Caffeine as a cardiovascular protective agent: a comprehensive review of mechanisms and outcomes

BACKGROUND: Caffeine, predominantly consumed through coffee and tea, has received growing attention for its potential cardioprotective actions. Evidence suggests a non-linear association between habitual intake and cardiovascular risk, with moderate consumption offering the most favorable profile. Given that caffeine is often ingested within complex beverage matrices, distinguishing the effects of pure caffeine from those of coffee components and preparation methods is essential for accurate interpretation. METHODS: This study synthesizes findings from epidemiological research, Mendelian randomization analyses, mechanistic experiments, and clinical trials to evaluate caffeine's cardiovascular impact. We assess key outcomes such as coronary artery disease, heart failure, stroke, hypertension, and arrhythmias. Mechanistic pathways are explored, including adenosine receptor antagonism, modulation of autonomic tone, influences on endothelial function and arterial stiffness, anti-inflammatory and antioxidant effects, and indirect metabolic actions on glucose and lipid regulation. Additional analyses examine how genetics, comorbid conditions, and concomitant medications may modify individual responses. RESULTS: Integrated evidence from observational studies demonstrates a non-linear, J-shaped association between coffee and caffeine intake and cardiovascular outcomes, with moderate consumption associated with the lowest observed risk; however, Mendelian randomization analyses generally do not support a clear causal protective effect of caffeine. Pure caffeine and coffee-derived effects diverge in several respects: unfiltered coffee may elevate lipid levels due to diterpenes, whereas filtered coffee generally has neutral lipid effects. Habitual use is shown to attenuate the acute pressor response through tolerance development. Variability in cardiovascular responses is influenced by genetic polymorphisms, baseline blood pressure phenotype, concurrent illnesses, and interacting medications. CONCLUSION: Overall, moderate caffeine intake generally appears safe for cardiovascular health. The cardioprotective links seen in epidemiological studies may be affected by coffee components, how it is prepared, and residual behavioral confounding, while solid evidence for a direct protective effect of caffeine is still limited. Remaining uncertainties highlight the need for future trials that isolate caffeine's dose-response from coffee matrices, incorporate genotype-based stratification, evaluate baseline hemodynamic phenotypes, and use standardized clinical endpoints. Such work is essential to clarify causal pathways and optimize the clinical relevance of caffeine-related recommendations.