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Plasma CCL3 predicts adverse heart failure outcomes in patients with arrhythmogenic cardiomyopathy
Hao Cui1,2, Songren Shu1,3, Ningning Zhang1
1The Cardiomyopathy Research Group, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing, 100037, China.
Insights
Fibro-fatty tissue in arrhythmogenic cardiomyopathy (ACM) shows increased saturated triglycerides and inflammatory markers, correlating with heart failure (HF) progression. Plasma CCL3 levels predict adverse events in ACM patients, aiding in risk stratification.
Area of Science:
- Cardiology
- Pathology
- Biochemistry
Background:
- Arrhythmogenic cardiomyopathy (ACM) involves fibro-fatty myocardial replacement, linked to heart failure (HF) progression.
- Investigating the characteristics of fibro-fatty tissues and plasma chemokine levels in ACM patients is crucial for understanding HF burden.
Purpose of the Study:
- To characterize fibro-fatty tissues in ACM patients, focusing on fat markers, lipidomics, and immune cell infiltration.
- To assess the correlation between fibro-fatty tissue composition, plasma chemokine levels (CCL3), and HF progression in ACM.
- To evaluate the predictive value of plasma CCL3 for adverse cardiovascular events in ACM.
Main Methods:
- Quantitative real-time PCR for fat markers (brown, beige, white).
- Lipidomics (LC-MS) and single-cell RNA sequencing of myocardial tissue.
- Immunostaining and ELISA for CCL3 expression in tissue and plasma.
- Longitudinal follow-up of ACM patients to assess HF incidence and outcomes.
Main Results:
- ACM fibro-fatty tissues exhibit higher beige and brown fat marker expression and increased saturated triglycerides compared to controls.
- ACM myocardium shows accumulation of proinflammatory macrophages and elevated proinflammatory markers.
- CCL3 expression in fibro-fatty tissue correlates positively with HF progression.
- Plasma CCL3 levels are elevated in ACM patients and predict HF incidence and heart transplantation/death (AUC 0.814 for HF, 0.756 for HTx/death).
Conclusions:
- Increased saturated triglycerides and CCL3 in ACM fibro-fatty tissues may drive HF progression.
- Plasma CCL3 serves as a valuable biomarker for predicting HF-related adverse events in ACM patients.
- Further validation in larger cohorts is needed to confirm the predictive utility of plasma CCL3.
Background:
Fibro-fatty replacement of the myocardium plays a key role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) and may be associated with progressive heart failure (HF). We aimed to investigate the characteristic of the fibro-fatty tissues of ACM patients and the plasma chemokines levels according to HF burden.
Methods:
The expression level of markers for brown, beige, and white fat of fibro-fatty tissues was determined using a quantitative real-time polymerase chain reaction. Lipidomics analysis of fibro-fatty tissues (n = 10 for normal control [NC]; n = 24 for ACM patients) was conducted using LC-MS. Single-cell RNA sequencing (n = 2 for NC; n = 6 for ACM patients) was used to compare the immune environment in the myocardium. Immunostaining and enzyme-linked immunosorbent assay were used to examine the expression of CCL3 in the myocardium and plasma samples, respectively.
Results:
The expression level of beige (TBX1 and TMEM26) and brown (TNFRSF9) fat markers were higher in the fibro-fatty tissues of ACM patients compared to NC. The fibro-fatty tissues revealed a significant increased level of saturated triglycerides (TGs) in ACM patients compared with NC. Single-cell RNA sequencing revealed the obvious accumulation of proinflammatory macrophages and a high expression level of proinflammatory markers in the myocardium of ACM patients compared to NC. The expression of CCL3 in the fibro-fatty tissues was positively correlated with HF progression in patients with ACM. Plasma CCL3 levels were significantly higher in patients with ACM compared to healthy volunteer. A total of 102 patients with ACM have been followed for a median of 7.8 years, indicating that plasma CCL3 levels could successfully predict the incidence of HF and heart transplantation (HTx)/death in patients with ACM (hazard ratio = 3.122 [95% confidence interval, 1.556-6.264]). The ROC curve analysis revealed the AUC value reached 0.814 for HF and 0.756 for HTx/death.
Conclusions:
The increased level of saturated TGs and CCL3 in the fibro-fatty tissues might promote HF progression in ACM patients. Plasma CCL3 levels are useful for predicting HF-related adverse events in patients with ACM, but requiring further validation in larger and independent cohorts.
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