New Insight Into Binge Drinking-Related Arrhythmias

Fran Lowry

April 04, 2018

Researchers have come closer to finding the mechanisms that underlie "holiday heart syndrome," where excessive drinking of alcohol in a short period results in paroxysmal atrial fibrillation (PAF) several hours later.

In the Journal of the American College of Cardiology, Jiajie Yan, PhD, Rush University Medical Center, Chicago, Illinois, and colleagues report that binge drinking activates c-jun N-terminal kinase (JNK) 2 in atria, which in turn drives calmodulin kinase II (CaMKII) activation, prompting aberrant sarcoplasmic reticulum (SR) Ca2+ waves and, thus, enhanced susceptibility to atrial arrhythmias.

"Our results reveal a previously unrecognized form of alcohol-driven kinase-on-kinase proarrhythmic crosstalk," the authors write, adding that: "Atrial JNK2 function represents a potential novel therapeutic target to treat and/or prevent AF."

In earlier work, the researchers showed that JNK activation promotes atrial fibrillation in aged hearts and also that direct JNK activation by a JNK activator increased the risk of atrial fibrillation in young healthy animals.

The findings prompted them to explore whether JNK plays a role in binge drinking and AF, and, more specifically, to understand how alcohol-evoked JNK regulates CaMKII, a proarrhythmic molecule that drives SR Ca2+ mishandling.

The researchers used animal models as well as samples from human hearts that were from donors with a history of repeated binge drinking or no alcohol use. The animals were infused with alcohol or saline.

The myocytes from the human and animal samples were isolated, and confocal Ca2+ imaging, membrane potential dual-channel optical mapping, and biochemical assays were conducted.

The experiments showed that the inducibility and the duration of AF in animals exposed to alcohol and in human tissue exposed to alcohol exceeded that of sham-treated animals or non-alcohol-exposed human tissue.

In an accompanying editorial, Thomas G Di Salvo, MD, and Jeffrey Winterfield, MD, both from Medical University of South Carolina, Charleston, write that the authors provide additional mechanistic insight into binge alcohol-associated PAF, reporting "in convincing fashion that an alcohol-activated" JNK/CaMKII pathway "underlies the susceptibility to alcohol-induced PAF."

In an interview with | Medscape Cardiology, Di Salvo called it "a well-done paper."

"It's not perfect in that some of the experimental methods were used across different species and different cell lines, but I think it's one in the theory of ongoing work of the investigators that will add to the evolving literature," he said. "And I found that the mechanistic links between binge alcohol use and activation of the intracellular pathways convincing and compelling."

What remains unclear is the actual specific mediator of JNK2 activation, Di Salvo said.

"Is it the alcohol molecule itself or some toxic, metabolic intermediary or stress-related response that alcohol creates? The authors, at least in this paper, did not address that as clearly, but I think there is a strong association between binge alcohol use and the activation of that JNK2 kinase," he said.

Di Salvo continued, "It is always helpful when a common clinical condition is linked to specific molecular triggers because that affords an opportunity for targeted pharmacologic preventative strategies, or maybe therapeutic strategies for the future as well. Our current ability to prevent paroxysmal atrial fibrillation is relatively mediocre in many patients, and it would be a wonderful thing to reduce the burden of atrial fibrillation."

Co-editorialist Winterfield added, "We've known for many years that there is a condition of alcohol triggering atrial fibrillation, or so-called holiday heart syndrome. This paper provides at least some mechanistic underpinning for the paroxysms of atrial fibrillation that are observed after an acute alcohol binge."

"JNK2 signalling is a ubiquitous signaling pathway in response to physiologic stress of some kind, in this case alcohol. The downstream effect was to result in mishandling of cellular calcium that results in triggering arrhythmias," he said.

Understanding the mechanistic underpinnings that lead to alcohol-induced arrhythmias may lead to identification of the biochemical and biophysical basis of the disease itself, Winterfield said.

The study was supported by the National Institutes of Health. The authors and the editorialists have disclosed no relevant financial relationships.

J Am Coll Cardiol. Published April 3, 2018. Abstract, Editorial

 For more from | Medscape Cardiology, follow us on Twitter and Facebook


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.