue M, Tsugane S. The impact of green tea and coffee consumption on the reduced risk of stroke incidence in Japanese population. The Japan Public Health Center-Based Study Cohort. Stroke 2013;44:1369e1374. 18. Larsson SC, Orsini N. Coffee consumption and risk of stroke: a doseresponse meta-analysis. Am J Epidemiol 2011;174:993e1001. 19. Mostofsky E, Rice MS, Levitan EB, Mittleman MA. Habitual coffee consumption and risk of heart failure. A dose-response meta-analysis. Circ Heart Fail 2012;5:401e405.
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