Caffeine in Beverages: Cardiovascular Effects

CAFFEINE IN BEVERAGES: CARDIOVASCULAR EFFECTS

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Anna Vittoria Mattioli, Matteo Ballerini Puviani, Alberto Farinetti Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy

8.1  Caffeine and Mechanisms of Action Caffeine is the most widely consumed active substance in the world. The major intake of caffeine in adults comes from coffee, on the contrary the intake of caffeine in young people is mainly due to beverages like soda cola and energy drinks (EDs) (Mattioli, 2014a; EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015). In many surveys, coffee was the predominant source of caffeine for the adult population in Europe and contributed between 40% and 94% to total caffeine intake. In Ireland and the UK, tea was the main source of caffeine, which contributed 59% and 57%, respectively, to total caffeine consumption (EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015). The ESFA (Education and Skills Funding Agency) document produces data on consumption of caffeine in Europe (Table 8.1). The estimated caffeine from coffee consumption in Italy is about 198 mg/day per person, similar to that reported in the United States, 210 mg/day (Mattioli, 2014a). The ingestion of a single cup of espresso coffee provides a dose of 0.4–2.5 mg/kg of caffeine (calculated as 80–90 mg/cups of Italian espresso) (Mattioli, 2014a, 2007a). In addition, caffeine is present in a number of dietary sources other than coffee, consumed worldwide, that is, tea, cocoa beverages, chocolate bars, and soft drinks. The contents of caffeine are in the following ranges: 4–180 mg/150 mL for coffee, 24–50 mg/150 mL for tea, 15–29 mg/180 mL for cola, 2–7 mg/150 mL for cocoa, 1–36 mg/28 mg for chocolate, and 80–160 mg/355 mL for EDs (Mattioli, 2007a) (Tables 8.2 and 8.3). Caffeine is an alkaloid naturally present in coffee beans. Caffeine is a nonselective competitive antagonist of adenosine receptors, both Caffeinated and cocoa based beverages. https://doi.org/10.1016/B978-0-12-815864-7.00008-8 © 2019 Elsevier Inc. All rights reserved.

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Table 8.1  Consumption of Caffeine in Europe (Range) Range Years/Old 1 to <3 yr (main source chocolate) From 3 to <10 yr (main source chocolate) 10 to <18 yr (main source soda cola) 18 to <65 yr (main source coffee) 65 to <75 yr (main source coffee) ≥75 yr (main source coffee)

Minimal Values (mg/kg/die)

Maximal Values (mg/kg/die)

0.3

30.3

3.5

47.1

17.6

69.5

31.3

319.4

22.6

362.1

21.8

416.8

Modified from EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015. Scientific opinion on the safety of caffeine: safety of caffeine. EFSA J. 13 (5), 4102.

Table 8.2  Caffeine in Different Beverages: Coffee and Tea Coffee Instant coffee Espresso coffee Decaffeinated coffee Espresso coffee decaffeinated Tea Nestea Starbucks Tazo Chai Tea Latte (grande) Arizona Iced Tea (verde)

Dose (mL)

Caffeine (mg)

240 240 30 240 30 240 355 475 475

133 (range 102–200) 93 (range 27–173) 40 (range 30–90) 5 (range 3–12) 4 53 (range 40–120) 26 100 15

Modified from EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015. Scientific Opinion on the safety of caffeine: safety of caffeine. EFSA J. 13 (5), 4102.

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Table 8.3  Caffeine in Different Beverages: Soda Cola and Energy Drinks Cola Soda

Dose (mL)

Caffeina (mg)

FDA limits for Cola and anhalcholoci beverages Coka-Cola (regular or sugar free) Mountain Dew (regular or sugar free) Pepsi (regular or sugar free) Monster Energy Red Bull Monster Energy 5-Hour Energy

355 355 355 355 475 245 475 60

71 range 35–47 54 range 36–38 160 80 160 215

Modified from EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015. Scientific Opinion on the safety of caffeine: safety of caffeine. EFSA J. 13 (5), 4102.

A1 and A2A subtypes, and acts on the autonomic nervous system. The plasmatic concentration of caffeine, reached after coffee consumption, antagonizes adenosine receptors, whereas other caffeine effects, such as inhibition of phosphodiesterase or calcium release from intracellular stores, occur at higher concentrations (Mattioli, 2014a, 2007a; Turnbull et al., 2017). Adenosine has a sedative and vasodilator action. This action is achieved through the inhibition of a series of neurotransmitters, such as norepinephrine, dopamine, and acetylcholine. Caffeine, by blocking the activity of adenosine, makes these neurotransmitters more available, particularly dopamine, which generates an effect of behavioral reinforcement. For this reason, the long-term consumption also induces dependence (Van Soeren and Graham, 1998; Sprier et al., 1992). Acting as a psychostimulant substance, caffeine increases mental alertness, wakefulness, the flow of thought becomes faster and lighter, and also increases the restlessness. All tissues with adenosine receptors may be influenced by caffeine assumption. Caffeine stimulates fat oxidation in muscle, free fatty acid release from peripheral tissues, and increases basal energy consumption (Van Soeren and Graham, 1998; Sprier et al., 1992). Caffeine might impair insulin action by stimulating the release of epinephrine, a potent inhibitor of insulin activity and decreases insulin sensitivity in muscle (Keijzers et al., 2002). In addition caffeine exerts a stimulating action also on the heart, which increases contractility and stroke causing at the same time a

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coronary vasodilation. When coronary vessels dilate brain vessels constrict and blood flow to the brain vessels. This effect is useful in some cases of headache or migraine. Caffeine doses as low as 100 mg were associated with alertness, well-being, sociability, energy, and willingness to work (Richardson et al., 1995). Many central stimulants reduce appetite, via mechanisms that are incompletely understood. Caffeine appears to have a small reducing effect on caloric intake. This effect is similar to, although less marked than, that seen after amphetamine. For both stimulant drugs the effect is on the number of meals consumed rather than on meal size. Given that many caffeine-containing drinks are typically consumed in social settings, surprisingly little is known about the possible effects of caffeine on social behavior. Mc Cusker and Golberger tested the amount of caffeine in different espresso and brewed specialty coffee and found a wide range of caffeine in different preparation. The amount of caffeine in 240 mL of brewed coffee ranged from 72 to 130 mg while caffeine in espresso coffee ranged from 58 to 76 mg in a single shot (28 mL) (McCusker et al., 2003). Food Standards Authority of Australia and New Zealand defined caffeine intake levels as low, moderate and high: 80–250 mg/day “low intake” (1.1–1.3 mg/kg in a 70-kg weight adult), 300–400 mg day “moderate intake” (4–6 mg/kg in a 70-kg weight adult), >500 mg/day “high intake” (7 mg/kg in a 70-kg weight adult) (http://www.foodstandards. gov.au/Pages/default.aspx). The variability in caffeine content in coffee may be due to different factors: modality of preparation, quality of coffee beans, roasting method, and length of brewing time (Mattioli, 2007a). The major concern on caffeine consumption is related to a potential detrimental effect on health. To explore this field several data on effects of coffee on mortality has been recently reported. Results on mortality from EPIC study found that coffee drinking was associated with reduced risk of death from various causes. This relationship did not vary by country. The EPIC study reported 41,693 deaths during a mean follow-up of 16.4 years. Compared with nonconsumers, participants in the highest quartile of coffee consumption had statistically significantly lower all-cause mortality (men: HR, 0.88 [95% CI: 0.82–0.95]; P for trend <.001; women: HR, 0.93 [CI: 0.87–0.98]; P for trend = .009). Among women, there was a statistically significant inverse association of coffee drinking with circulatory disease mortality (HR, 0.78 [CI: 0.68–0.90]; P for trend <.001) and cerebrovascular disease mortality (HR, 0.70 [CI: 0.55–0.90]; P for trend = .002) and a positive association with ovarian cancer mortality (HR, 1.31 [CI: 1.07–1.61]; P for trend = .015) (Gunter et al., 2017).

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The ATTICA study evaluated the association between coffee consumption and 10-year cardiovascular disease (CVD), and whether this is modified by the presence or absence of metabolic syndrome (MetS) at baseline. They analyzed 3042 healthy adults (1514 men and 1528 women) living in the larger area of Athens, the 10-year follow-up was performed in 2583 participants. After controlling for potential CVD risk factors, the multivariate analysis showed a J-shaped association between daily coffee drinking and the risk for a first CVD event in a 10-year period. The odds ratio for low (<150 mL/day), moderate (150–250 mL/day), and heavy coffee consumption (>250 mL/day), compared to abstention, were 0.44 (95% CI: 0.29–0.68), 0.49 (95% CI: 0.27–0.92), and 2.48 (95% CI: 1.56–1.93), respectively. This inverse association was also verified among participants without MetS at baseline, but not among participants with the MetS. Authors concluded that there is a protective effect of drinking moderate quantities of coffee (equivalent to approximately 1–2 cups daily) against CVD incidents. This protective effect is only significant for participants without MetS at baseline (Kouli et al., 2017). Among 90,317 US adults without cancer or history of CVD at study enrollment, 8718 died. Following adjustment for smoking and other potential confounders, coffee drinkers, as compared with nondrinkers, had lower hazard ratios for overall mortality (<1 cup/day: hazard ratio (HR) = 0.99 [95% confidence interval (CI): 0.92, 1.07]; 1 cup/ day: HR = 0.94 (95% CI: 0.87, 1.02); 2–3 cups/day: HR = 0.82 (95% CI: 0.77, 0.88); 4–5 cups/day: HR = 0.79 (95% CI: 0.72, 0.86); ≥6 cups/day: HR = 0.84 (95% CI: 0.75, 0.95)). Similar findings were observed for decaffeinated coffee and coffee additives. Inverse associations were observed for deaths from heart disease, chronic respiratory diseases, diabetes, pneumonia and influenza, and intentional self-harm, but not cancer. Authors concluded that coffee may reduce mortality risk by favorably affecting inflammation, lung function, insulin sensitivity, and depression (Loftfield et al., 2015). The National Institutes of Health (NIH)-AARP Diet and Health Study evaluated the association between coffee consumption and total or cause-specific mortality (Freedman et al., 2012). The analysis involved more than 400,000 participants and 52,000 deaths, and had ample power to detect even modest associations and allowed for subgroup analyses according to important baseline factors, including obesity, diabetes, and smoking. Coffee consumption at baseline was associated with several other lifestyle factors. Coffee drinkers were more likely to smoke cigarettes and consume more than three alcoholic drinks per day, and consumed more red meat. Coffee drinkers reported lower levels of consumption of fruits, vegetables, and were less likely to engage in vigorous physical activity.

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Nevertheless, coffee drinkers, especially women, were less likely to report having diabetes. Results after multivariate adjustment for potential confounders, particularly smoking showed a modest inverse association between coffee drinking and total mortality for both sexes. The HRs for death among men who drank coffee, as compared with men who did not drink coffee, were as follows: 0.99 (95% CI: 0.95–1.04) for less than 1 cup of coffee per day, 0.94 (95% CI: 0.90–0.99) for 1 cup, 0.90 (95% CI: 0.86–0.93) for 2 or 3 cups, 0.88 (95% CI: 0.84–0.93) for 4 or 5 cups, and 0.90 (95% CI: 0.85–0.96) for 6 or more cups (P < .001 for trend across categories). The HRs among women who drank coffee, as compared with those who did not, were as follows: 1.01 (95% CI: 0.96– 1.07) for less than 1 cup of coffee per day, 0.95 (95% CI: 0.90–1.01) for 1 cup, 0.87 (95% CI: 0.83–0.92) for 2 or 3 cups, 0.84 (95% CI: 0.79–0.90) for 4 or 5 cups, and 0.85 (95% CI: 0.78–0.93) for 6 or more cups (P < .001 for trend across categories). Coffee consumption appeared to be inversely associated with most major causes of death in both men and women, including heart disease, respiratory disease, stroke, diabetes, and infections with the exception of cancer (Freedman et al., 2012). Authors concluded that there is a dose-dependent inverse association between coffee drinking and total mortality, after adjusting for potential confounders (smoking status in particular). As compared with men who did not drink coffee, men who drank 6 or more cups of coffee per day had a 10% lower risk of death, whereas women in this category of consumption had a 15% lower risk. A very interesting data was that similar associations were observed regardless of whether participants drank predominantly caffeinated or decaffeinated coffee. These results support the idea that the mechanism of prevention is not related to caffeine but probably to one of the other compounds of coffee. The bioavailability and the distribution of each compound and its metabolites contribute to coffee mechanisms of action. One hypothesis is related to effects of coffee and caffeine on cardiovascular risk factors and mostly depends on its antioxidant compounds.

8.2  Caffeine and Risk Factors for Atherosclerosis The relationship between coffee consumption and CVD has been studied extensively, however, some controversial issues persist. It is well known that lifestyle, specifically diet and physical activity, play an important role in the development of atherosclerosis (Mattioli et al., 2017a,c).

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Coffee is part of Mediterranean diet, one of the healthiest diets. The characteristics and virtues of the Mediterranean diet were recently accompanied by a declaration from UNESCO which classified the Mediterranean diet as a “cultural heritage of humanity” (Mattioli et al., 2017a). In addition, caffeine and other active components of coffee, including chlorogenic acid (CGA), and the diterpene alcohols cafestol and kahweol, can also have long-term effects on risk factors for CVD, such as blood pressure, plasmatic cholesterol levels, and homocysteine, (Cornelis and El-Sohemy, 2007). An Italian study evaluated the relation between alcohol, smoking, and coffee and risk of nonfatal acute myocardial infarction. This study found that heavy, but not moderate, coffee drinking was positively associated with risk of myocardial infarction. Decaffeinated coffee was not related to risk, but the frequency of use in the study population was low. Smoker patients who had heavy coffee consumption had an elevated risk of myocardial infarction, as well as tobacco smoking in abstainer from alcohol (Tavani et al., 2001). Italian patients consumed mostly espresso coffee and mocha coffee, and the authors suggested a mechanism mediated by the coffee-dependent rise in blood pressure, low-density lipoprotein cholesterol, and plasma total homocysteine concentrations (Tavani et al., 2001). Woodward and Tunstall-Pedoe followed a Scottish population for 8 years and found that a higher coffee consumption was associated with a lower risk of CVD in men but not in women (Woodward and Tunstall-Pedoe, 1999). Chronic coffee consumption is associated with a slight increase in blood pressure, plasma homocysteine, and plasma cholesterol (only for unfiltered coffee), coffee intake is not associated with the incidence of hypertension, and reduces the incidence of type 2 diabetes mellitus. Moreover, in a cohort study of older subjects, there was an inverse correlation, particularly in women, between coffee consumption and coronary calcifications, a marker for atherosclerosis in coronary arteries, suggesting that chronic coffee consumption does not adversely affect the development of atherosclerosis (van Woudenbergh et al., 2008). In a study of a Korean population, women who consumed ≥3 cups of coffee daily had a lower risk for CHD compared with women who consumed <1 cup of coffee daily. There was a dose-response relationship between coffee consumption and CHD risk as estimated using the Framingham risk score; the risk appeared to be higher among women who consumed <1 cup of coffee daily. An inverse association between coffee consumption and CHD risk was observed in women but not in men. The association was not modified by socioeconomic factors, antihypertensive drug use, antidyslipidemic drug use, general and abdominal obesity, or tea consumption (Noh et al., 2017).

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Although coffee consumption was significantly associated with lower CHD risk in women, there was no association in men. Other studies have reported a relationship between coffee consumption and lower risk for CHD in women (van Woudenbergh et al., 2008; Wu et al., 2009; Kleemola et al., 2000). However, little is known about the effect of gender on the relationship between coffee and CHD risk. The explanation for this association is not clear. This sex difference may be due to unmeasured confounding factors. The Korean study had more elderly participants, smokers, and high-risk alcohol consumers among the men than among the women. Smoking, in particular, was strongly associated with coffee consumption both in men and in women, but the prevalence of smoking was much higher among men than among women (Noh et al., 2017). The difference in lifestyle factors between men and women may influence gender difference in the association between coffee consumption and CHD risk. Coffee consumption might be associated with unhealthy lifestyle habits, such as smoking, and the beneficial effect of coffee consumption on CHD risk in men could be attenuated by the negative effects of unhealthy behaviors. The relationship between coffee and smoking is complex and has been extensively studies. Caffeine absorption from the gastrointestinal system is rapid and reaches 99% in about 45 min after ingestion. Absorption is not complete when the substance is taken as coffee (Bonati et al., 1982). There is ample evidence that smokers metabolize caffeine by approximately 50% more rapidly than nonsmokers (Bonati et al., 1982). Moreover, there is a positive correlation between drinking coffee and smoking and it is well known that smokers are particularly liable to smoke when drinking coffee (Palatini et al., 2017; Swanson et al., 1994). There are also a larger proportion of patients who do not consume caffeine among nonsmokers than among smokers (Palatini et al., 2017). All these observation support the hypothesis that a non-healthy lifestyle is associated with increased risk of atherosclerosis. Data on heavy coffee consumption in smokers suggest a relation with inflammation (Zampelas et  al., 2004; Tsioufis et  al., 2006). The ATTICA study found a dose-response relation between coffee consumption and increase in inflammatory markers. Compared with nondrinking patients the authors reported a mean increase of 30% CRP, 50% IL-6, and 12% higher SAA in men who consumed more than 200 mL coffee/day. The difference was significant only when the consumption of coffee exceeds 200 mL/day compared with subjects who did not drink coffee (Tsioufis et al., 2006). Increased adiponectin levels were found in trials comparing filtered coffee/caffeinated coffee with placebo or comparing its levels at

Chapter 8  Caffeine in Beverages: Cardiovascular Effects   265

baseline and after consumption of medium or dark roasted coffee, but no change was seen in caffeine trials. No changes in C-reactive protein (CPR) have been found in studies assessing the effects of coffee, on the contrary caffeine induced a decrease in CPR levels (Paiva et al., 2017). Data suggest a predominant antiinflammatory action of coffee but not of caffeine consumption. Moreover, the proinflammatory and antiinflammatory responses to caffeine point to its complex effects on the inflammatory response. In the EPIC biomarkers subcohort, higher coffee consumption was associated with lower serum alkaline phosphatase; alanine aminotransferase; aspartate aminotransferase; γ-glutamyltransferase; and, in women, CPR, lipoprotein(a), and glycated hemoglobin levels (Gunter et al., 2017). Several reports underline antioxidant properties of coffee mediated by flavonoids, potassium, magnesium, and other components that could have antiinflammatory effects (Svilaas et al., 2004). Caffeine is a well-documented antioxidant with activity comparable to glutathione, a potent endogenous antioxidant that protects against cellular damage caused by free radicals and peroxides (Devasagayam et al., 1996). Studies have shown that caffeine and its metabolites theobromine and xanthine protect against the production of free radicals, such as hydroxyl radical (.OH), peroxyl radical (ROO.), and singlet oxygen resulting in decreased lipid peroxidation in vitro (Devasagayam et al., 1996; Azam et al., 2003). Additional studies have shown that coffee preparations that contained higher concentrations of caffeine displayed higher levels of antioxidant activity (Vignoli et al., 2011). Epidemiologic studies suggested that regular consumption of food and beverages rich in flavonoids is associated with a decreased risk of cardiovascular mortality including coronary artery disease (CAD) and stroke (Mattioli et al., 2017a; Knect et al., 2004). One hypothesis involves a protective effect related to bioactive compound in food and beverages that reduce oxidative stress. A condition that arises when the formation of reactive oxidants outstrips the antioxidant defense and the oxidative damage occur (Mattioli et  al., 2017a, 2013; Lopez-Garcia et al., 2006b). Another plausible mechanism involves activation of genes encoding proteins in the antioxidant defense system and silencing of genes that may contribute to the oxidative stress (Wild and Mulcahy, 2000; Sen and Packer, 1996). Among several different bioactive compounds, dietary antioxidants are suggested to play a role in transcriptional regulation via these response elements (Wild and Mulcahy, 2000; Sen and Packer, 1996; Farinetti et al., 2017). Svilaas and coworkers identified coffee as major contributor to total antioxidant intake. The intake of coffee contributed to 64% of the total

266  Chapter 8  Caffeine in Beverages: Cardiovascular Effects

antioxidant intake, followed by fruits and berries (Svilaas et al., 2004). High antioxidant levels in coffee were recently reported but this high contribution to the total dietary intake of antioxidant was not noted (Svilaas et al., 2004). Green and black coffee beans contain different quantity of antioxidant, 15.9 and 22.6 mmol tot antioxidant/100 g, respectively. This difference depends on the roasting process that damages some antioxidants (Vignoli et al., 2011). The CGAs have been extensively studies as the major phenolic components in coffee beans. The CGA have a similar antioxidants activity as ascorbic acid. It seems that CGA activity can play a role in the reduction of the risk of development chronic disease induced by coffee drinking, specifically diabetes and atherosclerosis. Green coffee is very rich in CGA and is used to enrich regular instant coffee, however, CGA composition of coffee seeds varies considerably during fruit maturation and reduces during senescence. The content of CGA in brewed coffee varies depending on blend, roasting degree, proportion of coffee to water, brewing, and length of duration for which coffee is in contact with water. The content of CGA in commercial instant coffee may vary largely between 2.2% and 0.7 g%. The daily ingestion of CGA is calculated to be less than 100 mg in abstainer from coffee and ranged from 100 to 1000 mg/day for modest and heavy coffee drinkers. Another aspect that could influence bioavailability is the interaction with protein, mainly with casein. When consumed with milk, CQA interact with casein, and these complexes are resistant to gastrointestinal enzyme. This leads to a reduced absorption of antioxidants. The same phenomenon occurs with tea (Vignoli et al., 2011).

8.3  Caffeine Effects on Endothelial Function There is evidence that dietary factors could influence the risk of CVD through modulation of endothelial function. Several experimental studies examined the effect of acute caffeine consumption from coffee (80 and 240 mg caffeine), black tea (150 mg), ED (80 and 230 mg) and capsule (200 mg) on flow-mediated dilation (FMD) of the brachial artery or reactive hyperemia. Papamichael and coworkers found that a cup of coffee (caffeine 80 mg) led to a decrease of brachial FMD, lasting for 1 h after intake, compared to a decaffeinated beverage (caffeine 2 mg) in healthy young adults (Papamichael et al., 2005). A study reported an increase in FMD following the ingestion of 54.5 mg caffeine from instant coffee (Noguchi et al., 2015), while another study reported no change after the ingestion of 120 and 240 mg caffeine from regular coffee (Agudelo-Ochoa et al., 2016).

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A study evaluated the effect of EDs and reported an increase in FMD (Molnar and Somberg, 2015). These controversial results could be due to the effects of other compounds included in coffee. Coffee has many ingredients such as antioxidants, polyphenols, etc., that could act differently on peripheral vessels and on endothelial function. Similarly, studies evaluating the acute effects of caffeine, not coffee, lead to controversial results. In a review article, Papaioannou and coworkers reported that acute caffeine ingestion influences the cardiovascular system, not only through a peripheral blood pressure elevation but also through an increase in arterial stiffness and an enhancement of arterial wave reflections. Moreover, they suggested that peripheral pressure measurements might have underestimated caffeine pressor effects, as a significantly greater response is observed in aortic pressures (Papaioannou et al., 2005). Shechter and coworkers demonstrated that 200 mg of caffeine improved brachial endothelial function in subjects with and without CAD. Moreover, the increase of serum caffeine levels by almost 4 μg/mL in two groups of patients was associated with a reduction in inflammatory markers such as hs-CRP. Furthermore, it was associated with an increase in serum adiponectin levels, an adipocyte-derived plasma protein that has antidiabetic and antiatherogenic properties (Shechter et al., 2011; Kojima et al., 2005; Matsuzawa et al., 2004; Otsuka et al., 2006). Similar results were obtained by Umemura et  al. who demonstrated that acute caffeine ingestion of 300 mg of caffeine increased ­endothelium-dependent vasodilation in healthy men through an increase in nitric oxide production (Umemura et al., 2006).

8.4  Coffee and Coronary Artery Disease Despite decades of research, the question as to whether caffeine and/or coffee intake increases the risk of CAD remains controversial. Coffee drinking has been associated with increased cardiovascular morbidity in some but not all prospective studies (Woodward and Tunstall-Pedoe, 1999; Kawachi et al., 1994; Grobbee et al., 1990). Although case-control studies found a positive association between coffee consumption and risk of CAD, prospective cohort studies underlined a lower risk among individuals with higher coffee consumption (Hammar et al., 2003; Kleemola et al., 2000). Several metaanalyses evaluated the relationship between coffee consumption and CAD. Meyers and Basinski only evaluated prospective cohort studies, and found no association between coffee consumption and CAD (Myers and Basinski, 1992).

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On the contrary, Greenland, Kawachi et al. and Sofi et al. have included both case-control studies and prospective cohort studies in their analysis. They all found a positive association between coffee consumption and CAD in the group of case-control studies, whereas they found no association or a weak association in prospective studies (Greenland, 1993; Kawachi et al., 1994; Sofi et al., 2007). Sofi et al. have reported that the combined OR from 13 case-control studies showed significant associations between coffee consumption and CHD for the group with the highest intake (>4 cups per day; OR, 1.83; 95% CI: 1.49–2.24) and for the group with the second-highest intake (3–4 cups per day; OR 1.33; 95% CI: 1.04–1.71), compared with those who did not consume coffee (Sofi et al., 2007). In a large prospective study, Lopez-Garcia and coworkers did not find any detrimental effect of coffee consumption on risk of CAD in either men or women. No association was observed for decaffeinated coffee or tea. These results provide evidence against the hypothesis that coffee consumption increases the risk of CHD (Lopez-Garcia et al., 2006a). Interestingly, the age-adjusted analyses found no association between long-term coffee consumption and the risk of CAD in men but found a positive association for women. This positive association disappeared when the analysis was adjusted for smoking habits. The study did not find interaction between coffee consumption and smoking in relation to CAD risk. Moreover, they reported that the moderate reduced risk for cardiovascular mortality was independent of caffeine intake. The consumption of more than 6 cups/days was associated with a slightly lower risk of fatal CAD in men and women (LopezGarcia et al., 2006a). In contrast, a retrospective study from Klatsky et al. reported an increased risk for CAD in subjects drinking more than 6 cups of coffee/ day, but only in ex-smokers (Klatsky et al., 2008). Another case-control study showed an association between caffeine intake and nonfatal myocardial infarction, with an estimated population attributable risk of 12.8% (95% CI 5.9–25.7%) (Kabagambe et al., 2007). Prospective studies have not shown a strong positive association between coffee intake and CAD, whereas retrospective studies reported such an association. It is plausible that the retrospective studies were more likely to suffer from bias and confounding factors, in particular recall bias (Kawachi et al., 1994; Sofi et al., 2007). However, this discrepancy could also be interpreted in favor of an acute rather than chronic negative effect of coffee on CAD: retrospective studies might provide a more accurate assessment of coffee intake in the period right before the coronary event, in contrast to the prospective studies, in which coffee consumption is assessed years before the event. Therefore, the discrepancy between the results of the

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Fig. 8.1  Effects of coffee on coronary artery disease. Reproduced with permission from Riksen, N.P., Rongen, G.A., Smits, P., 2009. Acute and long-term cardiovascular effects of coffee: implications for coronary heart disease. Pharmacol. Ther. 121, 185–191. Elsevier Journal Permission No. 4223731300321.

case-control and prospective studies might also be compatible with the hypothesis that coffee has an acute effect (i.e., triggering a coronary event) rather than a long-term adverse effect (i.e., promoting atherosclerosis) (Riksen et al., 2009) (Fig. 8.1). Another key point is the effect of coffee on cholesterol levels. It is well known that boiled coffee is associated with increase in both plasma total cholesterol and low-density lipoprotein cholesterol. A metaanalysis based on 12 randomized controlled trials of coffee consumed daily for 45 days showed that caffeine intake led to statistically significant increases in total serum cholesterol (mean increase 8.1 mg/dL), low-density lipoprotein cholesterol (mean increase 5.4 mg/dL), and triglycerides (mean increase 12.6 mg/dL). The greater increases in lipid levels were observed for boiled coffee compared to filtered coffee, and decaffeinated coffee had little effect on blood lipid levels (Bak and Grobbee, 1989; Cai et al., 2012). Little information is available on genetic pattern and influence of caffeine on gene. Kleemola and coworkers evaluated a Finnish population and, in a follow-up lasted 10 years, found that men with high coffee consumption (more than 7 cups a day) had a lower risk of nonfatal myocardial infarction whereas a slightly increased mortality for CAD (Kleemola et  al., 2000). It is possible that controversial results depend on different genotype, patients with a CYP1A2 genotype predicting slow caffeine metabolism. These subjects had an increased risk of nonfatal myocardial infarction even for 2–3 cups of coffee/day (Comelis et al., 2006).

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8.5  Caffeine and Blood Pressure Similar to CAD, studies evaluating the effect of caffeine and coffee on blood pressure led to controversial results. Data from a variety of epidemiological studies on the effects of coffee consumption on blood pressure appear to be inconsistent, demonstrating no effects or positive relations or inverse relations (Zhang et al., 2011). It is possible that genetics, smoking, and other aspects of the lifestyle may modify the effects. Most observational cohort studies identified no statistically significant association between daily coffee consumption at various levels and blood pressure changes (Zhang et al., 2011). A metaanalysis by Zhang included >170,000 adults and >32,000 new cases of hypertension and reported no association between ­caffeine intake and the development of hypertension (Zhang et  al., 2011). An ambulatory blood pressure study that investigated 24-h urinary caffeine and caffeine metabolites levels in more than 800 adults reported that each doubling of caffeine excretion was associated with about 0.6 mm Hg lower blood pressure. The caffeine effects were significant even after statistical adjustment for blood pressure medication use (Guessous et al., 2015). When we translate the acute effects of coffee to the effects induced by daily consumption we need to remember that a tolerance effects has been described and this can explain the controversial results in different studies. In 1981, Robertson and coworkers found that the pressor response and the increase in (nor) epinephrine levels after a dose of 250 mg of caffeine in healthy subjects was lost after 3 days of daily caffeine administration (Robertson et al., 1981). More recent studies, however, have reported that only approximately half of all subjects show complete tolerance to the acute pressor effect of caffeine (Lovallo et al., 2004; Farag et al., 2005). There is a difference in the half-life of caffeine that could influence the observed interindividual variation in the development of tolerance to the acute effects of caffeine (Riksen et al., 2009). In a review of controlled trials, Nurminen et al. reported an acute increase in both SBP and DBP in the hours after the intake of caffeine; however, results on the effect of caffeine intake for more than 7 days were inconclusive (Nurminen et al., 1999). A metaanalysis of 11 controlled trials reported that coffee consumption for 1 day led to a slight increase in BP (Jee et al., 1999). Similarly, in a subsequent metaanalysis of randomized controlled trials of coffee or caffeine intake for more than 7 d, Noordzij et al. concluded that both interventions raised BP, although the effect of coffee was much smaller than that of caffeine (Noordzij et al., 2005).

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The discrepancy between the two analysis can be explained by the different dosage of caffeine, Jee included trials with a high caffeine dose (greater than 410 mg/day) in which the rise in systolic blood pressure was larger than in trial with a lower caffeine dose (Jee et al., 1999). In addition Jee and coworkers included short-term trial that were excluded from the analysis performed by Noordzij (Jee et  al., 1999; Noordzij et  al., 2005). The smaller effects of coffee in studies lasting for more than 2 weeks could reflect the adaptation to cardiovascular effects of coffee drinking. Both reviews suggest that coffee consumption is associated with increase in both systolic and diastolic blood pressure, nevertheless results from observational studies failed to identify a pressor effect of habitual coffee consumption. Winkelman and coworkers found no relation between coffee intake and incident hypertension in a cohort of 155.594 women followed for more than 10 years (Winkelmayer et al., 2005). On the contrary, in a study group of 1017 men followed up for over 33 years, coffee drinkers had a greater incidence of hypertension, however, the nonsignificant association with incident hypertension after multivariate analysis may suggest that coffee drinking plays only a minor role (Klang et al., 2002). Short-term administration of caffeine in noncoffee drinkers increases blood pressure, plasma renin activity, and catecholamines (Robertson et  al., 1978). Corti and coworkers found that coffee and caffeine induced increases in muscle sympathetic nervous activity in nonhabitual coffee drinkers, whereas habitual coffee drinkers exhibited lack of blood pressure increase despite sympathetic activation to coffee (Corti et al., 2002). Certainly habitual coffee drinkers developed a tolerance to acute caffeine effects and the effects on blood pressure are lower in this group of subjects. This is concordant with trials showing that one develops a tolerance to the acute hemodynamic effects of caffeine in response to habitual moderate consumption (Jee et al., 1999; Noordzij et al., 2005; Mattioli et al., 2018).

8.6  Coffee and Arrhythmias The effects of coffee on arrhythmias have been mainly related to caffeine. Among its pro-arrhythmic effects symptoms such as palpitations have been reported. Moreover, some clinical case reports have identified episodes of ventricular tachycardia (VT) and atrial fibrillation (AF) triggered by caffeine intake (Mattioli, 2014a; EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015). A case report underlines the correlation between the appearance of arrhythmia induced by the consumption of chocolate in an adult taking salbutamol. The salbutamol is a short-acting selective β2 adrenergic receptors

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a­ gonist. The combined effects of methylxanthines contained in the coffee/tea and chocolate and salbutamol would increase the probability of triggering of arrhythmia (Patanè et al., 2009). However, there are still many discrepancies on the effects of caffeine and despite the theoretical relationship between caffeine and arrhythmias, there is no evidence, in humans, that caffeine at doses which is commonly consumed can directly cause abnormal heart rhythms. Several studies investigated the relationship between caffeine (or coffee) and AF. The Multifactor Primary Prevention Study found that less than 4 cups of coffee/day was associated with an increased risk of AF, on the contrary drinking more than 4 cups a day was not associated with a risk of AF (Wilhelmsen et al., 2001). The Danish Diet, Cancer and Health study, a large follow-up study, did not find any risk of AF or flutter associated with caffeine consumption (Frost and Vestergaard, 2005). The incidence rate for AF was the same reported from the Framingham study and the Manitoba ­follow-up study (Benjamin et al., 1994; Krahn et al., 1995). In a case-control study we found that increasing level of coffee consumption was associated with a greater risk of acute AF (Mattioli et al., 2005). High espresso coffee consumption (>3 cups a day) was associated with an increased risk of AF and the risk was more marked in non-habitual coffee drinkers. This effect could be the consequence of the more marked sympathetic activation induced by caffeine in nonhabitual coffee drinkers. Some studies suggested a protective effect of high coffee consumption on cardiovascular risk factors mainly due to its antioxidant properties, which appear to reduce the risk of CVD (Mattioli et  al., 2011). In this study the intake of antioxidants by coffee was quite high. However, the selection of a population that had a strong adherence to Mediterranean diet could have influenced the results. The pathophysiology of arrhythmias has been described in detail, however, the mechanism underlying these changes and the possible triggering factors remain largely unknown. The topic is controversial and the effects of coffee consumptions seem to be mediated by several other factors, mainly the diet, the modality of preparation of coffee (filtered or not), and the interference of food and drugs on its bioavailability. A metaanalysis found that it is unlikely that caffeine consumption causes AF (Cheng et al., 2014). Moreover, habitual caffeine consumption might offer a moderate protective effect against AF. There are several mechanisms through which caffeine might reduce AF risk. A moderate amount of caffeine intake does not seem to not increase arrhythmia susceptibility acutely. Studies evaluating effects of caffeine on ECG showed that a dose of 400 mg did not induce any change in P-wave indices, QRS duration,

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corrected QT interval, RR interval, or corrected QT interval dispersion in healthy subjects (Caron et al., 2001; Ammar et al., 2001). In addition, in habitual caffeine consumers, the adrenergic effects of caffeine are greatly attenuated and it is possible that acute proarrhythmia effect was reduced (Corti et al., 2002). Another potential protective effects can be due to the antifibrosis effect observed in habitual caffeine consumption (Molloy et al., 2012; Anty et al., 2012; Arauz et al., 2013). Although there are few studies that evaluated the antifibrosis effect of caffeine on the heart, it is possible that caffeine also prevent cardiac fibrosis (Swartz et al., 2012; den Uijl et al., 2011; Burstein and Nattel, 2008).

8.7  Caffeine and Energy Drinks In recent years the consumption of EDs (e.g., Red Bull, Monster, etc.) has increased constantly among young individuals and it has been recently linked with cardiac arrhythmia and young unexpected death (Babu, 2008; Mattioli et al., 2017b, 2016). The EDs are consumed by young because they enhance focus, attention, and reactivity. These drinks are very popular within young people because they increase supervision during the evening hours. Moreover, they are sold in cans, are unrestricted, and marketing campaign identify it as safe products able to improve the physical and mental performance. The highest prevalence of “energy drink consumers” was observed in adolescents (9% in the Netherlands, 7% in the UK, and 5% in Finland) and adults (8% in Ireland, 4% in the Netherlands, and 3% in the UK) (EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015). The caffeine content is very variable: generally a quantity slightly higher or slightly equivalent to 80–85 mg of a cup of coffee and superior to 23 mg of a classical Soda Cola. On the basis of discrepancies regarding the effects of the consumption of coffee/caffeine, the Food and Drug administration (FDA) recognized as “safe” the intake of some popular beverages containing a concentration of 0.02% of caffeine (see Table 8.3) (McCusker et al., 2006). Comparing the different EDs in the market, a can of a popular ED of 8.2 g contains about 80 mg of caffeine (0.03%), while a can of another popular ED contains about 141 mg of caffeine (EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015; McCusker et al., 2006). In 1999, the SCF (1999) considered that the contribution of “EDs” to caffeine intakes in nonpregnant adults was not of concern on the assumption that “EDs” would replace other caffeine sources, such as coffee or tea. For children, the SCF concluded that the consumption of 160 mg caffeine per day from 0.5 L of “EDs,” equivalent to 5.3 mg/kg

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bw per day for a 10-year-old, 30-kg child, could result in transient behavioral changes, such as increased arousal, irritability, nervousness, or anxiety (EFSA, Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015). In 2003, the SCF (2003) considered that it is unlikely that d-­ glucurono-γ-lactone would interact with caffeine, taurine, alcohol, or the effects of exercise. Caffeine exerts stimulatory effects on the central nervous system and, although taurine generally acts as an inhibitory neuromodulator, the SCF could not rule out the possibility of stimulatory effects of caffeine and taurine on the central nervous system. In 2009, the Panel on Food Additives and Nutrient Sources Added to Food (ANS Panel) concluded that exposure to taurine and d-­ glucurono-γ-lactone at levels commonly used in “EDs” was not of safety concern, even for consumers of high levels European Food Safety Authority (EFSA). In 2008, the Federal Institute for Risk Assessment (BfR) assessed the safety of “EDs” in view of case reports on fatalities following reported consumption of these beverages, either alone or in combination with alcohol, which implicated, primarily, the cardiovascular system. Nevertheless the BfR considered that adverse health effects upon consumption of large amounts of “ED” in combination with intense physical exercise or alcohol could not be ruled out, and advised children, pregnant and lactating women, and individuals who are “sensitive” to caffeine (i.e., patients with cardiac arrhythmias) not to consume “EDs,” particularly in large amounts. The BfR stated that the consumption of “energy shots” poses no risk to health if consumed in accordance with the suggested daily intake levels of 50–200 mg caffeine (www.bfr.bund.de/en/home.html). The EDs do not show a great degree of toxicity when consumed by healthy subjects in moderate doses, however, when consumed in high doses or together with alcoholic beverages, they may cause arrhythmia (Mattioli et al., 2017b, 2016; Howland and Rohsenow, 2013; Emond et al., 2014; Berger and Alford, 2009). Although it has been acknowledged that adverse effects could be attributed to caffeine alone, additive and/or synergistic cardiovascular effects have been proposed for other components of “EDs” on cardiovascular outcomes, especially taurine. Literature suggests several cases of arrhythmic sudden death among young people seemingly caused by consumption of EDs and alcohol. After this discovery many North-European Countries have started prohibiting underage individuals from consuming EDs. Furthermore, FDA has sent several warnings to American cardiologic societies American College of Cardiology (ACC) in order to produce data and guidelines about ED consumption both on cardiopathic and healthy subjects (Hojsak et al., 2017).

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Besides caffeine, EDs contain several other psychoactive substances such as taurine, ginseng, gluconolactone, and guaranà, the concentration of which is often disparate and not well indicated. In addition guarana plant and berry has one of the highest naturally occurring levels of caffeine, at around 7%–8%, and there are also traces of theophylline and theobromine. Instead of referring to caffeine, many companies and websites market their products using the term “guaranine.” Other companies clearly label their products with the caffeine content, but the impression may be given to consumers that there is something additionally special about guarana (Mattioli, 2014b; Jeffries et al., 2012; Waldron, 2017). Guarana [Paullinia cupana var. sorbilis (Mart.) Kunth; Sapindaceae], widely used in the Brazilian beverage industry, is reported to have the highest concentration of caffeine (more than 6% in the seeds) in nature (Jeffries et al., 2012). The seeds are popular in Brazil for their stimulant effects. Roasted seed powder is used in preparations to enhance memory and to attenuate mental and physical stress. Guarana also contains significant amounts of phenolics, especially tannins like catechin, epicatechin and their polymers, and proanthocyanidins, which might also contribute to its properties. Guarana can attenuate markers of MetS, specifically waist circumference and cholesterol levels; this effect was demonstrated among seniors self-referred as guarana drinkers. A significant association between lower levels of advanced oxidative protein products and guarana consumption has been reported (Da Costa Krewer et al., 2011). The presence of herbs in the EDs could also induce some side effects. It is well known that herbs interact strongly with medications and could have direct effects on cardiovascular and hemostatic system (Tachjian et al., 2010). One of the effects is the QT interval prolongation leading to a pro-arrhythmic status. Although herbal remedies are perceived as being natural and therefore safe, many have adverse effects that can sometimes produce life-threatening consequences (Tachjian et al., 2010). Furthermore, these beverages are very often taken in combination with alcoholic drinks, triggering arrhythmias. The EDs have now a prevalent role in the enjoyment of alcohol. Among young people, the intake of ED-based cocktails is now a common habit (Howland and Rohsenow, 2013; Emond et al., 2014). Several case reports suggested the synergist effects of alcohol and EDs on the development of arrhythmias (Mattioli et al., 2017b, 2016; Howland and Rohsenow, 2013). Unfortunately, data on the side effects of these drinks are still partially unknown. The intake of high amounts of caffeine, about 1 g per day, and the combination alcohol and EDs can alter both central and peripheral nervous system. The increase of heart rate can cause major side effects such as anxiety, mood changes, insomnia, ­hypertension,

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and cardiac arrhythmias. The EDs associated with alcohol have been associated with renal impairment that seem to be related to the effects of taurine on the excretory system. The hypothesis that kidney damage is induced by taurine in EDs is supported by a recent study reporting renal failure developed after a high consumption of EDs (Schöffl et al., 2011). In addition, the mix generates a potential risk of dehydration because both alcohol and EDs have diuretic properties. The risk of dehydration is due to both an increase in diuresis and an increase in sweating. Moreover, the indiscriminate use of EDs and alcohol can lead to alcohol addiction and alcoholism in youth.

8.8  Coffee and Diabetes Type 2 diabetes has grown dramatically over the last decades and the projection identified diabetes mellitus type 2 (DM2) as the new “epidemic disease.” The DM2 is strongly related to obesity and lifestyle, which plays a fundamental role in the prevention of the disease (Fig. 8.2). The antiobesity and antidiabetic properties of CGAs have been linked to the metabolism of glucose (Meng et  al., 2013; Naveed et  al., 2017). It is also suggested that reduction in body weight and glucose absorption in human and animal models are associated with the CGA-enriched coffees which could be thought of due to the inhibition of glucose release by preventing hepatic glucose-6-phosphatase activity and inhibition of glucose absorption in the small intestine by preventing glucose-6-phosphate translocase 1 as well. This would diminish blood glucose in the general circulation, and thus cause less insulin activity (Meng et al., 2013; Naveed et al., 2017). Prospective studies found that regular coffee intake is associated with a reduction in DM2 risk. Majority of the 28 studies published between 2002 and 2013 confirmed a strong or partial protective effect of coffee intake against DM2 (Da Costa et al., 2014). Only three studies found no effect of coffee on DM2. Muley and coworkers found that habitual coffee consumption was associated with a lower risk of type 2 diabetes. Specifically, participants who drank 4–6 cups and more than 6–7 cups of coffee per day had a lower risk of type 2 diabetes compared with those who drank less than 2 cups per day. Advantage of filtered coffee over pot boiled, decaffeinated coffee over caffeinated coffee, and stronger inverse correlation in <60 years age group was also reported (Muley et al., 2012). Nowadays, there are many evidences of the reduced risk of developing type 2 diabetes by regularly consuming 3–4 cups a day. The effects

Chapter 8  Caffeine in Beverages: Cardiovascular Effects   277

Fig. 8.2  Relationship between food and diabetes.

were related to CGAs and caffeine, the two constituents of coffee in higher concentration after the roasting process. Both caffeinated and decaffeinated coffees are associated with lower onset of diabetes in a dose-dependent manner (Ding et  al., 2014b). Coffee intake is also associated with lower risk of CHD and stroke but in a nonlinear manner: compared with no intake, lowest risk is seen at 3–4 cups/day, with increasing risk at higher intakes (Ding et al., 2014a). Similar to coffee consumption, tea consumption is associated with lower risk of diabetes and CVD, especially comparing the very frequent consumption (3–4 cups/day) with none (Yang et al., 2014). Overall, observational studies support potential cardiometabolic benefits of coffee and tea. Salazar-Martínez et  al. (2004) examined the long-term relationship between the consumption of coffee and other caffeinated beverages and the incidence of T2DM in a prospective cohort study. The Nurses' Health Study and Health Professionals' Follow-up Study included 41,934 men and 84,276 women without diabetes, and documented 1333 new cases of DM2 in men and 4085 new cases in women. They found an inverse association between coffee intake and DM2, thus suggesting that long-term coffee consumption is associated with a significantly lower risk for the disease (SalazarMartínez et al., 2004). This effect was related to mineral and antioxidant contents, but the role of caffeine was not specified until the Pereira et al. study (Pereira et al., 2006). These authors demonstrated in a prospective analysis with a cohort of postmenopausal women free of diabetes that coffee intake, especially decaffeinated, was inversely associated with a risk of DM2. In conclusion acute administration of caffeine has controversial effects on CVD, on the contrary chronic consumption exerts some protective effects on heart and vessels.

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Further Reading Mattioli, A.V., 2007b. Coffee and caffeine effects on hypertension. Curr. Hypertens. Rev. 3 (4), 250–254.