Mechanisms of U-Shaped Association between Alcohol Intake and the Risk of Sudden Cardiac Death

Large cohort epidemiological studies have shown a U-shaped association between the relative risk of Sudden Cardiac Death (SCD) and the dose of alcohol consumed across both genders. The mechanisms of this relationship, i.e., too little or too high promoting SCD while moderate doses providing protection, remain elusive. In this brief review, we provide plausible electrophysiological and biochemical mechanisms of the U-shaped association of the dose of alcohol and the risk of SCD. At moderate doses alcohol causes partial cellular uncoupling “paradoxically” improves the conduction at narrow ventricular conducting pathways (source) that adjoins a large tissue mass (sink) eliminating preexisting Unidirectional Conduction (UCB) (from source-to-sink) and preventing re-entry formation. In contrast, higher doses of alcohol by further increasing cellular uncoupling cause conduction block at multiple ventricular sites (wavebreaks) in isolated tissues and patterned monolayers of cardiac myocytes leading to the formation of multiple reentrant and non-reentrant wave fronts simulating fibrillation-like state. In the absence of alcohol, the vulnerable narrow conducting pathways remain unchanged promoting UCB (i.e., conduction block from source-to-sink block) increasing the risk of reentry formation. Re-entry leads to Ventricular Fibrillation (VF), a major cause of SCD. Our hypothesis of U-shaped association between alcohol dose and SCD is based on the preponderance of clinical epidemiological data and on basic experimental studies using intact animal hearts and patterned monolayers of cardiac myocytes with vulnerable narrow strands of conducting pathways (source) abutting to a large tissue mass (sink).