Cui Hao, Shu Songren, Zhang Ningning, Wang Mangyuan, Yang Tianshuo, Wang Zhen, Chen Xiao, Fu Mengxia, Xu Mengda, Yang Yicheng, Wang Peizhi, Wang Chuangshi, Yang Qiaoxi, Gao Huimin, Jiang Yao, Song Jiangping
The 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.
Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
BMC Med. 2025 Apr 14;23(1):213. doi: 10.1186/s12916-025-04024-y.
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.
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.
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.
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.
心肌纤维脂肪替代在致心律失常性心肌病（ACM）的发病机制中起关键作用，且可能与进行性心力衰竭（HF）相关。我们旨在根据HF负担情况研究ACM患者纤维脂肪组织的特征及血浆趋化因子水平。
采用定量实时聚合酶链反应测定纤维脂肪组织中棕色、米色和白色脂肪标志物的表达水平。使用液相色谱-质谱联用（LC-MS）对纤维脂肪组织进行脂质组学分析（正常对照[NC]组n = 十；ACM患者组n = 二十四）。采用单细胞RNA测序（NC组n = 二；ACM患者组n = 六）比较心肌中的免疫环境。分别采用免疫染色和酶联免疫吸附测定法检测心肌和血浆样本中CCL3的表达。
与NC组相比，ACM患者纤维脂肪组织中米色（TBX1和TMEM26）和棕色（TNFRSF9）脂肪标志物的表达水平更高。与NC组相比，ACM患者的纤维脂肪组织中饱和甘油三酯（TGs）水平显著升高。单细胞RNA测序显示，与NC组相比，ACM患者心肌中促炎巨噬细胞明显积聚，促炎标志物表达水平较高。ACM患者纤维脂肪组织中CCL3的表达与HF进展呈正相关。ACM患者的血浆CCL3水平显著高于健康志愿者。共有102例ACM患者接受了中位时间为7.8年的随访，这表明血浆CCL3水平能够成功预测ACM患者HF的发生率以及心脏移植（HTx）/死亡情况（风险比= 3.122 [95%置信区间，1.556 - 6.264]）。ROC曲线分析显示，预测HF的AUC值达到0.814，预测HTx/死亡的AUC值为0.756。
纤维脂肪组织中饱和TGs和CCL3水平升高可能促进ACM患者HF的进展。血浆CCL3水平有助于预测ACM患者HF相关不良事件，但需要在更大规模的独立队列中进一步验证。
