Caffeine and Arrhythmias: A Critical Analysis of Cardiovascular Responses and Arrhythmia Susceptibility

Abstract

Caffeine is a frequently consumed stimulant in different foods and beverages: coffee, tea, chocolate, sodas, and energy drinks. While its effects on the cardiovascular system have been extensively studied, there remains controversy surrounding its potential risks, particularly in patients with heart disease. This review provides a complete overview of caffeine’s pharmacological properties, sources, and cardiovascular effects, particularly emphasizing its arrhythmogenic potential. The proarrhythmic potential of caffeine, particularly on atrial fibrillation and ventricular arrhythmias, is conducted. It explains the mechanism of action, including adenosine receptor antagonism, phosphodiesterase inhibition, calcium mobilization, and catecholamine release of caffeine. Epidemiological evidence and mechanistic insights are provided for both conditions, and caffeine consumption’s incidence, triggers, and impact on premature ventricular contractions are explained. It emphasizes the need for more research to comprehend the complex relationship between caffeine consumption and cardiovascular health, specifically in high-risk populations.

1. Introduction

Caffeine, which is chemically known as 1,3,7-trimethyl xanthine, is the most widely used psychoactive compound, with 90% of people reporting the regular usage of caffeine, which makes it the psychostimulant that is most consumed mainly out of the total population of the world [1,2]. Coffee, tea, and cocoa plants are about 60 plant species that naturally contain caffeine, stimulating humans’ central nervous system (CNS). It is an ingredient in everyday drinks, including energy and soft drinks [3]. The primary cause of the overall rise in caffeine consumption is a growing population to a more significant extent. Certain nations like Italy, Ethiopia, and Brazil are seeing a rise in the per capita usage of caffeine. Caffeine intake per capita and the Human Development Index (HDI) and Gross Domestic Product (GDP) showed a strong positive link for European nations that import coffee. In contrast, a strong negative correlation was observed for African countries that export coffee [4]. Consuming caffeine improves mental function, physical strength, alertness, and focus [5,6]. After acute ingestion, caffeine has an average half-life of 2.5–5 h. However, this can vary based on several factors, including the quantity consumed, smoking, genetic variation, health state, use of oral contraceptives, pregnancy, and other conditions [7]. Chronic coffee drinking has also been linked to a lower risk of cardiovascular disease (CVD), which includes heart failure, stroke, and coronary heart disease (CHD) [8]. There is a chance that caffeine use will have harmful psychological and physical repercussions. Overindulgence in caffeine is linked to exacerbating anxiety symptoms and sleep difficulties, aggravating psychotic symptoms and violence, and raising the risk of stroke [9].

There is ongoing controversy on the link between caffeine consumption and the risk of cardiovascular disease. Caffeine ingestion in the form of coffee or a tablet has an immediate negative impact on blood pressure (BP) and stiffness in the arteries. As coffee is consumed, BP rises sharply in those not susceptible to it [10]. According to recent data, there were over 500 million cases of CVD worldwide and around 20 million deaths annually from the disease, which significantly lowered life expectancy and raised the financial burden of illness on many families [11]. Consuming excessive amounts of caffeine can stimulate the central nervous system, raising sympathetic nerve activity and catecholamine concentrations in the blood [12]. The principal dietary source of caffeine, coffee, has been linked to favorable relationships with reduced risk of CVD, type 2 diabetes mellitus (T2DM), and all-cause and cardiovascular mortality in previous observational studies and meta-analyses. Comparable outcomes for CVD, such as coronary artery disease (CAD), have also been observed [13]. Adenosine is a coronary vasodilator, and its acute antagonism by caffeine impairs the expected increase in myocardial flow during exercise. It has been shown in some studies to attenuate adenosine-induced hyperemia fractional flow reserve measurements during coronary angiography [14]. According to the survey conducted by Chieng et al., using instant, ground, and decaffeinated coffee types, especially at 2–3 cups a day, was linked to a significant decrease in the incidence of CVD and death. Coffee that was high in caffeine but not decaffeinated was found to reduce arrhythmia [15]. Carlsson et al., comparing the coronary flow reserve (CFR) on MRI 12 and 24 h after caffeine ingestion, showed a remarkably lower CFR at 12 h caffeine abstinence than at 24 h [16]. The US Dietary Guidelines Advisory Committee (2015) proposed that consuming coffee up to five cups daily could benefit health and be considered a healthy diet component [17]. According to the results of a study with 20,487 people from Italy, moderate coffee drinking (3–4 cups per day) was linked to a lower risk of death from CVD. Furthermore, it was discovered that coffee consumption and NT-proBNP levels—the N-terminal portion of the B-type natriuretic peptide, which is linked to a high risk of stroke—correlated negatively [18]. Consequently, the majority of studies have found that moderate coffee or caffeine consumption has possibly positive and even protective effects on CVD, despite some studies linking high consumption to an elevated risk of CVD.

The primary objective of this review paper is to explore and analyze the cardiovascular effects of caffeine, with a particular focus on its potential to induce or exacerbate arrhythmias. Given the widespread consumption of caffeine in various forms, including coffee, tea, and energy drinks, it is crucial to understand its impact on cardiovascular health, especially concerning its arrhythmogenic potential. The review aims to synthesize existing research to evaluate how caffeine influences heart rate, blood pressure, and overall cardiac function. Additionally, it seeks to identify specific populations that may be more susceptible to the arrhythmogenic effects of caffeine, such as individuals with pre-existing cardiovascular conditions or genetic predispositions. The review also intends to provide insights into safe consumption levels and potential risk factors associated with caffeine intake by examining the mechanisms through which caffeine may contribute to arrhythmias. Ultimately, the paper aims to contribute to the broader understanding of caffeine’s cardiovascular effects and to inform clinical recommendations and public health guidelines regarding its consumption.

1.1. Search strategy

We searched two primary international data sources, PubMed and Embase, to assess all available evidence. We also checked the references for the included papers to ensure related studies are included. Figure 1 shows the article selection criteria for the present review.

Fig. 1.

Article selection criteria.

2. Pharmacological properties of caffeine

Caffeine is a methylxanthine derivative with a chemical formula of C₈H₁₀N₄O₂ and a molecular mass of 194.19°g/mol. It is an alkaloid molecule as it is a product of nitrogen metabolism [19,20]. The molecular structure of caffeine is depicted in Fig. 1. In its pure state, it exists as a white, odorless, fat- and water-soluble powder [21]. Caffeine shares consubstantial structural similarities with adenosine, a purine nucleoside comprising adenine and ribose [22].

Caffeine has various biochemical targets and different mechanisms that exert its effects, including adenosine receptor antagonism, phosphodiesterase inhibition, calcium mobilization, and catecholamine release [19]. Adenosine is believed to assist the regulation of sleep–wake cycles by interacting with high-affinity A1 and A2A receptors expressed in different brain areas. It may have varied functions in regulating and controlling sleep [23]. Each of the four P1 adenosine receptor subtypes are favored by caffeine. A2A and A2B receptors promote the activity of adenylate cyclase (AC) and raise intracellular cyclic adenosine monophosphate (cAMP) levels, whereas A1 and A3 receptors are negatively linked to AC and lower the concentration of cAMP. The central stimulating action of caffeine is explained by antagonizing adenosine receptors. It has been demonstrated that A2A agonists have pronociceptive effects, with an increase in cAMP levels directly correlated with pain severity. Furthermore, vasodilatation is brought on by the activation of A2A receptors in the pial artery, and this could lead to migraines and headaches. Caffeine is therefore used to counteract these effects in treating migraines [24,25]. Caffeine reduces memory deterioration in the aging brain, with A2A receptor antagonism being a mechanism responsible for caffeine’s beneficial impact on hippocampal long-term potentiation (LTP) associated with memory [26].

Caffeine is a non-specific/broad-spectrum phosphodiesterase inhibitor [27]. Phosphodiesterase is responsible for breaking down cAMP. Caffeine inhibits phosphodiesterase activity at higher doses. Caffeine also inhibits phosphodiesterase, which raises intracellular cAMP. It is well known that elevated intracellular cAMP levels promote neurotransmitter release. This will result in cAMP buildup and stop the cAMP breakdown. cAMP is one crucial intracellular second messenger in multiple signal transduction pathways for numerous biological processes. For example, the level of cAMP rises when coffee is present. High cAMP levels activate adipose tissue’s hormone-sensitive lipase and are necessary for lipolysis. As a result, caffeine encourages lipolysis, which releases glycerol and fatty acids. Additionally, research shows that caffeine enhances the turnover of several monoamine transmitters with CNS stimulatory effects, including dopamine, noradrenaline, and 5-hydroxytryptamine [19,28].

Caffeine’s initial suggested mode of action was intracellular calcium (Ca++) mobilization. The mechanisms by which caffeine affects the cardiovascular system include its capacity to raise catecholamine levels and release intracytoplasmic Ca++, which in turn affects myofilament contraction and electrical conduction [29]. It mobilizes Ca++ stored in the endoplasmic reticulum, leading to changes in nerve cell function, neurotransmitter secretion, and muscle contraction. Caffeine acts on ryanodine receptors, increasing intracellular Ca++ concentration in cardiac and skeletal muscle. This Ca++ concentration increases muscle contraction force [20]. Caffeine promotes the translocation of Ca++ across the plasma membrane and obstructs the absorption and retention of calcium in the sarcoplasmic reticulum of striated muscle cells at high concentrations (1–10 mM). As caffeine binds to ryanodine receptors in calcium channels in the brain and muscles, it raises myofilament sensitivity to Ca++. Caffeine also causes the sarcoplasmic reticulum to release Ca++ in cardiac and skeletal muscles. Supplementing with caffeine is correlated with higher Ca++ flow in a dose-dependent way; only levels exceeding 8 mg kg·bw–1 appear to successfully increase the sensitivity to Ca++ and its release, leading to gains in muscular strength [30].

In addition to increasing neuronal activity, releasing brain dopamine, norepinephrine, and serotonin, and raising circulatory catecholamines, caffeine competitively inhibits the A1 and A2A receptors [31]. One of the principal catecholamines of the sympathetic nervous system that coffee can boost is norepinephrine, released during stress responses. Research has demonstrated that the oxidation of catecholamines produces extremely hazardous compounds such as free radicals and aminochromes (such as adrenochrome), which act on myocellular membranes to induce intracellular Ca++ excess and damage to cardiac cells. Catecholamines stimulate the adrenergic receptors through the beta-adrenoceptor-adenylylcyclase-protein kinase pathway [32]. The high activation of β1 receptors caused by inhibiting adenosine cardiac receptors is the mechanism behind the arrhythmic action. Catecholamines’ impact on the density of β-adrenoceptors is a significant characteristic that can have varying effects on cardiac function based on receptor selectivity. Sympathetic activation of the myocardium may be enhanced by catecholamine-mediated increases in the total population, interaction capacity, and sensitivity of β1-adrenoceptors [29].

2.1. Pharmacokinetics and metabolism

The pharmacokinetics of caffeine refers to the processes of absorption, distribution, metabolism, and elimination in the body, which have been extensively studied [33]. Table 1 shows the pharmacokinetic properties of caffeine. Pharmacologically, caffeine is broadly dispersed throughout the body and quickly absorbed in the gastrointestinal tract. Nonetheless, the chemical and physical characteristics, pH, and mode of caffeine administration may impact its absorption [34]. The pharmacokinetics of caffeine indicate quick and thorough intestinal absorption. Because of its lipophilic characteristics, it can pass through both the biological membrane and the blood–brain barrier (BBB). Coffee inhibits the decarboxylase enzyme, which slows down the conversion of l-DOPA into dopamine (DA). Coffee’s inhibitory mechanism prolongs the half-life of l-DOPA in the brain and makes it easier for levodopa to be distributed to brain tissues through active transport. l-DOPA has a half-life of 60–90 min, but if it is provided after consuming more than two cups of coffee, the half-life will be more than quadruple [35]. Furthermore, due to the isoenzyme CYP1A2, which is in charge of caffeine metabolism, becoming saturated at larger dosages, there is a correlation between poorer clearance and caffeine [29].

Table 1.

Pharmacokinetic properties of caffeine.

Absorption	Parameters
Oral bioavailability	Up to 100%
tmax	0.5–2 h
Cmax	Up to 8–10 mg/L
Distribution
Volume of distribution	0.6 L/kg
Plasma protein binding	10%–36% (in vitro)
Half-life	Five hours (to be varied)
Metabolism
Enzymes of metabolism	CYP1A2, xanthine oxidase, N-acetyltransferase 2 (NAT2)
Key metabolites	Theobromine, theophylline, paraxanthine, 1-methylxanthine, 3,7-dimenthyluric acid
Elimination
Excretion	Renal (metabolites) caffeine is reabsorbed in the tubules
Clearance	0.078 L/kg/h (to be varied

t_max: time of peak plasma concentration, C_max: maximum plasma concentration.

The liver is the site of the intricate caffeine metabolism, involving multiple N-demethylations and a C-8 oxidation by CYP1A2, N-acetyltransferase, or xanthine oxidase to produce metabolites with varying pharmacological effects [32]. Moreover, caffeine stimulates microsomal enzymes, which promote both its own and other medicines’ metabolism. In light of the premature development of the hepatic microsomal system, newborns have a limited ability to metabolize caffeine. Concomitant drugs, smoking, and pregnancy all have a substantial impact on the metabolism of caffeine [28]. In the first step, the caffeine is subjected to 3-demethylation by cytochrome P450 isoform 1A2 (CYP1A2), leading to the formation of its primary metabolite 1,7-dimethylxanthine. Following this, the paraxanthine undergoes 1- and 7-demethylation, also catalyzed by CYP1A2, which consequently leads to the formation of 3,7-dimethylxanthine and 1,3-dimethylxanthine. A small proportion of the ingested caffeine (0.5–4.0%) is excreted in urine and bile without changing (Fig. 2) [21,36].

Fig. 2.

Pharmacokinetics of caffeine.

3. Sources of caffeine

More than sixty-three plant species’ seeds, leaves, and fruits naturally contain caffeine. Usually found in coffee and tea, it can also be found in yerba mate (eaten with boiling water in South America), guarana seeds (mainly used for soft drinks in Brazil), and kola nuts (chewn in Africa) [37]. Yerba mate is derived from the dried leaves of the Ilex paraguariensis shrub or tree, which can grow up to 15 m tall. It is particularly popular in countries such as Argentina, Paraguay, and Uruguay. It is often considered a healthier alternative to coffee and traditional teas due to its unique combination of caffeine and other beneficial compounds. Guarana seeds come from the Paullinia cupana plant. These seeds contain 3.6%–5.8% caffeine by weight and have been utilized for their stimulant properties for centuries, especially by indigenous tribes. In addition to caffeine, guarana seeds contain other stimulants such as theobromine and theophylline, as well as antioxidants like tannins, saponins, and catechins. Caffeine content varies significantly in brewed beverages depending on the type of plant and brewing method employed. Medications for headaches, colds, and allergies, both over-the-counter and prescribed, can include caffeine [19]. For instance, a single serving of brewed coffee can contain anywhere from 70 to 280 mg of caffeine, contingent on factors like the brand and preparation method [20]. One of the primary sources of caffeine is coffee, which also contains various other chemicals that impact human health. These include diterpenes 30, caffeic acid, trigonelline, caffeine, and chlorogenic acid [32]. It is obtained from the roasted coffee beans of Coffea arabica L. and Coffea canephora Pierre ex Froehner, belonging to the Rubiaceae family [21]. Coffeae semen, Theae folium, Colae semen, Mate folium, Guarana, and small amounts of cacao semen are the primary natural sources of caffeine. Caffeine levels in coffee beans vary depending on several factors (genetic, environmental, agronomic, etc.), but they typically range from 1.2% to 2.5% in C. arabica and 1.7%–2.5% in C. canephora [24]. Additionally, sources other than commonly ingested coffee and caffeine tablets—like caffeinated gums, mouthwash, sprays, powders, energy-boosting gels, etc.- have drawn attention recently [38]. The possible health effects of regularly consuming these caffeine-containing beverages are attracting more and more attention from the general public and scientific community [39]. The content of caffeine in common medications is represented in Table 2.

Table 2.

Common medications containing caffeine.

Pain Relievers	65–130 mg per dose
Excedrin
Anacin
Cold and allergy medications	30 mg–200 mg per dose
Alka-Seltzer XS
Tylenol Ultra
Stimulants	50 mg–200 mg
Excedrin
Anacin
Fioricet
Vivarin
Caffeine supplements	100 mg–200 mg per tablet

4. Effect of caffeine on the cardiovascular system

Energy drinks are touted as having more endurance and improving mental and physical performance, but they contain a lot of caffeine. Energy drinks such as Red Bull, monster energy, 5-h Energy, Celsius Heat, Rockstar Energy, Bang Energy, NOS Energy Drink, AMP Energy, Full Throttle, Bawls Guarana, Power horse, Power horse red rush, Cellucor C4 Carbonated Energy Drink, Boom Boom etc. vary in caffeine content, with most offering between 80 mg and 300 mg per serving. The primary components are artificially created caffeine, sugar, taurine, and glucuronolactone. Vitamins (niacin, pantothenic acid, B6, B12), flavorings, and colorants (riboflavin, caramel) are also included, along with isosorbol. Research on energy drinks has also revealed that, depending on how much caffeine they contain, they raise heart rate and BP. An increased cardiac workload may result from acute hemodynamic changes in BP, heart rate, and peripheral vascular resistance. Adverse cardiovascular events may also be caused by endothelial cell dysfunction and proagregatory potential [40]. Reduced vascular responsiveness, pro-adhesion, pro-thrombosis, pro-inflammation, pro-adhesion, and growth acceleration are all associated with endothelial cell failure or abnormal function [41].

Due to its vasoconstrictor properties, caffeine can raise blood pressure by reducing blood vessel lumen at high concentrations [42]. Except for an instantaneous BP elevation that occurs quickly after coffee consumption, most observational data regarding peripheral blood pressure seldom supports a long-term influence of coffee on rising blood pressure. Even after accounting for several CV risk variables, regular light and moderate coffee drinkers demonstrated lower arterial rigidity parameter values as well as peripheral and central blood pressure compared to non-habitual coffee users [43]. It is believed that caffeine stimulates the sympathetic nervous system, which raises peripheral vascular resistance and affects arterial stiffness [44]. Endothelium cells preserve endothelial function by secreting several vasodilators, including nitric oxide (NO) and endothelium-derived hyperpolarising factor, endothelium cells preserve endothelial function. Since caffeine functions as a NO stimulator, NO inhibitor, and blocker of NO second messenger cyclic guanosine monophosphate (cGMP) breakdown, its effect on endothelial function is more complicated [45]. Cardiovascular risk factors affect endothelial function in the early stages of atherosclerosis and vascular smooth muscle activity in the advanced stages of the disease (Fig. 3) [46].

Fig. 3.

Caffeine effect on the cardiovascular system.

5. Caffeine and arrhythmias

The activation of the sympathetic nervous system, particularly when consuming high amounts of coffee, may be linked to the risk of arrhythmias. Coffee consumption lowers the blood level of uric acid, which has proarrhythmic characteristics [47]. Caffeine treatment showed a minimal impact on refractory periods. An enhanced spatial dispersion of repolarisation, which may be seen at ten μMcaffeine, enhances the proarrhythmic effect of caffeine and encourages re-entry [48]. Catecholamine-induced activity has been proposed as a proarrhythmic mechanism of caffeine. Caffeine accentuates catecholamine release and sensitizes dopamine receptors in the myocardium. It also inhibits phosphodiesterase with increased accumulation of intracellular cyclic adenosine monophosphate, which enhances the catecholamine-mediated effect [49]. Fig. 4 shows the proarrhythmic potential of caffeine.

Fig. 4.

Proarrhythmic potential of caffeine.

The most common self-reported triggers in symptomatic atrial fibrillation (AF) patients are alcohol, caffeine, exercise, and lack of sleep, with vagal triggers tending to cluster together within individuals. Women are more often symptomatic, with a relative risk of asymptomatic AF of 0.57 compared to men, and have worse quality of life [50]. Numerous epidemiological studies conducted over the years have indicated that caffeine consumption may reduce the chance of developing AF. Large-scale observational investigations have demonstrated that persons who consume moderate levels of caffeine, as opposed to those who consume less or abstain totally, may be at lower risk of AF. These results point to a potential cardiac rhythm-protecting effect of caffeine. Furthermore, a few clinical investigations have failed to find a conclusive link between caffeine intake and a person’s chance of developing AF [51]. Studies reveal that the incidence of AF falls by 6% for every 300 mg/d increase in habitual intake of caffeine. The reduction in caffeine consumption is 11% for moderate levels and 16% for high doses. Those who drank less than 2 cups of coffee (12 ounces of coffee, or around 140 mg of caffeine) had a higher chance of developing AF than those who drank more. Conversely, AF incidence was less likely when daily caffeine intake was more than 436 mg. According to the Physicians Health Study, males consuming 1 to 3 cups of coffee in a day had a lower risk of atrial fibrillation [52]. Recent developments in cardiology have led to the discovery of numerous cellular and molecular pathways that imply inflammation has a role in the etiology of AF. Angiotensin II (AngII) promotes the recruitment of immune cells and the synthesis of proinflammatory cytokines in response to inflammatory stress. In the activation of the mitogen-activated protein kinase (MAPK)-mediators of AngII/AT1R and the consequent expression of the pro-fibrotic transforming growth factor beta 1 (TGFβ1), leading to fibroblast differentiation, the involvement of AngII has also been demonstrated in the fibrosis and structural remodeling of the heart tissue. Moreover, several renin and angiotensin gene polymorphisms and elevated pressure overload mediate the production of AngII and the stimulation of AngII receptors. AngII has been associated with nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) Oxidase [(NOX)] activation and oxidation-related irregularities in calcium handling, ultimately leading to the atria’s electric remodeling. Furthermore, NOX is a potent activator of nuclear factor-κB, a transcription factor that directly impacts the promoter regions of sodium channels, downregulating them and encouraging AF mechanics [52].

Caffeine is generally considered a potential trigger for cardiac arrhythmias in clinical practice. Table 3 represents the caffeine impact on the risk of arrhythmias. High-dose caffeine has been shown experimentally to induce ventricular tachyarrhythmias (VT) and deaths [53]. Prior animal research demonstrated that caffeine consumption at an average or high dose did not cause ventricular arrhythmias; caffeine at a hazardous level did. According to a study, individuals who had VT or ventricular fibrillation did not see a change in the inducibility of ventricular arrhythmia when they consumed 275 mg of caffeine orally. According to a study, individuals suffering from heart failure with reduced ejection fraction did not experience arrhythmias when they orally consumed 500 mg of coffee. While intravenous caffeine treatment did not cause ventricular arrhythmia, it did cause the right ventricle’s refractory time in patients with heart conditions and healthy volunteers to shorten by approximately 10 ms. According to this earlier research, modest consumption of oral caffeine alone does not appear to impact ventricular arrhythmias [54]. In individuals with structural heart disease (SHD), reentry is the primary mechanism responsible for ventricular arrhythmias. Reentry is most commonly engaged in prolonged VT but can also occur in single premature ventricular contractions (PVCs). Since these zones are typically associated with the locations of origin of ventricular arrhythmias in patients with SHD, the construction of voltage maps showing areas of scar tissue can also be helpful [55]. VT is a wide QRS complex rhythm (≥120 ms) at ≥100 bpm that is often regular. Hemodynamic breakdown occurs when VT lasts more than 30 s [56].

Table 3.

Studies showing the impact of caffeine on arrhythmias risk.

Author	Study Type	N (Subjects)	Findings	References
Marcus G. M.	Prospective, randomized, Case-crossover trial	100	Avoiding caffeine did not lead to a notably higher daily rate of premature atrial contractions than did drinking caffeinated coffee	[63]
Casiglia E.	Prospective	1475	In the 12-year epidemiological prospective setting, a higher daily caffeine intake (>165 mmol/day or > 320 mg/day) is linked to a decreased risk of atrial fibrillation	[64]
Zuchinali P.	Double-blinded randomized clinical trial with a crossover design	51	Patients with systolic cardiac failure and those at high risk of ventricular arrhythmias did not have arrhythmias when they acutely consumed large quantities of coffee	[65]
Xu J.	Prospective study	5972	Coffee drinking that is sporadic but not habitual is linked to a slightly higher incidence of incident AF	[66]
Kim E. J.	Large, prospective, population-based community cohort study	3,00,000	There was no indication that the association between frequent coffee drinking and arrhythmia risk was influenced by genetically mediated caffeine metabolism	[67]
Abdelfattah R.	Meta-analysis	1,76,675	Reduced risk of AF when daily caffeine intake surpassed 436 mg. Caffeine use and the risk of AF are unrelated.	[68]

Atrial and ventricular ectopic beats are premature beats that are commonly occur in the general population specially in patients with SHD. Possible causes of these ectopic beats are cardiac, pulmonary, endocrinopathies, and behavioral/other factors. Cardiac causes include hypertension with left ventricular hypertrophy, heart failure, acute myocardial infarction, hypertrophic cardiomyopathy, and congenital heart disease [57]. PVCs have the potential to cause a reversible form of cardiomyopathy and can worsen symptoms, including palpitations and dyspnoea, which can impair quality of life. Caffeine exerts its effects primarily through its action as a central nervous system stimulant and its influence on cardiac physiology. It inhibits phosphodiesterase, leading to increased levels of cAMP, which enhances cardiac contractility and can increase heart rate [58]. A study found that oral caffeine intake significantly amplified the number of PVCs during procedures involving isoproterenol, a drug that increases heart rate and contractility. Patients who consumed caffeine before catheter ablation showed a marked increase in PVC frequency compared to those who did not [54]. In a randomized trial, participants who consumed coffee showed a 54% increase in PVCs compared to those who avoided caffeine. Interestingly, this effect was more pronounced in individuals with faster caffeine metabolism, suggesting that genetic factors may influence how caffeine affects heart rhythm [59]. Three basic electrophysiologic mechanisms are responsible for the generation of these PVCs, including automaticity, triggered activity, and reentry. Most often, increased intracellular calcium mediates after-depolarizations, which in turn causes triggered activity. Early after depolarizations, which occur during the action potential’s plateau phase, typically originate from prolonged repolarisation. These PVCs can cause Torsades de pointes in those who have acquired or congenital long-QT syndrome. Delayed after depolarizations, which happen at repolarised membrane potentials, are typical signs of catecholaminergic polymorphic ventricular tachycardia or digitalis poisoning. It is well known that caffeine causes the sarcoplasmic reticulum to release calcium, which is delayed after depolarization. Diltiazem and verapamil are non-dihydropyridine calcium channel blockers that may prevent PVCs by lowering cytosolic calcium buildup through L-type calcium channel blocking. In contrast with a triggered mechanism, PVCs arising from automaticity may exhibit parasystole. Here, the PVCs will march through at the same cycle length, independent of the underlying rhythm. It is important to note that the absence of a PVC may occur intermittently because of ventricular refractoriness related to the separate underlying rhythm. Therefore, multiples of the parasystolic PVC interval should be considered before automaticity is excluded. Although reentry is usually considered most pertinent to sustained arrhythmias, it can play a role in single PVCs. Reentry requires two distinct electric pathways and either a transient or permanent unidirectional block in 1 limb. Those pathways may be anatomically quite different, such as a suitable ventricular PVC blocking in the retrograde limb of the right bundle (commonly attributable to phase 3 block), crossing the ventricular septum through cardiomyocytes, conducting in a retrograde fashion up the left bundle, and then continuing down the right bundle, producing a bundle-branch reentry complex (recognized as having a typical, usually left, bundle-branch block appearance) [60–62]. When taken orally, caffeine may also raise the frequency of PVCs. A modest dosage of 5 mg/kg, or two to three cups of coffee, may be consumed before, during, or after the process. The effects of caffeine on autonomic function and cardiac electrophysiology are diverse. Numerous complex elements, including intracellular calcium trafficking and autonomic activity, regulate the PVC frequency [54]. A study concluded that caffeine consumption and the prevalence of daily PVC were not related; however, more caffeine intake was associated with a higher risk of PVC. Among the limited studies highlighting a connection between coffee consumption and heart rhythm irregularities, one notable report revealed that a higher daily coffee intake was associated with a higher probability of PVCs observed during a 2-min electrocardiogram recording. Remarkably, a greater prevalence of PVC was associated with an elevated risk of heart failure.

6. Caffeine and sudden death risk

Moderate coffee consumption has been associated with a reduced risk of CVD events. However, higher intakes of caffeine, particularly from excessive coffee consumption, have been linked to an increased incidence of CVD. Specifically, each cup of tea consumed daily has been associated with a 4% increase in CVD risk, and for every 100 mg of caffeine consumed daily, there is a 14% increase in CVD risk [69]. According to a study, the odds of incident CVD were 7%, 11%, and 22% greater for decaffeinated, nonhabitual, and heavy coffee drinkers (more than 6 cups in a day) compared with light drinkers of coffee (1–2 cups in a day) after models accounting for demographic, lifestyle, anthropometric, health, and socioeconomic covariates in addition to baseline blood pressure. The U-shaped pattern primarily represented the relationship between incident CAD (6078 cases) and coffee consumption; however, the effect estimates for associations with fatal CVD (1892 cases) and stroke (2092 cases) were covered by significantly wider confidence intervals than those for CAD across all groups [70]. Since analgesics, CNS stimulant medications, and dietary supplements are more widely available in pharmacies, health stores, and online marketplaces, there has been a rise in the danger of caffeine intoxication. Caffeinated intoxication, often called “caffeinism” (a chronic toxicity state resulting from excessive caffeine use), is characterized by common symptoms such as anxiety, agitation, restlessness, sleeplessness, gastrointestinal disorders, tremors, psychomotor agitation, and, in rare cases, death. Caffeine intoxication symptoms might resemble those of affective disorders, including anxiety. When it comes to caffeine intake, athletes, mental health sufferers, and infants should all be given special consideration. Athletes use large amounts of caffeine to help them perform and project a positive image. However, because caffeine interacts with many psychiatric medications, its use in patients with mental illnesses should be regarded as a significant risk factor for potential intoxications. Lastly, it has been determined that infants are the final group of individuals for whom caffeine usage should be strictly avoided [71]. Observational studies have linked cardiovascular death to total homocysteine (tHcy). Drinking coffee is linked to tHcy, particularly when consuming large amounts of it [72]. A study shows a negative correlation between moderate coffee drinking and death from respiratory diseases. There is a strong inverse relationship between coffee consumption and mortality from non-CVD, non-cancer causes, which the inverse relationship between coffee and depression or mortality specific to respiratory diseases may have influenced. Increased tea drinking, defined as three cups (709.8 mL)/d) was linked to a lower risk of coronary heart disease, cardiac death, stroke, and overall mortality, according to a meta-analysis. According to a study, persons 70 years of age and beyond who drink tea regularly as part of a healthy habitual dietary pattern may have reduced risks of cardiovascular disease and all-cause mortality [73].

6.1. Clinical consequences

Individual tolerance to caffeine can vary significantly from person to person. This variability means that what may be a safe or beneficial amount of caffeine for one individual could lead to discomfort or health issues in another. Being informed about the caffeine content in different products is crucial for making educated dietary choices. For example, a standard cup of brewed coffee can contain anywhere from 95 to 200 mg of caffeine, while a typical energy drink may have even higher levels [74]. Caffeine is often sought after for its ability to provide a temporary energy boost and enhance alertness. Table 4 summarizes the caffeine content found in various products and natural sources.

Table 4.

Caffeine content in various products, natural sources, and medications.

Product/Source	Caffeine Content (mg per 100 mL or 100 g)
Brewed coffee	95–200
Espresso	212–270
Instant coffee	27–173
Black tea	20–60
Green tea	12–50
Soft drinks (Cola)	9–15
Energy drinks	30–50 (up to 500 in some brands)
Dark chocolate	43
Milk chocolate	20
Guarana powder	40–50
Caffeinated snacks	Varies (generally 10–50)
Dietary supplements	Varies (generally 30–200 per serving)

However, consuming too much can have several adverse effects, including anxiety, sleeplessness, and a fast heartbeat [75]. To mitigate these risks, moderation in caffeine consumption is generally advised. Health experts often recommend limiting caffeine intake to about 400 mg per day for most adults, roughly equivalent to four 8-ounce cups of brewed coffee. Caffeine can affect the metabolism of certain drugs, potentially enhancing or diminishing their effects primarily through its interaction with the cytochrome P450 enzyme system, particularly the CYP1A2 isoenzyme [76]. Table 5 shows the key drugs whose metabolism is influenced by caffeine.

Table 5.

Drugs metabolism affected by caffeine.

Drug Name	Effect of Caffeine on Metabolism
Clozapine	Increased plasma concentration by up to 97% when taken with caffeine.
Lithium	Elevated blood levels when consumed with caffeine, leading to enhanced effects.
Theophylline	Increased plasma concentration, which can enhance its effects as a bronchodilator.
Warfarin	Caffeine inhibits its metabolism, increasing anticoagulant effects.
Zolpidem	Caffeine modestly increases its concentration by 30–40%.
Melatonin	Increased bioavailability due to competitive inhibition of metabolism.
Dextromethorphan	Metabolism significantly inhibited, leading to prolonged effects.
Fluvoxamine	Higher blood concentration when taken with caffeine.
Mexiletine	Increased levels due to competitive inhibition by caffeine.
Ergotamine	Absorption and effectiveness may be altered by caffeine consumption.

Therefore, it is crucial for healthcare providers to routinely assess their patients’ caffeine intake, especially for those on medications that may interact negatively with caffeine. For instance, individuals with heart disease or those at risk for arrhythmias may need stricter limits on caffeine consumption. Personalized guidance can help patients make informed decisions that align with their health goals and conditions. Moderate caffeine consumption can be part of a healthy lifestyle for many individuals. By providing evidence-based, precise information, healthcare providers can encourage patients to make informed choices about caffeine consumption, ultimately supporting their overall well-being [77].

The relationship between caffeine consumption and arrhythmias is multifaceted. Few studies indicate a potential association between high caffeine intake and an elevated risk of arrhythmias, the evidence is far from conclusive and often inconsistent. This inconsistency can be attributed to several factors, including the specific type of arrhythmia being examined, individual susceptibility to caffeine, and the individual’s overall health status. While some studies indicate a potential association between high caffeine intake and an elevated risk of arrhythmias, the evidence is far from conclusive and often inconsistent. For instance, a large epidemiological study found that individuals consuming more than 320 mg of caffeine daily had a reduced incidence of atrial fibrillation compared to those with lower intake levels. Conversely, other studies have reported a potential increase in ventricular ectopy, particularly with very high caffeine consumption, indicating that individual responses can vary widely based on genetic predispositions and existing health conditions. In addition to caffeine consumption, various lifestyle factors contribute to the overall risk of developing arrhythmias. Individuals who smoke or consume alcohol excessively may have a heightened risk of arrhythmias, which could confound the relationship between caffeine and heart rhythm disorders [78,79]. Therefore, a comprehensive assessment of a patient’s lifestyle is crucial when evaluating their risk factors for arrhythmias. Given the mixed evidence surrounding caffeine’s effects on heart rhythm disorders, healthcare providers should approach recommendations with caution. Some patients may benefit from reducing caffeine intake, particularly if they experience palpitations or other symptoms correlated with caffeine consumption. In contrast, others may not need to limit their intake at all.

7. Conclusion

The pharmacological properties of caffeine reveal its complex mechanisms of action, including adenosine receptor antagonism, phosphodiesterase inhibition, calcium mobilization, and catecholamine release. These actions contribute to caffeine’s stimulatory effects on the heart, influencing heart rate and blood pressure. The pharmacokinetics of caffeine demonstrate variability in absorption and metabolism, influenced by factors such as age, genetics, and lifestyle habits, mainly smoking. Caffeine sources vary, ranging from natural products like coffee and tea to synthetic forms found in energy drinks and supplements. The caffeine content in these products varies significantly, necessitating careful label reading and portion control to manage intake effectively. Research on caffeine’s effects on the cardiovascular system indicates that acute consumption may lead to transient heart rate and blood pressure increases, chronic effects are unclear. Studies have shown mixed results regarding caffeine’s association with arrhythmias, particularly atrial fibrillation and ventricular arrhythmias, with some evidence suggesting a protective effect in specific populations.

Future studies should aim to clarify the relationship between caffeine and cardiovascular health by addressing existing gaps in the literature. Longitudinal studies with diverse populations can provide insights into the long-term effects of caffeine consumption on heart health. Additionally, research should explore the genetic factors influencing individual responses to caffeine and the interplay between caffeine and other lifestyle factors, such as diet and exercise, in relation to cardiovascular outcomes. Moreover, investigating the mechanisms by which caffeine may contribute to or mitigate arrhythmias could enhance our understanding of its role in heart rhythm disorders. As the consumption of caffeinated products continues to rise, particularly among younger populations, it is imperative to establish clear guidelines based on robust evidence.

In conclusion, caffeine remains a prevalent component of modern diets, with potential benefits and risks associated with its consumption. While current evidence suggests that moderate caffeine intake does not significantly increase the risk of cardiovascular issues for most individuals, the nuances of individual susceptibility and health conditions necessitate personalized recommendations. A balanced approach that considers both the potential advantages and drawbacks of caffeine consumption will be essential in guiding public health recommendations and individual dietary choices moving forward. As research continues to evolve, a deeper understanding of caffeine’s role in cardiovascular health will be crucial for optimizing health outcomes in diverse populations.

Abbreviation list

CNS

Central Nervous System

AC

Adenylate Cyclase

AF

Atrial Fibrillation

AngII

Angiotensin II

BBB

Blood–Brain Barrier

BP

Blood Pressure

Ca++

Calcium

CAD

Coronary Artery Disease

cAMP

cyclic Adenosine Monophosphate

CFR

Coronary Flow Reserve

cGMP

cyclic Guanosine Monophosphate

CHD

Coronary Heart Disease

CVD

Cardio Vascular Disease

CYP1A2

Cytochrome P450 Isoform 1A2

DA

Dopamine

GDP

Gross Domestic Product

HDI

Human Development Index

MAPK

Mitogen-Activated Protein Kinase

NADPH

Nicotinamide Adenine Dinucleotide Phosphate Hydrogen

NO

Nitric Oxide

NOX

NADPH Oxidase

PVC

Premature Ventricular Contractions

SHD

Structural Heart Disease

T2DM

Type 2 Diabetes Mellitus

TGFβ1

Transforming Growth Factor Beta 1

tHcy

total Homocysteine

VT

Ventricular Tachyarrhythmias