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

Abstract

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).in 12 ounces of regular beer (~5% per volume alcohol), in five ounces of wine (~12% per volume alcohol) and 1.5 ounces of spirits (~40% alcohol). Therefore, up to 15 g/day is considered "light-to-moderate, " and greater than 30 g/day is considered "high" [3,4].The potential benefits of light-to-moderate doses of alcohol consumption, however, has not received universal acceptance. A recent systematic review of epidemiological data by The Global Burden of Disease Study by Alcohol Collaborators challenged the health benefits of light-to-moderate levels of alcohol consumption. This meta-analysis concluded that the level of alcohol consumption that minimized harm "across all health outcomes particularly the risk of cancer, was zero" [10]. This seeming controversy stems from the fact that certain diseases like Atrial Fibrillation (AF), stroke, [11] hypertension, heart failure, cardiomyopathy, cancer, and liver disease do not manifest any benefit from alcohol, [5,12,13] while other diseases do. The potential mechanisms of the observed benefits of low-to-moderate alcohol consumption in CAD and SCD remain undefined because the observed epidemiologic data are associative and not causative, providing no mechanistic insight by which alcohol causes it's beneficial or its ill effects. Since the questions that motivate