Huoxin Pill Ameliorates Atrial Fibrillation by Modulating Autonomic Nervous Balance and Electrical Conduction Heterogeneity: Insights From Systems Pharmacology and Experimental Validation
Mimi Huang
Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation, Visualization, Writing - original draft
Search for more papers by this authorLingli Wang
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Methodology, Resources, Writing - original draft
Search for more papers by this authorZejun Xu
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Resources
Search for more papers by this authorChenxing Huang
Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation
Search for more papers by this authorSisi He
Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation
Search for more papers by this authorYiqiu Liao
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Resources
Search for more papers by this authorJiaxuan Li
Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation
Search for more papers by this authorFei Qin
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Resources
Search for more papers by this authorYongjun Chen
Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Writing - review & editing
Search for more papers by this authorQiqi Zhang
School of Acupuncture and Massage, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Formal analysis
Search for more papers by this authorCorresponding Author
Hongjun Yang
Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
Correspondence:
Hongjun Yang ([email protected])
Dongyan Liu ([email protected])
Taiyi Wang ([email protected])
Contribution: Resources, Writing - review & editing
Search for more papers by this authorCorresponding Author
Dongyan Liu
Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
Correspondence:
Hongjun Yang ([email protected])
Dongyan Liu ([email protected])
Taiyi Wang ([email protected])
Contribution: Resources, Supervision, Writing - review & editing
Search for more papers by this authorCorresponding Author
Taiyi Wang
Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Correspondence:
Hongjun Yang ([email protected])
Dongyan Liu ([email protected])
Taiyi Wang ([email protected])
Contribution: Conceptualization, Funding acquisition, Resources, Supervision, Writing - review & editing
Search for more papers by this authorMimi Huang
Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation, Visualization, Writing - original draft
Search for more papers by this authorLingli Wang
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Methodology, Resources, Writing - original draft
Search for more papers by this authorZejun Xu
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Resources
Search for more papers by this authorChenxing Huang
Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation
Search for more papers by this authorSisi He
Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation
Search for more papers by this authorYiqiu Liao
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Resources
Search for more papers by this authorJiaxuan Li
Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Investigation
Search for more papers by this authorFei Qin
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, People's Republic of China
Contribution: Resources
Search for more papers by this authorYongjun Chen
Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Writing - review & editing
Search for more papers by this authorQiqi Zhang
School of Acupuncture and Massage, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Contribution: Formal analysis
Search for more papers by this authorCorresponding Author
Hongjun Yang
Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
Correspondence:
Hongjun Yang ([email protected])
Dongyan Liu ([email protected])
Taiyi Wang ([email protected])
Contribution: Resources, Writing - review & editing
Search for more papers by this authorCorresponding Author
Dongyan Liu
Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
Correspondence:
Hongjun Yang ([email protected])
Dongyan Liu ([email protected])
Taiyi Wang ([email protected])
Contribution: Resources, Supervision, Writing - review & editing
Search for more papers by this authorCorresponding Author
Taiyi Wang
Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
Correspondence:
Hongjun Yang ([email protected])
Dongyan Liu ([email protected])
Taiyi Wang ([email protected])
Contribution: Conceptualization, Funding acquisition, Resources, Supervision, Writing - review & editing
Search for more papers by this authorBCPT recognizes the potential of Natural Product studies in the identification of new therapies but wishes to emphasize that findings based on uncharacterized mixtures of compounds are preliminary in nature and serve primarily as hypothesis-generating to form the basis for more elaborate investigations.
Mimi Huang and Lingli Wang contributed equally to this work.
Funding: This work was supported by the Taishan Scholar Youth Project of Shandong Province (tsqn202306188 to TW) and the Young Scientists Fund of the National Natural Science Foundation of China (82404908 to DL).
ABSTRACT
Huoxin Pill (HXP), a traditional Chinese medicine for cardiovascular diseases, demonstrates clinically reported anti-atrial fibrillation (AF) effects, though its mechanisms remain unclear. To investigate these mechanisms, we established an acetylcholine-calcium chloride (ACh-CaCl2)-induced AF model in rats divided into control, AF, HXP (HXP-L: 3.33; HXP-M: 10; HXP-H: 30 mg/kg) and verapamil (25 mg/kg) groups. Following daily modelling, treatments were administered via gavage from Days 4 to 10. Electrocardiography (ECG) subsequently assessed AF susceptibility while echocardiography evaluated cardiac function. Systems pharmacology predicted HXP's targets/pathways for AF amelioration, with heart rate variability (HRV) and nerve activity recording examining autonomic balance. Electrical mapping quantified activation time (AT), conduction velocity (CV), conduction dispersion and effective refractory period (ERP) in isolated hearts. Results demonstrated that the AF group exhibited increased AF incidence/duration and decreased left ventricular ejection fraction/fractional shortening (LVEF/LVFS). Systems pharmacology revealed significant enrichment in cardiovascular pathways (including AF), while HRV and nerve recording indicated autonomic imbalance. Isolated AF hearts showed prolonged AT, slowed CV, increased conduction dispersion and shortened ERP. HXP significantly ameliorated these alterations. In conclusion, these findings suggest that HXP improves ACh-CaCl2-induced AF, potentially through modulating autonomic nervous balance and atrial electrical conduction heterogeneity.
Summary
- This study investigated HXP, a traditional Chinese medicine, to understand how it prevents AF.
- Experiments in AF-induced rats showed that HXP reduced the occurrence and duration of AF while improving heart function.
- Systems pharmacology revealed that HXP is predominantly enriched in neuroinflammation and cardiac hypertrophy pathways. Additionally, HXP restored autonomic balance and stabilized irregular electrical signals in the heart.
- These findings suggest HXP may offer a natural, multitarget approach to managing abnormal heart rhythms, supporting further exploration of traditional medicines for AF.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
Filename | Description |
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bcpt70079-sup-0001-Supplementary_Material_1.docxWord 2007 document , 549.1 KB |
Figure S1. Quality control of HXP. (A) and (B) represent the total ion chromatograms (TIC) of Huoxin Pill in positive and negative ion modes, respectively. (C) and (D) show the TIC of mixed standards in positive and negative ion modes. Peaks labelled 1–6 correspond to ganoderic acid A, hydroxysafflor yellow A, tauro-ursodeoxycholic acid, cinobufagin, benzoylmesaconine and ginsenoside Re. FigureS2. Workflow schematic of systems pharmacology analysis. Figure S3. ECG results on Day 3. (A) Representative ECG tracing on Day 3. (B) Atrial fibrillation incidence rate on Day 3. |
bcpt70079-sup-0002-Supplementary_Material_2.xlsxExcel 2007 spreadsheet , 328 KB |
Data S1. Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1B. J. J. M. Brundel, X. Ai, M. T. Hills, M. F. Kuipers, G. Y. H. Lip, and N. M. S. de Groot, “Atrial Fibrillation,” Nature Reviews Disease Primers 8, no. 1 (2022): 21, https://doi.org/10.1038/s41572-022-00347-9.
- 2Y. F. Chen, Q. Song, P. Colucci, et al., “Basolateral Amygdala Activation Enhances Object Recognition Memory by Inhibiting Anterior Insular Cortex Activity,” Proceedings of the National Academy of Sciences of the United States of America 119, no. 22 (2022): e2203680119, https://doi.org/10.1073/pnas.2203680119.
- 3C. X. Wong, H. F. Tse, E. K. Choi, et al., “The Burden of Atrial Fibrillation in the Asia–Pacific Region,” Nature Reviews Cardiology 21, no. 12 (2024): 841–843, https://doi.org/10.1038/s41569-024-01091-1.
- 4L. O'Neill, J. Y. Wielandts, K. Gillis, et al., “Catheter Ablation in Persistent AF, the Evolution Towards a More Pragmatic Strategy,” Journal of Clinical Medicine 10, no. 18 (2021): 4060, https://doi.org/10.3390/jcm10184060.
- 5 Chinese Society of Pacing and Electrophysiology, Chinese Society of Arrhythmias, and Atrial Fibrillation Center Union of China, “Current Knowledge and Management of Atrial Fibrillation: Consensus of Chinese Experts 2021,” Chinese Journal of Cardiac Arrhythmias 26, no. 1 (2022): 15–88.
- 6Y. Takahashi, T. Yamaguchi, T. Otsubo, et al., “Histological Validation of Atrial Structural Remodelling in Patients With Atrial Fibrillation,” European Heart Journal 44, no. 35 (2023): 3339–3353, https://doi.org/10.1093/eurheartj/ehad396.
- 7Y. C. Chen, A. Voskoboinik, A. L. Gerche, T. H. Marwick, and J. R. McMullen, “Prevention of Pathological Atrial Remodeling and Atrial Fibrillation,” Journal of the American College of Cardiology 77, no. 22 (2021): 2846–2864, https://doi.org/10.1016/j.jacc.2021.04.012.
- 8E. N. Prystowsky, B. J. Padanilam, and R. I. Fogel, “Treatment of Atrial Fibrillation,” JAMA 314, no. 3 (2015): 278–288, https://doi.org/10.1001/jama.2015.7505.
- 9J. G. Andrade, M. W. Deyell, L. Macle, et al., “Progression of Atrial Fibrillation After Cryoablation or Drug Therapy,” New England Journal of Medicine 388, no. 2 (2023): 105–116, https://doi.org/10.1056/NEJMoa2212540.
- 10R. Peyronnet and U. Ravens, “Atria-Selective Antiarrhythmic Drugs in Need of Alliance Partners,” Pharmacological Research 145 (2019): 104262, https://doi.org/10.1016/j.phrs.2019.104262.
- 11A. Deshmukh, N. J. Patel, S. Pant, et al., “In-Hospital Complications Associated With Catheter Ablation of Atrial Fibrillation in the United States Between 2000 and 2010: Analysis of 93 801 Procedures,” Circulation 128, no. 19 (2013): 2104–2112, https://doi.org/10.1161/CIRCULATIONAHA.113.003862.
- 12Z. Shen, A. Shen, X. Chen, et al., “Huoxin Pill Attenuates Myocardial Infarction-Induced Apoptosis and Fibrosis via Suppression of p53 and TGF-β1/Smad2/3 Pathways,” Biomedicine & Pharmacotherapy 130 (2020): 110618, https://doi.org/10.1016/j.biopha.2020.110618.
- 13Y. M. Zhang, X. Y. Qu, L. N. Tao, et al., “XingNaoJing Injection Ameliorates Cerebral Ischaemia/Reperfusion Injury via SIRT1-Mediated Inflammatory Response Inhibition,” Pharmaceutical Biology 58, no. 1 (2020): 16–24, https://doi.org/10.1080/13880209.2019.1698619.
- 14Y. Li, J. Tang, H. Gao, et al., “Ganoderma Lucidum Triterpenoids and Polysaccharides Attenuate Atherosclerotic Plaque in High-Fat Diet Rabbits,” Nutrition, Metabolism, and Cardiovascular Diseases 31, no. 6 (2021): 1929–1938, https://doi.org/10.1016/j.numecd.2021.03.023.
- 15F. Zhao, H. Jiang, T. Zhang, et al., “Mechanism Repositioning Based on Integrative Pharmacology: Anti-Inflammatory Effect of Safflower in Myocardial Ischemia–Reperfusion Injury,” International Journal of Molecular Sciences 24, no. 6 (2023): 5313, https://doi.org/10.3390/ijms24065313.
- 16S. Guan, Y. Xin, Y. Ding, Q. Zhang, and W. Han, “Ginsenoside Rg1 Protects Against Cardiac Remodeling in Heart Failure via SIRT1/PINK1/Parkin-Mediated Mitophagy,” Chemistry & Biodiversity 20, no. 2 (2023): e202200730, https://doi.org/10.1002/cbdv.202200730.
- 17S. Yang, F. Li, S. Lu, et al., “Ginseng Root Extract Attenuates Inflammation by Inhibiting the MAPK/NF-κB Signaling Pathway and Activating Autophagy and p62-Nrf2-Keap1 Signaling In Vitro and In Vivo,” Journal of Ethnopharmacology 283 (2022): 114739, https://doi.org/10.1016/j.jep.2021.114739.
- 18X. Wang and G. Jiang, “Two Cases of Atrial Fibrillation Successfully Treated With Huoxin Pill as the Primary Therapy,” Heilongjiang Medicine Journal 6, no. 6 (1993): 48.
- 19Y. Li, T. Li, Y. Wang, D. Zhang, and L. Chen, “Therapeutic Efficacy Observation of Huoxin Pill in 60 Cases of Coronary Heart Disease,” Hubei Journal of Traditional Chinese Medicine 10, no. 3 (1988): 29–30.
- 20P. Tveden-Nyborg, B. Yang, U. Simonsen, and J. Lykkesfeldt, “BCPT Perspectives on Studies Involving Natural Products, Traditional Chinese Medicine and Systems Pharmacology,” Basic & Clinical Pharmacology & Toxicology 135, no. 6 (2024): 782–785, https://doi.org/10.1111/bcpt.14109.
- 21P. Tveden-Nyborg, T. K. Bergmann, N. Jessen, U. Simonsen, and J. Lykkesfeldt, “BCPT 2023 Policy for Experimental and Clinical Studies,” Basic & Clinical Pharmacology & Toxicology 133, no. 4 (2023): 391–396, https://doi.org/10.1111/bcpt.13944.
- 22M. Peng, M. Yang, Y. Lu, et al., “Huoxin Pill Inhibits Isoproterenol-Induced Transdifferentiation and Collagen Synthesis in Cardiac Fibroblasts Through the TGF-β/Smads Pathway,” Journal of Ethnopharmacology 275 (2021): 114061, https://doi.org/10.1016/j.jep.2021.114061.
- 23Y. Su, J. Huang, S. Sun, et al., “Restoring the Autonomic Balance in an Atrial Fibrillation Rat Model by Electroacupuncture at the Neiguan Point,” Neuromodulation 27, no. 7 (2024): 1196–1207, https://doi.org/10.1016/j.neurom.2022.11.005.
- 24J. Wang, Q. Zhang, L. Yao, et al., “Modulating Activity of PVN Neurons Prevents Atrial Fibrillation Induced Circulation Dysfunction by Electroacupuncture at BL15,” Chinese Medicine 18, no. 1 (2023): 135, https://doi.org/10.1186/s13020-023-00841-6.
- 25H. Badreldin, M. Elshal, A. El-Karef, and T. Ibrahim, “Empagliflozin Protects the Heart From Atrial Fibrillation in Rats Through Inhibiting the NF-κB/HIF-1α Regulatory Axis and Atrial Remodeling,” International Immunopharmacology 143 (2024): 113403, https://doi.org/10.1016/j.intimp.2024.113403.
- 26C. Yao, T. Veleva, L. Scott, et al., “Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation,” Circulation 138, no. 20 (2018): 2227–2242, https://doi.org/10.1161/CIRCULATIONAHA.118.035202.
- 27G. Hindricks, T. Potpara, N. Dagres, et al., “2020 ESC Guidelines for the Diagnosis and Management of Atrial Fibrillation Developed in Collaboration With the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the Diagnosis and Management of Atrial Fibrillation of the European Society of Cardiology (ESC) Developed With the Special Contribution of the European Heart Rhythm Association (EHRA) of the ESC,” European Heart Journal 42, no. 5 (2021): 373–498, https://doi.org/10.1093/eurheartj/ehaa612.
- 28Y. Zhang, M. Yuan, W. Cai, et al., “Prostaglandin I2 Signaling Prevents Angiotensin II-Induced Atrial Remodeling and Vulnerability to Atrial Fibrillation in Mice,” Cellular and Molecular Life Sciences 81, no. 1 (2024): 264, https://doi.org/10.1007/s00018-024-05259-3.
- 29S. K. Kim, M. K. Lee, H. Jang, et al., “TM-MC 2.0: An Enhanced Chemical Database of Medicinal Materials in Northeast Asian Traditional Medicine,” BMC Complementary Medicine and Therapies 24, no. 1 (2024): 40, https://doi.org/10.1186/s12906-023-04331-y.
- 30T. Wang, H. Streeter, X. Wang, et al., “A Network Pharmacology Study of the Multi-Targeting Profile of an Antiarrhythmic Chinese Medicine Xin Su Ning,” Frontiers in Pharmacology 10 (2019): 1138, https://doi.org/10.3389/fphar.2019.01138.
- 31T. Liu, L. Hwang, S. K. Burley, et al., “BindingDB in 2024: A FAIR Knowledgebase of Protein-Small Molecule Binding Data,” Nucleic Acids Research 53, no. D1 (2025): D1633–D1644, https://doi.org/10.1093/nar/gkae1075.
- 32G. Stelzer, N. Rosen, I. Plaschkes, et al., “The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses,” CP in Bioinformatics 54, no. 1 (2016): 1.30.1–1.30.33, https://doi.org/10.1002/cpbi.5.
10.1002/cpbi.5 Google Scholar
- 33Y. Zhou, Y. Zhang, D. Zhao, et al., “TTD: Therapeutic Target Database Describing Target Druggability Information,” Nucleic Acids Research 52, no. D1 (2024): D1465–D1477, https://doi.org/10.1093/nar/gkad751.
- 34C. Knox, M. Wilson, C. M. Klinger, et al., “DrugBank 6.0: The DrugBank Knowledgebase for 2024,” Nucleic Acids Research 52, no. D1 (2024): D1265–D1275, https://doi.org/10.1093/nar/gkad976.
- 35J. S. Amberger, C. A. Bocchini, A. F. Scott, and A. Hamosh, “OMIM.org: Leveraging Knowledge Across Phenotype–Gene Relationships,” Nucleic Acids Research 47, no. D1 (2019): D1038–D1043, https://doi.org/10.1093/nar/gky1151.
- 36 UniProt Consortium, “UniProt: The Universal Protein Knowledgebase in 2023,” Nucleic Acids Research 51, no. D1 (2023): D523–D531, https://doi.org/10.1093/nar/gkac1052.
- 37L. Wu, L. Li, X. Wang, et al., “The Inhibition of Rutin on Src Kinase Blocks High Glucose-Induced EGFR/ERK Transactivation in Diabetic Nephropathy by Integrative Approach of Network Pharmacology and Experimental Verification,” Phytomedicine 135 (2024): 156220, https://doi.org/10.1016/j.phymed.2024.156220.
- 38L. Zhang, B. Li, and L. Wu, “Heart Rate Variability in Patients With Atrial Fibrillation of Sinus Rhythm or Atrial Fibrillation: Chaos or Merit?,” Annals of Medicine 57, no. 1 (2025): 2478474, https://doi.org/10.1080/07853890.2025.2478474.
- 39W. Cao, Z. Yang, X. Liu, et al., “A Kidney-Brain Neural Circuit Drives Progressive Kidney Damage and Heart Failure,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 184, https://doi.org/10.1038/s41392-023-01402-x.
- 40Q. Zhou, G. Hao, W. Xie, et al., “Exenatide Reduces Atrial Fibrillation Susceptibility by Inhibiting hKv1.5 and hNav1.5 Channels,” Journal of Biological Chemistry 300, no. 5 (2024): 107294, https://doi.org/10.1016/j.jbc.2024.107294.
- 41Y. Liang, G. Wang, S. Fan, et al., “Brain-to-Heart Cholinergic Synapse-Calcium Signaling Mediates Ischemic Stroke-Induced Atrial Fibrillation,” Theranostics 14, no. 17 (2024): 6625–6651, https://doi.org/10.7150/thno.99065.
- 42Z. Cao, Y. Fu, Y. Ke, et al., “Mitochondrial Damage Mediates STING Activation Driving Obesity-Mediated Atrial Fibrillation,” Europace 27, no. 4 (2025): euaf081, https://doi.org/10.1093/europace/euaf081.
- 43S. Qiu, J. Sun, S. Su, et al., “Traditional Chinese Medicine YangxinDingji Alleviates Arrhythmias Through Inhibition of Sodium and L-Type Calcium Channels,” Journal of Ethnopharmacology 347 (2025): 119803, https://doi.org/10.1016/j.jep.2025.119803.
- 44D. Li, Y. Liu, C. Li, et al., “Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2,” Circulation 150, no. 2 (2024): 111–127, https://doi.org/10.1161/CIRCULATIONAHA.123.067517.
- 45G. N. Kowlgi, S. J. Asirvatham, and K. C. Siontis, “What Is the Mechanism of Atrial Fibrillation Initiation?,” Circulation 151, no. 1 (2025): 120–122, https://doi.org/10.1161/CIRCULATIONAHA.124.072920.
- 46J. S. Steinberg, V. Shabanov, D. Ponomarev, et al., “Effect of Renal Denervation and Catheter Ablation vs. Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension,” JAMA 323, no. 3 (2020): 248, https://doi.org/10.1001/jama.2019.21187.
- 47S. Stavrakis, J. A. Stoner, M. B. Humphrey, et al., “TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation),” JACC Clinical Electrophysiology 6, no. 3 (2020): 282–291, https://doi.org/10.1016/j.jacep.2019.11.008.
- 48E. P. Gerstenfeld, M. Mansour, W. Whang, et al., “Autonomic Effects of Pulsed Field vs Thermal Ablation for Treating Atrial Fibrillation,” JACC Clinical Electrophysiology 10, no. 7 (2024): 1634–1644, https://doi.org/10.1016/j.jacep.2024.05.005.
- 49B. Lee, J. Park, S. Kwon, et al., “Effect of Wild Ginseng on Scopolamine-Induced Acetylcholine Depletion in the Rat Hippocampus,” Journal of Pharmacy and Pharmacology 62, no. 2 (2010): 263–271, https://doi.org/10.1211/jpp.62.02.0015.
- 50W. Xue, Y. Gao, P. P. Xie, et al., “Plasma and Intracerebral Pharmacokinetics and Pharmacodynamics Modeling for the Acetylcholine Releasing Effect of Ginsenoside Rg1 in mPFC of Aβ Model Rats,” Journal of Asian Natural Products Research 23, no. 3 (2021): 294–306, https://doi.org/10.1080/10286020.2020.1803289.
- 51J. f. Wan, G. Wang, F. y. Qin, et al., “Z16b, a Natural Compound From Ganoderma cochlear Is a Novel RyR2 Stabilizer Preventing Catecholaminergic Polymorphic Ventricular Tachycardia,” Acta Pharmacologica Sinica 43, no. 9 (2022): 2340–2350, https://doi.org/10.1038/s41401-022-00870-1.
- 52J. Dong, H. Li, Y. Bai, and C. Wu, “Muscone Ameliorates Diabetic Peripheral Neuropathy Through Activating AKT/mTOR Signalling Pathway,” Journal of Pharmacy and Pharmacology 71, no. 11 (2019): 1706–1713, https://doi.org/10.1111/jphp.13157.
- 53V. Taneja, H. H. Siddiqui, and R. B. Arora, “Studies on the Anti-Inflammatory Activity of Moschus moschiferus (Musk) and Its Possible Mode of Action,” Indian Journal of Physiology and Pharmacology 17, no. 3 (1973): 241–247.
- 54S. Zafeiropoulos, I. Doundoulakis, I. T. Farmakis, et al., “Autonomic Neuromodulation for Atrial Fibrillation Following Cardiac Surgery,” Journal of the American College of Cardiology 79, no. 7 (2022): 682–694, https://doi.org/10.1016/j.jacc.2021.12.010.
- 55M. Lei, L. Wu, D. A. Terrar, and C. L. H. Huang, “Modernized Classification of Cardiac Antiarrhythmic Drugs,” Circulation 138, no. 17 (2018): 1879–1896, https://doi.org/10.1161/CIRCULATIONAHA.118.035455.
- 56Y. Wang, J. Wang, L. Shi, et al., “CIB2 Is a Novel Endogenous Repressor of Atrial Remodeling,” Circulation 147, no. 23 (2023): 1758–1776, https://doi.org/10.1161/CIRCULATIONAHA.122.062660.
- 57Y. K. Iwasaki, K. Nishida, T. Kato, and S. Nattel, “Atrial Fibrillation Pathophysiology,” Circulation 124, no. 20 (2011): 2264–2274, https://doi.org/10.1161/CIRCULATIONAHA.111.019893.
- 58C. Beyer, L. Tokarska, M. Stühlinger, et al., “Structural Cardiac Remodeling in Atrial Fibrillation,” JACC: Cardiovascular Imaging 14, no. 11 (2021): 2199–2208, https://doi.org/10.1016/j.jcmg.2021.04.027.
- 59Y. He, Q. Liu, Y. Li, et al., “Protective Effects of Hydroxysafflor Yellow A (HSYA) on Alcohol-Induced Liver Injury in Rats,” Journal of Physiology and Biochemistry 71, no. 1 (2015): 69–78, https://doi.org/10.1007/s13105-015-0382-3.
- 60X. Peng, L. Li, J. Dong, et al., “Lanostane-Type Triterpenoids From the Fruiting Bodies of Ganoderma applanatum,” Phytochemistry 157 (2019): 103–110, https://doi.org/10.1016/j.phytochem.2018.10.011.
- 61L. Li, X. R. Peng, J. R. Dong, et al., “Rearranged Lanostane-Type Triterpenoids With Anti-Hepatic Fibrosis Activities From Ganoderma applanatum,” RSC Advances 8, no. 55 (2018): 31287–31295, https://doi.org/10.1039/C8RA05282D.