Background:The association between binge alcohol ingestion and atrial fibrillation (AF), often termed “holiday heart syndrome”, has long been recognized. However, the underlying cellular and molecular mechanisms are unknown.

Methods and Results:An experimental model of binge alcohol-induced AF was developed to elucidate the mechanisms linking acute ethanol exposure to changes in ion channel transcription and AF susceptibility. AF-susceptibility during transesophageal electrical stimulation was enhanced 8 h after, but not immediately or 24 h after, acute alcohol intake. T-type calcium channel (TCC) blockade and calcineurin inhibition diminished the AF-promoting effect of ethanol. Long-term (8–24 h) exposure to ethanol augmented TCC isoform-expression (Ca_v3.1 and Ca_v3.2) and currents in cardiomyocytes, accompanied by upregulation of the transcription factors, Csx/Nkx2.5 and nuclear factor of activated T-cells (NFAT), in the nucleus, and of phospho-glycogen synthesis kinase 3β (GSK3β) in the cytosol. Inhibition of protein kinase C (PKC) during the 7- to 8-h period following ethanol exposure attenuated susceptibility to AF, whereas acute exposure did not. GSK3β inhibition itself upregulated TCC expression and increased AF susceptibility.

Conclusions:The present study results suggest a crucial role for TCC upregulation in the AF substrate following binge alcohol-drinking, resulting from ethanol-induced PKC-activation that hyperphosphorylates GSK3β to cause enhanced calcineurin-NFAT-Csx/Nkx2.5 signaling. These observations elucidate for the first time the potential mechanisms underlying the clinically well-recognized, but mechanistically enigmatic, “holiday heart syndrome”.

背景：酗酒与心房颤动 (AF)（通常称为“假日心脏综合征”）之间的关联早已得到认可。然而，潜在的细胞和分子机制尚不清楚。

方法和结果：建立了酗酒诱发 AF 的实验模型，以阐明急性乙醇暴露与离子通道转录和 AF 易感性变化之间的联系机制。在急性酒精摄入后 8 小时，但不是立即或 24 小时后，经食道电刺激期间的 AF 易感性增强。T 型钙通道 (TCC) 阻断和钙调神经磷酸酶抑制减弱了乙醇的 AF 促进作用。长期（8-24 小时）暴露于乙醇增强了 TCC 同种型表达（Ca _v 3.1 和 Ca _v3.2) 和心肌细胞中的电流，伴随着细胞核中转录因子 Csx/Nkx2.5 和活化 T 细胞 (NFAT) 的核因子以及细胞质中磷酸糖原合成激酶 3β (GSK3β) 的上调. 乙醇暴露后 7 至 8 小时期间蛋白激酶 C (PKC) 的抑制减弱了对 AF 的易感性，而急性暴露则不会。GSK3β 抑制本身上调 TCC 表达并增加 AF 易感性。

结论：本研究结果表明，TCC 在酗酒后 AF 底物中的上调具有关键作用，这是由于乙醇诱导的 PKC 激活导致 GSK3β 过度磷酸化，从而导致钙调神经磷酸酶-NFAT-Csx/Nkx2.5 信号传导增强。这些观察结果首次阐明了临床公认但机械上神秘的“假日心脏综合征”的潜在机制。