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Colchicine attenuates cardiac hypertrophy by targeting the macrophage-driven Interleukin-6 suppression
Nianwei Zhou1, Wenjun Wang2, Xuemei Wei1
1Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, Shanghai Institute of Medical Imaging, Shanghai 200032, China.
Insights
Colchicine, an anti-inflammatory drug, shows promise in treating hypertrophic cardiomyopathy (HCM). This study found it reduces inflammation and fibrosis in HCM mouse models, potentially lowering sudden cardiac death risk.
Area of Science:
- Cardiology
- Pharmacology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, often leading to heart failure and sudden cardiac death (SCD).
- The exact mechanisms driving HCM progression are not fully understood, and effective treatments are limited.
- Existing HCM models often lack high-risk mutations associated with SCD.
Purpose of the Study:
- To investigate the therapeutic potential of colchicine, an anti-inflammatory agent, in preclinical models of hypertrophic cardiomyopathy (HCM).
- To evaluate colchicine's effects on myocardial inflammation, fibrosis, and cardiac function in established HCM mouse models.
Main Methods:
- Developed two murine models of hypertrophic cardiomyopathy (HCM) with mutations linked to high sudden cardiac death (SCD) risk.
- Utilized single-cell RNA sequencing to analyze myocardial changes.
- Assessed the impact of colchicine treatment on cardiac remodeling, inflammation, and fibrosis markers.
Main Results:
- Colchicine treatment significantly reduced cardiomyocyte hypertrophy, myocardial fibrosis, and cardiac stress markers (Anp, Bnp).
- The drug decreased pro-inflammatory macrophage populations and suppressed Interleukin-6 (IL-6) expression.
- Colchicine attenuated fibrotic mediators (Ctgf, Col1a1, Col3a1) and preserved cardiac function.
Conclusions:
- Colchicine effectively alleviates myocardial inflammation and fibrosis in preclinical hypertrophic cardiomyopathy (HCM) models.
- These findings suggest colchicine as a potential therapeutic strategy to mitigate fibrosis and reduce sudden cardiac death (SCD) risk in HCM patients.
- Further research is warranted to explore colchicine's clinical efficacy in managing HCM and improving patient outcomes.
Abstract:
Hypertrophic cardiomyopathy (HCM), the most prevalent inherited cardiovascular disease, is strongly linked to progressive heart failure and sudden cardiac death (SCD). However, its underlying pathogenic mechanisms remain incompletely understood, and effective therapeutic strategies are still lacking. Here, we established two murine HCM models harboring high SCD risk-associated mutations. Single-cell RNA sequencing revealed immune activation and enhanced fibrotic remodeling in the myocardium of these models. Therefore, we hypothesized that colchicine, a widely used anti-inflammatory drug known to reduce cardiovascular events in multiple cardiac disorders, may also represent a promising therapeutic candidate for HCM. As we expected, colchicine treatment attenuated pathological remodeling in our study, as evidenced by reduced cardiomyocyte hypertrophy, decreased fibrosis, and downregulation of cardiac stress markers (Anp, Bnp) and fibrotic mediators (Ctgf, Col1a1, Col3a1). In addition, colchicine attenuated pro-inflammatory macrophage populations and suppressed IL-6 expression, thereby contributing to the preservation of cardiac function. These findings provide the first preclinical evidence that colchicine alleviates myocardial inflammation and fibrosis in HCM, underscoring its potential as a novel therapeutic strategy to reduce fibrosis, lower SCD risk, and improve patient outcomes.
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