Caffeine (1,3,7-trimethylxanthine) is an alkaloid which act as a central nervous system (CNS) stimulant, that is naturally found in many different plants such as coffee beans, cocoa beans, tea leaves, guarana berries and the kola nut. It can also be artificially synthesized for use as a food additive, in dietary supplements, even medications in over the counter or pharmaceutical preparations where synthetic caffeine is identical to intrinsic or plant-derived caffeine. Many studies says that intake of caffeine in the safe dose range has been associated with a reduction in the risk of chronic diseases, especially cardiovascular disease. There is evidence that caffeine intake has both protective and negative effects on cardiovascular diseases, so we named caffeine as a double edge sword. In this review, we had explained about safe dose range of caffeine, positive and negative effects of caffeine in cardiovascular health.

1. EFFECT OF CAFFEINE IN CARDIOVASCULAR
HEALTH- A DOUBLE EDGE SWORD
PRESENTED BY,
1*D.E. NIRMAN KANNA,
Perfusionist Intern,
Department of Cardio-Thoracic and Vascular Surgery,
Meenakshi Academy of Higher Education and Research,
Chennai, Tamil Nadu.
CO- INVESTIGATOR,
2SUBBULAKSHMI PACKIRISAMY, MSc., (Ph.D.),
Assistant Professor,
Department of Pharmacology,
Meenakshi Ammal Dental College and Hospital,
Chennai, Tamil Nadu.

2. INTRODUCTION
Caffeine (1,3,7-trimethylxanthine) is an alkaloid which acts as a
central nervous system (CNS) stimulant that is naturally found in
many different plants such as coffee beans, cocoa beans, tea leaves,
guarana berries and the kola nut, etc…
Caffeine is a safe xanthine alkaloid for human consumption in a
wide range of doses, which has unique properties such as central
nervous stimulating effect, antioxidant properties, lipolytic and
diuresis-enhancing properties.

3. Cardiovascular disease (CVD) is one of the frequently diagnosed chronic disease in the world, which
remains the major cause of premature death and disability in humans. Recent studies suggests that the
prevalence rate of CVD was over 500 million people and ~20 million people died from CVD per year
which seriously reduced quality of life and increased the burden of disease for many families.
Many studies suggest that intake of caffeine in the safe dose range has been associated with a reduction
in the risk of chronic diseases, especially cardiovascular disease.
There is evidence that caffeine intake has both protective and negative effects on cardiovascular
diseases, so we named caffeine as a “Double Edge Sword.”
In this presentation, I am going to explain about safe dose range of caffeine, positive and negative
effects of caffeine in cardiovascular health.

4. SOURCE
 1 cup or 8 ounces of brewed coffee = 95 mg caffeine
 1 cup of instant coffee = 60 mg caffeine
 1 cup of black coffee = 95-140 mg caffeine
 1 cup of black tea = 47 mg caffeine
 1 cup of green tea = 28 mg caffeine
 1 cup of milk added tea = 32 mg caffeine
 100 grams of dark chocolate = 80 mg caffeine
 100 grams of chocolate = 43 mg caffeine

5. PHARMACOKINETICS AND PHARMACODYNAMICS OF CAFFEINE
Caffeine is absorbed within about 45 minutes after consuming and reaches it peaks in the blood
within 15 minutes to 2 hours.
Caffeine in beverages such as coffee, tea, soft drinks and chocolates is quickly absorbed in the
gut and dissolves in fat and water molecules in the body. It has the ability to cross blood brain
barrier (BBB) and reaches the brain.
Intake of insoluble fibers interferes with caffeine and delays the absorption in blood.
Caffeine is metabolized in the liver, but it can remain in the blood from 1.5 to 9.5 hours,
depending on various factors such as smoking which speeds up the metabolism of caffeine,
whereas pregnancy and oral contraceptives can slow down the breakdown process.
Caffeine has a half-life of approximately 6 h, and nearly 100% bioavailability.
 Consumption of caffeine more than 600mg/day is considering as unsafe dose which is associated
with adverse effects resulting in acute caffeine toxicity.

6. CAFFEINE TOXICITY
 Intake of 1.2 grams or more in a single dose causes caffeine toxicity.
 Intake of 10-14 grams at a single serve is consider as fatal dose.
 Caffeine intake up to 10 grams per day will cause convulsions and vomiting.
 Intake of 1 gram caffeine induce restlessness, irritability, nervousness, vomiting,
nausea, rapid heart rate, and tremors.
 Consumption of caffeine more than 600mg/day or 10 cups of coffee per day is
considering as unsafe dose which is associated with adverse effects resulting in
acute caffeine toxicity.

7. SAFE DOSE OF CAFFEINE
Intake of 100mg per day is consider as safe dose
of caffeine in pediatrics, geriatrics and pregnant
women.
For a healthy adults without any comorbidities
such as renal and liver impairments can intake
upto 300mg/day.

8. EFFECT OF CAFFEINE IN
CARDIOVASCULAR HEALTH

9. EFFECT OF CAFFEINE IN CVD
Endocarditis, coronary artery disease (CAD), cerebrovascular disease, peripheral artery disease (PAD),
and aortic atherosclerosis, rheumatic heart disease (RHD), and conduction system abnormalities are
the common cardiovascular diseases.
CAD causes decreased myocardial perfusion which leads to angina due to ischemia and can result in
myocardial infarction (MI) and heart failure.
Cerebrovascular disease is the entity associated with strokes, also termed cerebrovascular accidents
(CVA), and transient ischemic attacks (TIAs).
Peripheral arterial disease (PAD) is an arterial disease which is predominantly involving the limbs that
may result in claudication.
Aortic atherosclerosis is associated with thoracic and abdominal aneurysms. RHD is associated with
valvular heart diseases.
Consumption of caffeine 100 to 300 mg per day shows the protective effect in cardio vascular disease
(CVD).
Consumption of caffeine more than 600mg per day results in increased risk of CVD.

10. MECHANISM
• Caffeine blocks PCSK9 gene expression and PCSK9 protein
production in liver cells
• It prevents SREBP2 activation and the expression of PCSK9
in the liver cells
• It inhibits the secretion of PCSK9 proteins and increased
LDLRs
• This results in decreasing the LDL levels in the blood and
prevents deposition of LDL in arteries by increasing the
metabolism of LDL in liver.
Proprotein Convertase Subtilisin/Kexin Type 9
(PCSK9)
Sterol Regulatory Element-Binding Protein 2
(SREBP2)
Low Density Lipid (LDL)
Low Density Lipid Receptor (LDLR)

11. CORONARY ARTERY DISEASE (CAD) AND ACUTE MYOCARDIAL INFARCTION
Coronary artery disease is a condition in which there is an inadequate
supply of blood and oxygen to the myocardium, which results in hypoxic
and Ischemic damage of heart. It results from occlusion of the coronary
arteries and results in increased tissue perfusion demand (I.e., decreased
oxygen supply) It typically involves the formation of plaques in the lumen
of coronary arteries that impede blood flow results in myocardial
infarction (MI).
Many studies suggest that daily intake of caffeine (100mg/day) reduces
the risk of CAD, by improving endothelial function of blood vessels as
assessed by brachial artery flow mediated dilation but it has an
antagonizing effect on the coronary vasodilatory action of adenosine.

12. ATRIALARRHYTHMIAS
 Current evidence suggests that intake of caffeine in
optimum amount is safe and may even protect against
atrial arrhythmias, in particular atrial fibrillation (AF).
 The mechanism of caffeine against arrhythmias are due
to cardiomyocyte adenosine receptor antagonism and
antioxidant effects.
 A meta-analysis results that incidence of AF had been
decreased by 6% for every 300 mg/day increment in
caffeine intake.
Atrial fibrillation (AF)

13. CEREBROVASCULAR DISEASE
• Acute physiological effect of caffeine includes cerebral
vasoconstriction through adenosine receptor blockage,
• The high dose of caffeine consumption increases risk of stroke, by
the cerebral vasoconstriction effect which reduces the cerebral
blood flow results in Cerebrovascular accident (CVA).
• Patient with complains of CVA or who prone to CVA should avoid
consumption of caffeine.

14. HYPERTENSION
Many studies suggests that consumption of caffeine more than 100-400mg
per day results in either increased systolic blood pressure (SBP) or
increased both systolic and diastolic blood pressure (DBP) due to
vasoconstrictive effect.
Peoples with risk of hypertension should be avoid intake of caffeine
regularly because its magnitude of increasing SBP is high and sustained for
long time.
Even at moderate dose of caffeine can show this hypertensive effect

15. CONCLUSION
 We conclude that mild- moderate habitual consumption of caffeine per day, has the beneficial
effects on metabolic syndrome, coronary heart disease, arrhythmia, heart failure and
cardiovascular mortality.
Habitual coffee and tea consumption may be considered part of a healthy lifestyle and need not be
prohibited in patients with cardiovascular, but it should be avoided in patients with hypertension,
stroke and pregnant women.
Consumption of caffeine more than the safe dose causes constriction of blood vessels in the
uterus and placenta, which could reduce the blood supply to the fetus and inhibit growth of fetus.
Consumption of caffeine even 200mg per day is consider as toxic in pregnant women.

16. REFERENCES
1. Osz BE, Jîtcă G, Ștefănescu RE, Pușcaș A, Tero-Vescan A, Vari CE. Caffeine and Its Antioxidant Properties-It Is All about Dose and Source. Int J Mol Sci. 2022 Oct 28;23(21):13074. doi:
10.3390/ijms232113074. PMID: 36361861; PMCID: PMC9654796.
2. Zheng H, Lin F, Xin N, Yang L, Zhu P. Association of Coffee, Tea, and Caffeine Consumption with All-Cause Risk and Specific Mortality for Cardiovascular Disease Patients. Front Nutr.
2022 Jun 23; 9:842856. doi: 10.3389/fnut.2022.842856. PMID: 35811963; PMCID: PMC9261910.
3. Chieng D, Kistler PM. Coffee and tea on cardiovascular disease (CVD) prevention. Trends Cardiovasc Med. 2022 Oct;32(7):399-405. doi: 10.1016/j.tcm.2021.08.004. Epub 2021 Aug 9.
PMID: 34384881.
4. de Vreede-Swagemakers JJ, Gorgels AP, Weijenberg MP, Dubois-Arbouw WI, Golombeck B, van Ree JW, Knottnerus A, Wellens HJ. Risk indicators for out-of-hospital cardiac arrest in
patients with coronary artery disease. J Clin Epidemiol. 1999 Jul;52(7):601-7. doi: 10.1016/s0895-4356(99)00044-x. PMID: 10391652.
5. van Dam RM, Hu FB, Willett WC. Coffee, Caffeine, and Health. NEJM. 2020 Jul 23; 383:369-378.
6. Harvard Education- The nutrition source of caffeine, https://www.hsph.harvard.edu/nutritionsource/caffeine/
7. Olvera Lopez E, Ballard BD, Jan A. Cardiovascular Disease. 2022 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30571040.
8. D.E. Nirman Kanna, Subbulakshmi Packirisamy, Deepa Rajendiran. (2023). Current updates on angina pectoris- A deadly oxygen thirst of the heart. Dr. R.B. Tripathi, Dr. Kena P.Anshuman,
D.E. Nirman Kanna. (Eds), Current Research in Life Sciences. India: Thanuj International Publishers.
9. Shahjehan RD, Bhutta BS. Coronary Artery Disease. 2022 Nov 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 33231974.
10. G.M. Agudelo-Ochoa, I.C. Pulgarin-Zapata, C.M. Velasquez-Rodriguez, M. Duque-Ramirez, M. Naranjo-Cano, M.M. Quintero-Ortiz, O.J. Lara-Guzman, K. Munoz-Durango
11. Coffee consumption increases the antioxidant capacity of plasma and has no effect on the lipid profile or vascular function in healthy adults in a randomized controlled trial,
J. Nutr., 146 (3) (2016), pp. 524-531.
12. H.N. Ahmed, E.B. Levitan, A. Wolk, M.A. Mittleman, Coffee consumption and risk of heart failure in men: an analysis from the cohort of Swedish men.
13. Brown JC, Gerhardt TE, Kwon E. Risk Factors For Coronary Artery Disease. 2022 Jun 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32119297.
14. Atrial fibrillation. Nat Rev Dis Primers. 2022 Apr 7;8(1):20. doi: 10.1038/s41572-022-00354-w. PMID: 35393431.
15. Inoue-Choi M, Ramirez Y, Cornelis MC, Berrington de González A, Freedman ND, Loftfield E. Tea Consumption and All-Cause and Cause-Specific Mortality in the UK Biobank: A
Prospective Cohort Study. Ann Intern Med. 2022 Sep;175(9):1201-1211. doi: 10.7326/M22-0041. Epub 2022 Aug 30. PMID: 36037472.
16. Chen S, Li J, Gao M, Li D, Shen R, Lyu L, Shen J, Shen X, Fu G, Wei T, Zhang W. Association of caffeine intake with all-cause and cardiovascular mortality in elderly patients with
hypertension. Front Nutr. 2022 Dec 20; 9:1023345. doi: 10.3389/fnut.2022.1023345. PMID: 36606229; PMCID: PMC9807616.
17. Batista P, Rodrigues PM, Ferreira M, Moreno A, Silva G, Alves M, Pintado M, Oliveira-Silva P. Validation of Psychophysiological Measures for Caffeine Oral Films Characterization by
Machine Learning Approaches. Bioengineering (Basel). 2022 Mar 11;9(3):114. doi: 10.3390/bioengineering9030114. PMID: 35324803; PMCID: PMC8945337.