Holiday Heart Syndrome, Atrial Fibrillation, and RyR2 antagonist

Abstract

The Holiday Heart Syndrome (HHS) refers to binge alcohol-associated cardiac arrhythmia of which atrial fibrillation (AF) being the most occurred arrhythmia type. Excessive alcohol consumption is a serious public health and economic issue in the US and globally. Despite a tremendous education effort, binge drinking among the population of young and older adults continues to rise. During this current COVID-19 pandemic, social isolation has significantly increased alcohol consumption nationwide. In this issue, Greco et al. reported a straightforward study on the role of RyR2 dysfunction in binge alcohol-evoked AF using an HHS rat model, and evaluated the anti-AF potential of dantrolene, an RyR channel blocker. However, further investigations including off-target effects of dantrolene and therapeutic potential of other RyR2 blockers in AF are needed.

The holiday heart syndrome (HHS) refers to the occurrence of cardiac arrhythmias after binge drinking, which happens frequently during weekends and especially holidays.(1) Atrial fibrillation (AF) is the most commonly diagnosed arrhythmia among HHS patients.(1) AF is known to substantially increase the risk of morbidity and mortality predominantly due to embolic stroke and heart failure (HF), which adds vast economic burden upon the US health care system. Clinical data suggest that one-third of all new onset AF cases are related to alcohol intoxication; and a moderate or excessive amount of binge alcohol consumption can lead to an episode of AF even in young and healthy individuals without pre-existing cardiovascular conditions.(1) Although alcohol abstinence is an ideal approach to reverse new onset AF cases, AF recurrence is common in repeat bingers.(1) Despite the nation-wide education effort, binge drinking among the population of young and older adults continues to rise.(1) Thus, an ever-growing body of research focuses on understanding the mechanisms of binge alcohol-evoked AF in the hope of developing effective treatment strategies to meet clinical needs.

In this issue, Greco et al.(2) reported a straightforward study regarding the role of RyR2 (Ca²⁺ triggered Ca²⁺ release channel) dysfunction in binge alcohol-evoked AF in an HHS rat model and evaluated the anti-AF potential of dantrolene, an RyR channel blocker. The HHS rat model used for the current study shares similar features with previously published HHS mouse and rabbit models, including binge alcohol-evoked atrial arrhythmic remodeling and AF susceptibility. (3, 4) It is worth noting that HHS patients often appear in an emergency room 12 to 36 hours after cessation of binge drinking, and the blood alcohol content has already been cleared during that period of time. It is thus logical to think that the contribution of acute alcohol intoxication triggered a catecholamine surge and the sympathetic response of the body may have been diminished. This was indeed confirmed by Greco et al. as they found that the level of norepinephrine in the blood stream was at the baseline level in their HHS rat model 24h after the last binge episode. In response to alcohol exposure, ventricular function may be altered, which could be involved in AF development. The authors provided detailed ventricular functional characterization including echocardiographic cardiac dimensions and hemodynamics assessment and showed unchanged cardiac function, which is well aligned with that of HHS mouse and rabbit models,(3) suggesting the unlikelihood of the contribution of ventricular remodeling in this binge alcohol-evoked AF arrhythmogenesis. Therefore, other mechanisms such as post-binge alcohol-evoked stress signaling as we recently reported(3, 4) are likely involved in the atrial arrhythmic remodeling.

We have recently revealed that the stress response kinase JNK2 causatively drives sarcoplasmic reticulum (SR) Ca²⁺ dynamic dysfunction and triggered arrhythmic activity that prompts binge alcohol-evoked AF genesis.(3, 4) Normal Ca²⁺ homeostasis is essential in conversion of an electrical signal to mechanical function in the heart from beat to beat. In myocytes, Ca²⁺ entry via L-type Ca²⁺ channels (I_Ca) triggers a large SR Ca²⁺ release through RyR2 channels.(5) And this Ca²⁺ triggered Ca²⁺ release (CICR) event transiently increases intracellular Ca²⁺, driving myocardial contraction.(5) Extensive studies have demonstrated that abnormal diastolic RyR2 opening (or SR Ca²⁺ leak) elevates diastolic intracellular Ca²⁺ concentration and prolongs Ca²⁺ removal, which could evoke Ca²⁺ sparks/waves and result in abnormal arrhythmogenic triggered activities (i.e. delayed afterdepolarization, DADs).(3–8) The main finding of the current study is that diastolic SR Ca²⁺ leak was significantly increased in isolated atrial myocytes from HHS rats, which was suggested by enhanced frequency of Ca²⁺ sparks from confocal Ca²⁺ imaging. While the limitation of this study is that diastolic Ca²⁺ leak was not measured, this binge alcohol-evoked SR Ca²⁺ dysfunction has been thoroughly characterized in the HHS mouse and rabbit models.(3, 4) Specifically, the stress kinase JNK2 is activated in response to binge alcohol exposure. And this activated JNK2 directly activates CaMKII, a pro-arrhythmic molecule, and drives CaMKII-dependent RyR2 channel dysfunction that consequently enhances diastolic SR Ca²⁺ leak and triggered arrhythmic Ca²⁺ activities.(3, 4, 6) This conclusion was supported by increased RyR2 channel open probability due to JNK2-CaMKII-mediated sensitization of RyR2 channels (by RyR2 single channel recording), which leads to increased diastolic SR Ca²⁺ leak (by tetracaine-sensitive Ca²⁺ leak measurement in isolated atrial myocytes) and consequently increases pacing induced atrial Ca²⁺ sparks and waves (by intravital confocal Ca²⁺ imaging in the intact heart) and DADs (by patch clamp in isolated myocytes) as triggered arrhythmic activities as well as pacing induced AF incidence in the intact heart.(3, 4, 6) It is known that a higher SR Ca²⁺ load can augment diastolic SR Ca²⁺ leak, which fosters a higher likelihood to trigger arrhythmic activities when RyR2 channels are sensitized by hyperphosphorylated RyR2 proteins.(4–6) Unfortunately, the SR load in HHS atrial myocytes was not systematically assessed in the current study by Greco et al.(2). However, our group recently reported another JNK2-specific action (independent of CaMKII) in SR Ca²⁺ overload via enhanced SERCA2 activity that in turn increased SR Ca²⁺ uptake and SR Ca²⁺ content.(4) And this JNK2-specific action in the SR Ca²⁺ overload exacerbates the JNK2-CaMKII-evoked diastolic SR Ca²⁺ leak via RyR2 channels, which consequently drives triggered activities and promotes AF genesis.(4) Thus, binge alcohol impaired RyR2 channel function plays a key role in AF pathogenesis. (Central Figure)

Considering the importance of binge alcohol evoked RyR2 channel dysfunction, the studies by Greco et. al. tested the therapeutic potential of RyR antagonist dantrolene through blocking diastolic SR Ca²⁺ leak.(Central Figure) Previous reports suggest that dantrolene decreases RyR2 opening frequency without altering its mean opening time.(9) Clinically, dantrolene is the only accepted treatment for malignant hyperthermia. Recently, there is a growing interest in testing its therapeutic potential in Alzheimer’s disease, and cardiac pathologies including but not limited to HF, catecholaminergic polymorphic ventricular tachycardia (CPVT), and AF.(10) The common notion about RyR2-mediated arrhythmogenesis is that aberrant diastolic Ca²⁺ leak increases diastolic intracellular Ca²⁺ level which forces Ca²⁺ extrusion from Na⁺/Ca²⁺ exchanger (NCX) and cellular Na⁺ entry in return, resulting in unstable membrane potential that could culminate into DADs and ectopic depolarization.(5, 7, 8) In several animal models and human cardiac muscle/myocyte preparations, dantrolene has been shown to inhibit SR diastolic leak but at the same time increase SR Ca²⁺ load.(9) As a result, dantrolene can reduce aberrant triggered Ca²⁺ events and simultaneously increase SR Ca²⁺ load (failing hearts have significantly reduced SR load) to improve cardiac contraction.(7, 9)

As we have discussed above, binge alcohol exposure increases SR load via JNK2-dependent yet CaMKII-independent pathways, while it enhances diastolic RyR2 Ca²⁺ leak regulated by the JNK2-CaMKII-dependent signaling.(3, 4) Thus, the effect of dantrolene on increasing SR Ca²⁺ load could become a double-edged sword when aberrant diastolic SR Ca²⁺ leak is accompanied by SR overload, as this occurs in HHS hearts and in hearts under other stressed conditions including aging and paroxysmal AF.(4, 6, 8) With the higher SR load in the HHS heart, dantrolene may be insufficient to effectively stop AF in vivo. Whether dantrolene increased load is the result of stopping the SR leak via stabilizing the RyR2 channel or whether it regulates the load through other underlying mechanisms demands further investigation. Currently, several RyR antagonists are being tested clinically to tackle the issue of leaky-RyR-contributed cardiac diseases such as HF.(7) Such agents include but are not limited to K201 (JTV519), tetracaine-derivatives (EL20), azidodantrolene, S107, R-Propafenon.(9, 10) Future study on eliminating diastolic SR Ca²⁺ leak and triggered arrhythmic Ca²⁺ activities with dantrolene and other promising RyR-antagonists would shed light on their anti-AF therapeutic potential for HHS patients.