Inhibition of the INa/K and the activation of peak INa contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs

Wang, Xiangchong; Jia, Qingzhong; Yu, Yulou; Wang, Handong; Guo, Huicai; Ma, Xindi; Liu, Chuntong; Chen, Xueyan; Miao, Qingfeng; Guan, Bing‐Cai; Su, Suwen; Wei, Heming; Wang, Chuan

doi:10.1038/s41401-020-0467-6

Cited by 16 publications

(7 citation statements)

References 41 publications

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“…It has been reported that TAF15 can stabilize SMAD3 (SMAD family member 3) mRNA level 30 . SMAD3, a downstream target of TGF‐ β , initiates the progression of fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Novel algorithm for diagnosis of Arrhythmogenic cardiomyopathy and dilated cardiomyopathy: Key gene expression profiling using machine learning

Zhang

Xie

et al. 2022

The Journal of Gene Medicine

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Background: It is difficult to distinguish between arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM) because of their similar clinical manifestations. This study aimed to develop a novel diagnostic algorithm for distinguishing ACM from DCM.Methods: Two public datasets containing human ACM and DCM myocardial samples were used. Consensus clustering, non-negative matrix factorization and principal component analysis were applied. Weighted gene co-expression network analysis and machine learning methods, including random forest and the least absolute shrinkage and selection operator, were used to identify candidate genes. Receiver operating characteristic curves and nomograms were performed to estimate diagnostic efficacy, and Spearman's correlation analysis was used to assess the correlation between candidate genes and cardiac function indices.Results: Both ACM and DCM showed highly similar gene expression patterns in the clustering analyses. Hub gene modules associated with cardiomyopathy were obtained using weighted gene co-expression network analysis. Thirteen candidate genes were selected using machine learning algorithms, and their combination showed a high diagnostic value (area under the ROC curve = 0.86) for distinguishing ACM from DCM. In addition, TATA-box binding protein associated factor 15 showed a negative correlation with cardiac index (R = À0.54, p = 0.0054) and left ventricular ejection fraction (R = À0.48, p = 0.0015).Conclusions: Our study revealed an effective diagnostic model with key gene signatures, which indicates a potential tool to differentiate between ACM and DCM in clinical practice. In addition, we identified several genes that are highly related to cardiac function, which may contribute to our understanding of ACM and DCM.Youming Zhang, Jiaxi Xie and Yizhang Wu contributed equally and share the first authorship.

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“…It has been reported that TAF15 can stabilize SMAD3 (SMAD family member 3) mRNA level 30 . SMAD3, a downstream target of TGF‐ β , initiates the progression of fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Novel algorithm for diagnosis of Arrhythmogenic cardiomyopathy and dilated cardiomyopathy: Key gene expression profiling using machine learning

Zhang

Xie

et al. 2022

The Journal of Gene Medicine

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“…Aconitine, as an agonist to bind to voltage-gated Na + channels on the cell membrane, could cause abnormal activation of Na + channels and memorably increase Na + influx, leading to intracellular Na + overload. A previous study manifested that aconitine could augment the peak of I Na by irritating Na + influx in a concentration-dependent manner ( Wang et al, 2021 ). On the other hand, evidence also suggested that aconitine could sharply elevate the expression of calmodulin ryanodine receptor 2 (RyR2) and Na + -Ca 2+ exchanger (NCX), which may be the main culprit of its cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Jiang

Zhang²,

Zhang³

et al. 2022

Front. Pharmacol.

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Background: Most Aconitum species in traditional Chinese medicine have the effect of dispelling wind, dehumidifying, warming the meridian, and relieving pain. Aconitine is the characteristic chemical component with the function of anti-inflammation, analgesic, and heart-strengthening effects. However, improper use will produce cardiotoxicity and neurotoxicity. Currently, the mechanisms of cardiotoxicity caused by aconitine are wheels within wheels without being fully disclosed. The systematic review and meta-analysis were therefore conducted to summarize the available evidence of myocardial toxicity caused by aconitine.Methods: We searched PubMed, Embase, Web of Science, National Knowledge Infrastructure, WANFANG, and VIP information database for relevant preclinical studies. All the data were analyzed by RevMan version 5.3.Results: Thirty-two studies met the final inclusion criteria, including both in vivo and in vitro study types. After aconitine treatment, the heart rate of animals was obviously abnormal, and the morphology and function of myocardial cells were significantly changed. Aconitine can induce changes in the electrophysiological activity of cardiac myocytes by regulating Na+, Ca2+, and K+ currents. Meanwhile, the mechanisms of cardiotoxicity of aconitine may be related to triggering mitochondrial dysfunction by inducing mitochondrial apoptosis and autophagy. It should not be ignored that the overactivation of NLRP3 inflammasome also exacerbates aconitine’s cardiotoxicity.Conclusion: The altered ion channels and mitochondrial function, as well as the signaling pathways interacting with NLRP3, may deserve further study for aconitine-induced cardiotoxicity.

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“…Several fundamental studies have explored the mechanism of aconitine-induced cardiotoxicity, but the exact mechanism has not been fully understood. It has been shown that aconitine increases the peak Na + current (iNa) by accelerating Na + channel activation and Na + /K + pump inhibition, thereby inducing various ventricular arrhythmias in guinea pigs[ 11 ]. In addition, aconitine also significantly exacerbates Ca 2+ overload, leading to arrhythmia, and ultimately promotes the development of apoptosis through the phosphorylation of P38 mitogen-activated protein kinase (MAPK)[ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Acute myocardial necrosis caused by aconitine poisoning: A case report

Liao¹,

Shen²,

Cai³

et al. 2022

World J Clin Cases

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BACKGROUND Herbal medicine has a long history of use in the prevention and treatment of disease and is becoming increasingly popular globally. However, there are also widespread concerns about its safety. Among them, the cardiotoxicity of aconitine has been described. CASE SUMMARY We report a case of a 61-year-old male with aconitine poisoning presenting with malignant arrhythmia and severe cardiogenic shock, which was successfully managed with aggressive advanced life support and heart transplantation. CONCLUSION This is the first case wherein in vivo cardiac pathology was obtained, confirming that aconitine caused acute myocardial necrosis.

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Inhibition of the INa/K and the activation of peak INa contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs

Cited by 16 publications

References 41 publications

Novel algorithm for diagnosis of Arrhythmogenic cardiomyopathy and dilated cardiomyopathy: Key gene expression profiling using machine learning

Novel algorithm for diagnosis of Arrhythmogenic cardiomyopathy and dilated cardiomyopathy: Key gene expression profiling using machine learning

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Acute myocardial necrosis caused by aconitine poisoning: A case report

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