The Role of Xenobiotic Caffeine on Cardiovascular Health: Promises and Challenges
Abstract
:1. Introduction
2. Metabolism of Caffeine
2.1. Sources, Metabolism, and Pharmacokinetics of Caffeine
2.2. Genetic Modifiers of Caffeine Metabolism
3. Cardiovascular Benefits of Caffeine
3.1. Hypertension
Type of CVD | Subjects of the Study | Source of CAF | Main Findings | Limitations | Year | Reference |
---|---|---|---|---|---|---|
Hypertension | 11 groups of 6 rats | CAF (5–25 mg/kg) and caffeic acid (5–25 mg/kg) administrated orally by gavage | Anti-hypertensive effect of CAF. Systolic blood pressure ↓ ACE activity ↓ Arginase activity ↓ NO levels ↑ MDA levels ↓ | Small size group of rats | 2021 | [75] |
Hypertension | 1010 human subjects (meta-analysis) | Coffee (725 mL/day) or CAF (410 mg/day) | Systolic pressure ↑ | None | 2005 | [76] |
Hypertension | 63,257 human subjects (aged 45–74 years) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | 1 cup of coffe/week or more than 2 cups/day reduced risk of hypertension compared to consuming 1 cup of coffee per day | Other ingredients in coffee may offset the effect of CAF | 2018 | [77] |
Hypertension | 196,256 human subjects (meta-analysis) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Moderate coffee intake is not associated with higher risk of hypertension | A cause-effect relationship between coffee consumption and risk of hypertension cannot be stated based on the evidence available | 2019 | [78] |
Hypertension | 48 human subjects (men aged 20–39 years) | CAF (3.3 mg/kg) | Diastolic blood pressure ↑ in patients with borderline hypertension | Small-size cohort groups. Gender biased. | 1996 | [79] |
Hypertension | 182 human subjects (men aged 25–40 years) | CAF (3.3 mg/kg, average 260 mg/person or fixed dose of 250 mg) | No impact on blood pressure in non-hypertensive subjects;Blood pressure in patients at stage 1 hypertension ↑ | Gender biased | 2000 | [80] |
Hypertension | Human subjects (46,395 men and 64,190 women aged 40 to 79 years) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | CVD mortality in patients with grade 2–3 hypertension ↑ | Other ingredients in coffee/tea may offset the effect of CAF | 2023 | [81] |
Hypertension | 6076 humans (elderly hypertensive patients aged aged ≥65 years) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Risk of all-cause and cardiovascular mortality in patients with moderate CAF intake ↓ | Cohort limited to US country. | 2022 | [82] |
Hypertension | 29,985 human subjects (post-menopausal normotensive women aged 50–79 years old) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Caffeinated coffee, decaffeinated coffee, and CAF are not associated with risk of incident hypertension | Other ingredients in coffee/tea may offset the effect of CAF | 2016 | [83] |
Hypertension | 31 human subjects (men): 20 subjects at low risk and 11 at high risk for hypertension | CAF (3.3-mg/kg) | CAF + stress increased cortisol levels and blood pressure; CAF intake increased mean systolic blood pressure in 46% of high risk subjects | Small-size cohort groups. Gender biased. | 2000 | [85] |
Hypertension | 52 human subjects (26 men and 26 women aged 18–29) with family history of hypertension | CAF (3.3-mg/kg) | Systolic blood pressure during stress response ↑; Stress interacted with CAF and sex altering cortisolm fibrinogen, systolic blood pressure | Small-size cohort groups. | 2013 | [86] |
Hypertension | 8780 human subjects | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Risk of hypertention was lower for subjects consuming 1–3 cups/day compared to non-coffee drinkers | Self-reported data on dietary intake and coffee consumption may have resulted in some misclassification and residual confounding | 2021 | [87] |
Hypertension | 19,133 human subjects (Taiwanese adults aged 30–70) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Subject carrying cytochrome P450 1°2 rs762551 AC + CC genotype was associated with lower risk of hypertension | Cohort limited to Taiwan country | 2021 | [88] |
Hypertension | 98,765 human subjects (aged 40–69) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Moderate consumption of unsweetened was associated with a lower risk of hypertension | Comorbidities that accompany a new diagnosis of hypertension were not considered | 2024 | [89] |
Hypertension | 453,913 human subjects (207,324 men and 246,589 women aged 39–74) | Daily coffee and caffeinated products consumption (food-frequency questionnaire); assumption of 75 mg of CAF/cup of coffee and 40 mg of CAF/cup of tea | Hypertensive patients who drank 0.5–1 cup/day displayed the lower risk of dementia | Self-report of coffee and tea consumption at baseline may be subject to information bias | 2024 | [90] |
Hypertension | 3010 human subjects (aged 13–17 with equal distribution between male and female) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | CAF consumption was not associated with alterations in blood pressure, dyslipidemia, glomerular hyperfiltration, albuminuria, or insulin resistance | The study was based on single-day recall questionnaires. Lack of longitudinal data on the participants in the study. No differentiation between different sources of CAF intake. | 2024 | [91] |
Hypertension | 18,914 human subjects (with pre-diabetes and diabetes, aged >20; average age 54.8 years; 9746 men, 9168 women) | 24-h dietary recall interviews | Pre-diabetic and diabetic subjects: increased CAF intake → reduced all-cause mortality; Pre-diabetic individuals: significant negative correlation between CAF intake and CVD events. | CAF intake levels were self-reported at baseline, which may result in a different level over long-term follow-up | 2024 | [92] |
Hypertension | 30 humans (athletic and non-athletic women, aged 18–30 years) | CAF (80–120 mg) | CAF consumption does not significantly affect blood pressure in either athletic or non-athletic women | Small-size cohort groups. Gender biased. | 2024 | [93] |
Hypertension | 12,093 human subjects (5687 men, 6406 women) | 24-h dietary recall interviews; CAF (100–400 mg/day) | Moderate CAF intake may be beneficial for hypertensive patients | CAF intake was assessed based on a single day of the interview, which may not accurately represent the long-term intake patterns | 2024 | [94] |
3.2. Arrhythmia
3.3. Dyslipidemia
3.4. Acute Coronary Syndrome
3.5. Angina Pectoris
3.6. Heart Failure
3.7. Other CVDs
Type of CVD | Subjects of the Study | Source of CAF | Main Findings | Limitations | Year | Reference |
---|---|---|---|---|---|---|
Arrhythmia | 13 dogs | CAF | Dose-dependent arrhythmogenecity of CAF | Small-size group To be confirmed in human clinical trial. | 1997 | [95] |
Arrhythmia | 14 male wistar rats | CAF-sodium salicylate (15 mg/kg/min) | CAF triggered sinus tachycardia and ectopic beats of heart resulting in fatal ventricular fibrillation | Small-size group To be confirmed in human clinical trial | 1999 | [96] |
Arrhythmia | 34 adult male Japanese white rabbits | CAF (0.3 or 1.0 mg/kg per min) | CAF administration was correlated with an increased risk of ventricular tachycardia | To be confirmed in human clinical trial | 1996 | [97] |
Arrhythmia | 33,638 women | Daily coffee and caffeinated products consumption (median caffeine intakes across increasing quintiles of caffeine intake were 22, 135, 285, 402, and 656 mg/d, respectively) | High caffeine consumption was not associated with an increased risk of incident atrial fibrillation | Only two measures over years may miss short-term effects; limited to middle-aged, white, female health professionals, affecting generalizability to men or other female populations; limited statistical power to find associations in small beverage subgroups; no ECG screening: possibly missing undetected AF cases; difficult to accurately defining AF onset, potentially introducing small bias if the time of incidence is incorrectly specified | 2010 | [98] |
Arrhythmia | 57,053 Danish subjects (27,178 males and 29,875 females) aged 50–64 years | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Coffee consumption was inversely correlated with atrial fibrillation occurrence | No distinction between impacts of caffeinated or decaffeinated coffee; No information on brewing method or genetic polymorphism; Limited to cases with recorded hospitalizations or deaths for AF | 2016 | [99] |
Arrhythmia | 41,881 men and 34,594 women | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Coffee intake was not associated with atrial fibrillation incidence | AF cases in the cohort are symptomatic, possible bias introduced if patients with with first episode of less seious AF reduced coffe consumption; Assessment of coffee consumption can show some measurement error because it was assessed with self-administered questionnaire and only at baseline: no information on the type of coffee and preparation method | 2015 | [100] |
Arrhythmia | 130,054 human subjects | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Inverse association between coffee and CAF intake and hospitalization for arrhythmias | No data about follow-up coffee use; Incomplete caffeine data: no data about circumstances leading to hospitalization, coffee preparation method, cup size, and time of day for the coffee intake | 2011 | [101] |
Arrhythmia | 1416 human subjects (44.1% men, 55.9% women) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | No relationship between chronic consumption of caffeinated products and ectopy | No evidence of a clinically large effect; Patients self-reporting; absence of total caffeine quantification; no discrimination among amounts of daily consumption | 2016 | [102] |
Arrhythmia | 51 patients with moderate-to-severe left ventricular systolic dysfunction (37 men; 14 women, mean age 60.6 years) | CAF (total of 500 mg during a 5-h protocol) | No significant association between CAF intake and the incidence of ventricular and supraventricular premature beats | Small-size cohort groups. | 2016 | [103] |
Arrhythmia | 101 patients presenting for regadenoson stress myocardial perfusion imaging | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | No significant association between use of CAF and arrhythmia was detected | Patient self-reporting | 2020 | [104] |
Arrhythmia | 47,949 human subjects aged 50–64 years (22,533 men and 25,416 women) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | No significant association between CAF intake with the incident of atrial fibrillation or atrial flutter was detected | Self-reported data on the consumption of caffeine; caffeine content change across brands | 2005 | [105] |
Arrhythmia | Animals and humans (meta-analysis) | CAF | Increased risk of ventricular premature beats in humans. Mean change of −2.15 mA in ventricular fibrillation threshold was detected in studies involving animals | Effects found in animal studies areprobably the result of excessive caffeine doses that are not consumed on regular daily basis in humans (35 mg/kg) | 2016 | [106] |
Arrhythmia | 18,983 and 6479 human subjects (meta-analysis) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | No association was identified for higher levels of caffeinated coffee intake (>1 cup per day). Average levels (1–7 cups/week) were found to be associated with a reduction in atrial fibrillation risk | Possibility of reverse causality in the association between coffee consumption and AF cannot be excluded | 2021 | [107] |
Arrhythmia | 449,563 human subjects(median 58 years, 55.3% females) | Daily coffee and caffeinated products consumption(0, <1, 1, 2–3, 4–5, and >5 cups/day) | Coffee consumption reduced CVD risk and reduction of all-cause death. Decaffeinated coffee decreased arrhythmia incidence. | Participant self-reporting; outcome assessment relied on ICD-10 codes; detection of certain arrhythmias may be missed; predominantly Caucasian population | 2022 | [108] |
Arrhythmia | 3835 human patients (Swiss-AF, n = 2387; Beat-AF, n = 1507) | “daily” and “not-daily” coffee consumers | Daily coffee intake was associated with a 23% lower hazard for major cardiovascular events | The main population of study was of European origin; coffee consumption was self-assessed by the patients; male patients are overrepresented | 2024 | [109] |
Arrhythmia | 449,563 human subjects; median age 58 years; 55.3% females, of which 100,510 (22.35%) were controls (non-coffee drinkers) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | 4–5 cups/day of ground coffee was associated with a significant reduction in incident arrhythmia including atrial fibrillation | Coffee consumption was self-reported; ICD-10 codes is susceptible to measurement and reporting errors; population of the study is predominantly Caucasian therefore study conclusions may not be entirely applicable to populations of other ethnicities. | 2023 | [110] |
Dyslipidemia | 96 4-week old male, Sprague-Dawley rats | Coffee (average amount of coffee intakes per rat: 0.12 g freeze-dried instant coffee/100 g body weight/d). | Triglycerides ↑ HDL cholesterol ↓ | Applying study results to athletes performance is difficult | 2013 | [115] |
Dyslipidemia | 60 humans (obese women aged 30–50 years) | Green coffee bean extract (500 mg) | Levels of total cholesterol ↓ | Small-size cohort groups. Short duration of the study. Gender biased. | 2019 | [116] |
Dyslipidemia | 1182 human subjects (meta-analysis, aged 18–70 years) | Daily coffee consumption | Serum levels of triglycerides ↑ Total cholesterol ↑ LDL ↑ | Small sample size; Different type and concentration of coffee; no enough evidence to assess effect of coffee consumption on HDL-C | 2020 | [117] |
Dyslipidemia | 1017 human subjects (meta-analysis) | Daily coffee consumption | Total cholesterol ↑ LDL ↑ Triglycerides ↑ Individuals affected by hyperlipidemia were more inclined to coffee-induced dyslipidemia effects | Bias in the meta-analysis of total cholesterol | 2012 | [118] |
Dyslipidemia | Humans (1987 subjects from Belgium and 900 subjects from Swiss; in both studies 53% of subjects were females) | CAF-derived metabolites plasma levels (methylxanthines) | Total cholesterol ↑ LDL ↑ Triglyceride levels ↑ | Population biased. No information about source of plasma methylxanthines source | 2021 | [119] |
Dyslipidemia | Human subjects (2527 men and 2371 women) | Daily coffee consumption | Female subjects: minor alleles of ADORA1 rs10800901, ADORA2B rs2779212, and ADORA3 rs2786967 → higher protective effects from coffee intake against dyslipidemia Male subjects: minor allele ADORA3A rs3393 → lower risk | Small-size cohort group; No information regarding amount of CAF consumed; Physical activity could influence the blood lipid profile | 2020 | [120] |
Dyslipidemia | 9876 human subjects | Daily coffee consumption | High plasma CAF levels may decrease adiposity and type-2 diabetes risk | Two-sample Mendelian randomization design; causal findings may not be applied to clinical or public health interventions; use of only two SNPs reduced analysis power; results may not be generalisable to non-European populations | 2023 | [121] |
Acute Coronary Syndrome | 103 human subjects with acute STEMI (males) | Coffee or decaffeinated coffee (352.5 ± 90 mg (4.7 ± 1.1 cups) of CAF per day and 4.5 ± 1.3 cups per day of decaffeinated beverage) | CAF can be considered to be safe regarding cardiovascular adverse effects | Small-size cohort group; post-STEMI dysrhythmias did not allow for the interpretation of 24-h HRV analyses | 2009 | [125] |
Acute Coronary Syndrome | 928 human subjects with acute coronary syndrome | Daily coffee and caffeinated products consumption | Moderate coffee intake was inversely correlated with total mortality | No information about brewing process or coffee type | 2021 | [126] |
Acute Coronary Syndrome | 1369 and 1902 human subjects (meta-analysis) | Daily coffee consumption | Intake > 2 cups/day was associated with a risk ratio of 0.54 | No information about brewing process or coffee type Publication bias | 2016 | [127] |
Angina Pectoris | 17 male rats | CAF (ranging 1 µg–1 mg) | CAF exposure boosts the release of prostacyclin (PGI2) which could be responsible for the beneficial effect of CAF in angina | Small-size group. To be confirmed in human clinical trial | 1994 | [133] |
Angina Pectoris | 17 male subjects with coronary artery disease | Daily coffee and caffeinated products consumption | 2 cups/day intake increased the exercise duration of 12% until angina onset | Small-size cohort groups. Gender biased. | 1985 | [134] |
Heart Failure | 14 male Sprague-Dawley rats | CAF 10 µg/kg/min | CAFenhances basal renin secretion by blocking intrarenal adenosine receptors and, in case of increased sympathetic activity, CAF boosts renin release in part by blockade of brain adenosine receptors, which results in enhanced central sympathetic tone | Small-size cohort groups. | 1996 | [138,139] |
Heart Failure | Seven male, 9-month-old SHHF/Mcc-facp rats; Seven 9-month-old SHRs eight 9-month-old normotensive WKY rats; Fifteen aged (14-month-old) male lean SHHF/Mcc-facp rats | CAF (10 mg/kg + 150 μg/min over 40 min) | 10 mg/kg CAF followed by 150 g/min over 40 min enhanced both heart rate and left-ventricular peak systolic pressure and enhanced plasmatic norepinephrine, epinephrine, and renin activity levels | Small-size cohort group Long-term studies are needed | 1999 | [140] |
Heart Failure | 10 human subjects (7 men, 3 women) | CAF (4 mg/kg) intravenously | CAF intake enhanced both exercise duration and performance | Small-size cohort group | 2006 | [141] |
Heart Failure | 20,433 men (mean age 66.4) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | No significant correlation between coffee and CAF intake and the risk of HF | CAF intake was based on participant self-reporting, with the attendant risk of reporting bias | 2020 | [142] |
Heart Failure | 140,220 human subjects (meta-analysis) | Daily coffee and caffeinated products consumption | 4 cups/day intake of coffee seems to be protective against HF | Other ingredients in coffee may offset the effect of caffeine | 2012 | [144] |
Heart Failure | 1668 human subjects (751 men, 917 women, aged 58.8–80.5) | Daily coffee and caffeinated products consumption (food-frequency questionnaire) | Introducing > 230 mg/day CAF present a reduced risk of heart failure, while CAF intake > 280 mg/day can reduce risk of cerebrovascular events and arrhythmic events | CAF intake was based on participant self-reporting, with the attendant risk of reporting bias | 2023 | [145] |
Hypothyroidism | 60 female Wistar albino rats | CAF 10 mg/kg/day in water via gavage for 2 months | CAF administration could improve thyroid and cardiac irregularities | Lack of dose dependent observations due to the use of a single concentration | 2025 | [146] |
Systemic vascular resistance | 77 infants (<32 weeks gestational age; 39 male and 38 female) | CAF citrate 5 mg/kg | CAF administration was associated with increased systemic vascular resistance and more negative tissue oxygenation-heart rate reactivity index values | Lack of continuous capnography monitoring | 2024 | [147] |
Cardiovascular Health | 11 women (mean age 24) | CAF 4 mg/kg | CAF intake did not induce any negative effects on the cardiovascular system | Small-size cohort group | 2023 | [148] |
Abdominal aortic calcification | 2548 adult subjects (age mean 58.71) | 24-h dietary recall interviews | Heavy coffee consumption (>390 g/day) was associated with higher abdominal aortic calcification scores among individuals with hypertension, diabetes, and CVDs | A causal relationship between coffee consumption and abdominal aortic calcification could not be considered due to the crosssectional study design | 2023 | [149] |
Liver sinusoidal endothelial cells defenestration | Primary rat LSECs | CAF (8 and 150 μg/mL) | LSECs porosity and fenestration distribution was affected by high CAF amounts. A dose-dependent rise in fenestration number was detected upon CAF treatment. | Very high doses of CAF | 2023 | [151] |
4. Caffeine Intoxication
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Campagna, R.; Vignini, A. The Role of Xenobiotic Caffeine on Cardiovascular Health: Promises and Challenges. J. Xenobiot. 2025, 15, 51. https://doi.org/10.3390/jox15020051
Campagna R, Vignini A. The Role of Xenobiotic Caffeine on Cardiovascular Health: Promises and Challenges. Journal of Xenobiotics. 2025; 15(2):51. https://doi.org/10.3390/jox15020051
Chicago/Turabian StyleCampagna, Roberto, and Arianna Vignini. 2025. "The Role of Xenobiotic Caffeine on Cardiovascular Health: Promises and Challenges" Journal of Xenobiotics 15, no. 2: 51. https://doi.org/10.3390/jox15020051
APA StyleCampagna, R., & Vignini, A. (2025). The Role of Xenobiotic Caffeine on Cardiovascular Health: Promises and Challenges. Journal of Xenobiotics, 15(2), 51. https://doi.org/10.3390/jox15020051