Exploration of Clozapine-Induced Cardiomyopathy and Its Mechanism.

IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Toxicology Pub Date : 2024-11-01 Epub Date: 2024-08-17 DOI:10.1007/s12012-024-09909-7
Shangyu Zhang, Pengyue Jin, Li Yang, Yujie Zeng, Yongguo Li, Renkuan Tang
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Abstract

In this study, by pooling the clinical data of patients who died with a history of long-term clozapine use and by examining their hearts, it was found that long-term clozapine use can lead to cardiomyopathy and that its presentation resembles arrhythmogenic cardiomyopathy (ACM), i.e., it exhibits a predominantly right ventricular fatty infiltration with mild left ventricular damage. The transcriptomic data of rat cardiomyocytes after clozapine intervention were analyzed by transcriptomic approach to explore the causes of clozapine cardiomyopathy. The cause of clozapine cardiomyopathy was then explored by a transcriptomic approach, which revealed that its clozapine action on cardiomyocytes enriched cardiomyocyte-related differential genes in biological processes such as muscle development and response to hypoxia, as well as pathways such as fatty acid metabolism and cellular autophagy. Transcriptomic analysis showed that Egr1, Egr2, ler2, Jun, Mapk9, Nr1d2, Atf3, Bhlhe40, Crem, Cry1, Cry2, Dbp were hub genes for clozapine injury to the myocardium, and that these genes may play an important role in the myocardial ACM-like changes caused by clozapine. Combined with the results of pathological examination and transcriptomic analysis, it can be concluded that the long-term action of clozapine on cardiomyocytes leads to cellular autophagy and subsequent structural remodeling of the heart, and in the remodeling affects fatty acid metabolism, which eventually leads to ACM-like changes.

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探索氯氮平诱发心肌病及其机制
在这项研究中,通过汇集有长期服用氯氮平病史的死亡患者的临床数据,并通过检查他们的心脏,发现长期服用氯氮平可导致心肌病,其表现类似于心律失常性心肌病(ACM),即主要表现为右心室脂肪浸润,左心室轻度损伤。通过转录组学方法分析了氯氮平干预后大鼠心肌细胞的转录组数据,以探索氯氮平心肌病的病因。随后,通过转录组学方法探讨了氯氮平心肌病的病因,发现氯氮平对心肌细胞的作用富集了心肌细胞相关的差异基因,这些差异基因涉及肌肉发育、缺氧反应等生物过程,以及脂肪酸代谢和细胞自噬等通路。转录组分析表明,Egr1、Egr2、ler2、Jun、Mapk9、Nr1d2、Atf3、Bhlhe40、Crem、Cry1、Cry2、Dbp是氯氮平损伤心肌的枢纽基因,这些基因可能在氯氮平引起的心肌ACM样变中发挥重要作用。结合病理检查和转录组学分析结果,可以得出结论:氯氮平对心肌细胞的长期作用导致细胞自噬,进而导致心脏结构重塑,在重塑过程中影响脂肪酸代谢,最终导致ACM样变。
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来源期刊
Cardiovascular Toxicology
Cardiovascular Toxicology 医学-毒理学
CiteScore
6.60
自引率
3.10%
发文量
61
审稿时长
>12 weeks
期刊介绍: Cardiovascular Toxicology is the only journal dedicated to publishing contemporary issues, timely reviews, and experimental and clinical data on toxicological aspects of cardiovascular disease. CT publishes papers that will elucidate the effects, molecular mechanisms, and signaling pathways of environmental toxicants on the cardiovascular system. Also covered are the detrimental effects of new cardiovascular drugs, and cardiovascular effects of non-cardiovascular drugs, anti-cancer chemotherapy, and gene therapy. In addition, Cardiovascular Toxicology reports safety and toxicological data on new cardiovascular and non-cardiovascular drugs.
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