Coffee in Health and Disease Prevention http://dx.doi.org/10.1016/B978-0-12-409517-5.00078-4 © 2015 Elsevier Inc. All rights reserved. 699 CHAPTER 78 Caffeine Cardiovascular Toxicity: Too Much of a Good Thing Cláudia Deus, Ana F. Branco, Paulo J. Oliveira, Vilma Sardão CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal List of Abbreviations AC Adenylate cyclase ACE Angiotensin converting enzyme ADP Adenosine diphosphate AMP Adenosine monophosphate A r Adenosine receptors ATP Adenosine triphosphate cAMP Cyclic adenosine monophosphate cAMP PDE 3,5-Cyclic nucleotide phosphodiesterase CICR Calcium-induced calcium release FCCP Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone GMP Guanosine monophosphate IMP Inosine monophosphate LDL Low-density lipoprotein MPT Mitochondrial permeability transition PKA Protein kinase A RAS Renin-angiotensin system RCR Respiratory control ratio SR Sarcoplasmic reticulum TPP + Tetraphenylphosphonium cation 78.1 INTRODUCTION The cardiovascular toxicity of caffeine is still con- troversial and continues to be under active research. Although several studies reported that moderate doses of caffeine are not harmful to the heart, 1 improv- ing physical and cognitive performance 2 and prevent- ing stroke episodes, 3 other reports show that excessive caffeine consumption is harmful. 4,5 However, despite the controversy, it is concluded that, for each individ- ual, caffeine toxicity depends on pharmacokinetic and pharmacodynamic variations, clinical condition, and, of course, on the dose consumed. 78.2 CAFFEINE AND THE HEART 78.2.1 Caffeine during Pregnancy: Any Concern for Fetal Heart Development? Human exposure to caffeine can start in the womb of the progenitor. During pregnancy, the half-life of caf- feine increases from 3–6 h to 10–20 h, 6 increasing conse- quently the exposure of the organism to that molecule. Since caffeine is a hydrophobic compound, it crosses the placenta and reaches fetal bloodstream. 7 However, neonatal and fetal hepatic detoxification systems are inadequately developed, which increases the half-life of caffeine to 80 h. 7 As a consequence, toxic caffeine concen- trations can be quickly achieved and cause perturbations in the fetal heart rate. 8 Cases of fetal arrhythmias result- ing from excessive caffeine intake by pregnant women have been reported. In one of those cases, a mother gave birth to a boy with irregular heart rhythm, after drinking 10 cups of coffee during the last hour before initiating spontaneous labor. The effect was reversible since three days later the heart rhythm returned to nor- mal, although traces of caffeine were still detected in the baby’s urine. 8 Although the effects observed in the baby’s heart rate induced by excessive consumption of caffeine dissipated several days after birth, the impact on the cardiac tissue can persist and reverberate later in the offspring’s life. In fact, a study performed with C57BL/6 mice revealed that chronic administration of caffeine to pregnant females (20 mg/kg, corresponding to two cups of coffee in humans) promoted a persistent activation of local renin-angiotensin system (RAS) in the heart of the adult offspring, altering their blood pressure and cardiac