An Anti-arrhythmic Action and Novel Molecular Mechanisms of Alda-1 in Holiday Heart Syndrome
Abstract Body: Introduction: Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol intake. Atrial fibrillation (AF) is the most common arrhythmia in HHS patients. With a worldwide rising trend in heavy alcohol consumption despite significant prevention efforts, effective drugs against alcohol-evoked AF are in urgent need. Methods: We assessed the effect of Alda-1, a cardiac protective agent, on mitigating binge alcohol-evoked AF and alcohol-activated stress kinase JNK2 in 50mM alcohol-exposed (24hr) H9c2 differentiated myocytes and in a well-characterized HHS mouse model (2g/kg ethanol i.p., 4 injections, every other day). Alda-1’s effect on alcohol-evoked RyR2 channel-mediated Ca2+ waves/sparks & tachycardia/fibrillation (AT/AF) incidence were measured in intact mouse atria. RyR2 channel open probability was assessed in human RyR2 single-channel recordings. Results: We found that Alda-1 significantly reduced atrial arrhythmia inducibility in HHS mouse atria, as evidenced by a decreased incidence of alcohol-evoked AT/AF (0 vs. 0.21 incidences/pacing attempts/animal; n=6, 8). Alda-1 is an agonist of aldehyde dehydrogenase 2 (ALDH2; a key enzyme in alcohol detoxification), which inhibits cellular apoptosis. We found that ALDH2 was increased by 42%±6 in HHS mice compared to controls, and which remained elevated upon Alda-1 treatment (n=6,7,7; p<0.05). HHS hearts showed unchanged apoptotic signaling pathways, suggesting alternative mechanisms in AF genesis. Our lab recently revealed a critical role of activated cardiac stress kinase JNK2 in AF risk. Intriguingly, Alda-1 suppressed alcohol-activated JNK2 by 70%±13 (immunoprecipitated JNK2-specific activity; n=9,9, p<0.001) (but not JNK1, the other cardiac JNK isoform) in cells, while JNK2 inhibition alleviated alcohol-evoked RyR2 channel dysfunction in human RyR2 channels as well as Ca2+-triggered atrial arrhythmic activities and AT/AF (0 out of 8; p<0.05) in intact mouse hearts. Conclusion: Alda-1 effectively mitigates binge alcohol-evoked atrial arrhythmogenesis by suppressing JNK2 activity independently of an ALDH2-mediated anti-apoptosis effect. Our findings highlight the potential of Alda-1 as a therapeutic agent for the increasing incidence of alcohol-evoked AF.
Khanal, Saugat
( The Ohio State University
, Columbus
, Ohio
, United States
)
Yan, Jiajie
( The Ohio State University
, Columbus
, Ohio
, United States
)
Cao, Yuanyuan
( The Ohio State University
, Columbus
, Ohio
, United States
)
Ricchiuti, Nikola
( The Ohio State University
, Columbus
, Ohio
, United States
)
Nani, Alma
( Rush University
, Chicago
, Illinois
, United States
)
Chen, Wayne
( University of Calgary
, Calgary
, Alberta
, Canada
)
Fill, Michael
( Rush University
, Chicago
, Illinois
, United States
)
Bare, Dan
( The Ohio State University
, Columbus
, Ohio
, United States
)
Ai, Xun
( The Ohio State University
, Columbus
, Ohio
, United States
)
Author Disclosures:
Saugat Khanal:DO NOT have relevant financial relationships
| Jiajie Yan:No Answer
| Yuanyuan Cao:DO NOT have relevant financial relationships
| Nikola Ricchiuti:DO NOT have relevant financial relationships
| Alma Nani:No Answer
| Wayne Chen:No Answer
| Michael Fill:No Answer
| Dan Bare:DO NOT have relevant financial relationships
| Xun Ai:DO NOT have relevant financial relationships