Several mechanisms are theorized to be responsible for the arrhythmogenicity of alcohol. They may be characterized into two broad groups: direct effects on the myocardium and alcohol's effect on traditional risk factors for atrial fibrillation.

With regard to direct effects on the atrial myocardium, alcohol causes a autonomic nervous system imbalance. Alcohol increases sympathetic nervous system (SNS) activity (and its related increased secretion of epinephrine and norepinephrine), with resultant effects including an increased release of calcium into the myocytes from the sarcoplasmic reticulum. [3, 10] Increased SNS activity is further evidenced by a marked increase in the incidence of sinus tachycardia and reduced respiratory sinus arrhythmia during acute alcohol intoxication. [11] Consequently, the parasympathetic nervous system (PNS) is activated as well, with an increased intermittent vagal tone, which has been shown to also shorten the atrial refractory period and preciptate atrial fibrillation. [10] Note that the risk of atrial fibrillation persists into the "hangover" and/or withdrawal phase, which corresponds with an increased sympathetic tone. [3]

Other direct effects on the myocardium are perhaps less well studied. They include the effects of alcohol's primary metabolite acetaldehyde, which is associated with local inflammation and oxidative stress. [10] Alcohol itself can also directly decrease the myocyte sodium current and can affect intracellular pH, ether causing acidosis with low doses or alkalosis with higher doses. Interestingly, these effects may be species specific, with rabbits [12] and humans being similarly affected, whereas canine atria appear unaffected. [13] Research indicates that cardiac cells exposed to ethanol doses of 0.1% or greater undergo extrusion of magnesium (Mg2+), possibly owing to ethanol oxidation by cytochrome P-450 2E1; whether this contributes to alcoholic cardiomyopathy is not known. [14, 15]

A more recent study revealed that binge alcohol consumption activates the stress kinase JNK (c-Jun N-terminal kinase) (JNK2), which subsequently phosphorylates (and activates) the CaMKII protein, thereby enhancing CaMKII-driven mishandling of sarcoplasmic reticulum calcium—which prompts aberrant calcium waves and enhances susceptibility to atrial arrhythmia. [8] Conversely, CaMKII inhibition eliminates binge alcohol-evoked arrhythmic activities.

In another recent study involving isolated human atrial and murine atrial or ventricular cardiomyocytes, investigators indicated sarcoplasmic reticulum calcium leak as well as disordered excitation-contraction coupling as the basis for the arrhythmogenic and negative inotropic effects (reduced systolic calcium release) of acute ethanol exposure. [16] The investigators noted that production of reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) and oxidative activation of CaMKII appeared have key roles in the mechanism of action.

Analysis of electrocardiograms (ECGs) performed following the resolution of arrhythmias in patients who have consumed a large quantity of alcohol shows significant prolongation of the PR, QRS, and QT intervals compared to that of patients who experienced arrhythmias in the absence of alcohol consumption. [1, 17]

The arrhythmogenicity of alcohol has also been examined in the electrophysiology (EP) laboratory. In a study that evaluated 14 patients with a history of significant alcohol consumption, initially, the atrial and ventricular extrastimulus technique induced nonsustained ventricular tachycardia in a patient, nonsustained atrial fibrillation in another patient, paired ventricular responses in a third patient, and no response in the remaining 11 patients. [18] Following administration of alcohol, 10 of the 14 patients developed sustained or nonsustained tachyarrhythmias in response to the extrastimulus technique, with significant prolongation of His-ventricular conduction. [18] In another study, ingestion of whiskey resulted in no change in the atrial refractory period but facilitated induction of atrial flutter in individuals who were chronic drinkers and those who were nondrinkers. [2, 19] This evidence strongly suggests that alcohol possesses proarrhythmic properties. These seem to be more pronounced in patients with larger P-wave dispersion.

Although ventricular repolarization abnormalities on surface ECG were described, whether ventricular myocardium responds similarly to ethanol is uncertain. One case of ventricular fibrillation was described in a patient with heavy alcohol ingestion, but an electrophysiologic study (EPS) revealed only inducibility of atrial fibrillation with rapid ventricular response but no ventricular arrhythmias. Alcohol-induced atrioventricular block has been reported as a rare event that can occur at relatively low serum alcohol levels. [20] Investigators suggest that the mechanism for conduction slowing and block may be partly due to an exaggerated partial inhibition of calcium and, potentially, sodium currents in conductive tissue structures as result of elevated vagal tone. Impaired gap junction function may also play a role. [20]

With regard to alcohol's effect on traditional risk factors, one of the best studied is alcohol and its ability to exacerbate the severity of obstructive sleep apnea (OSA). OSA has clearly been associated with incident atrial fibrillation. [3] Alcohol consumption has been shown to increase the severity of sleep apnea, or the apnea-hypopnea index (AHI) through a variety of mechanisms. [21] In addition, it is clear that alcohol consumption (perhaps via activation of the SNS), increases systolic and diastolic blood pressure. [22] Furthermore, alcohol is also associated with worsening hypertension, obesity, and cardiomyopathy. [3] Although these risk factors are associated more with the long-term risk for development of atrial fibrillation, they are worth mentioning.