Holiday Heart Syndrome, Atrial Fibrillation, and RyR2 Antagonist

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 patients with HHS.1 AF is known to substantially increase the risk of morbidity and mortality predominantly because of embolic stroke and heart failure (HF), which adds vast economic burden on 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 al2 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 this 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 patients with HHS often appear in an emergency department 12–36 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 24 hours 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 binge alcohol-evoked atrial arrhythmogenesis. Therefore, other mechanisms such as postbinge alcohol-evoked stress signaling as we recently reported3,4 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 through L-type Ca2+ channels (ICa) triggers a large SR Ca2+ release through RyR2 channels.5 In addition, this Ca2+ triggered Ca2+ release 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 (ie, delayed afterdepolarization [DADs]).3–8 The main finding of this 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. Although 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 proarrhythmic molecule, and consequently drives CaMKII-dependent RyR2 channel dysfunction that results in enhanced diastolic SR Ca2+ leak and triggered arrhythmic Ca2+ activities.3,4,6 This conclusion was supported by increased RyR2 channel open probability because of 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 rat atrial myocytes was not systematically assessed in this 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 In addition, this JNK2-specific action in the SR Ca2+ overload exacerbates the JNK2-CaMKII–evoked diastolic SR Ca2+ leak through 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 (Fig. 1).FIGURE 1.: The steps (actual and hypothetical) of the current RyR2-centered, binge alcohol-evoked AF in a rat model of holiday heart syndrome.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 (Fig. 1). 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 disease and cardiac pathologies including but not limited to HF, catecholaminergic polymorphic ventricular tachycardia, 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 and cellular Na+ entry in return, resulting in unstable membrane potential that could culminate into DADs and ectopic activities.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 However, 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. In fact, this has been found in not only HHS hearts but in hearts under other stressed conditions including aging and paroxysmal AF.4,6,8 This is because that a higher SR load promotes diastolic leak and a combined higher load and CaMKII-sensitized RyR2 channel especially promote the diastolic leak as we and others have previously demonstrated.5 With the higher SR load in those hearts, the additive effect of dantrolene-caused elevation of SR Ca load may affect the effectiveness of anti-AF potential of dantrolene in patients. Whether dantrolene increased load is the result of stopping the SR leak through 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, and 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 patients with HHS.