PDF(Pubmed)
Abstract：
Dilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited.
Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster.
Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model).
This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.
Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster.
Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model).
This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.
摘要：
背景：扩张可能是第一个右心室改变，并加速致命性室性心律失常性右心室心肌病（ARVC）患者的室性快速性心律失常和心力衰竭的进展，但右心室扩张的治疗仍然有限.
方法：对来自8名研究参与者的血液和双心室心肌进行单细胞RNA测序（scRNA-seq），包括6例ARVC终末期心力衰竭患者和2例正常对照。然后对ScRNA-seq数据进行了深入分析，包括集群注释，细胞比例计算，以及细胞发育轨迹和相互作用的表征。对我们的单细胞数据和已发表的基于全基因组关联研究的数据的综合分析提供了对ARVC心律失常表型的细胞特异性贡献的见解。以Desmoglein2（Dsg2）mut/mut小鼠为ARVC模型，验证药物干预对已识别细胞簇的治疗作用。
结果：ARVC右心室富含CCL3+促炎巨噬细胞和TNMD+成纤维细胞。成纤维细胞优先在ARVC中受到影响，与ARVC相关的扰动与那些存在于与心律失常相关的遗传变异中的扰动重叠。促炎巨噬细胞与成纤维细胞强烈相互作用。Nod样受体蛋白3（NLRP3）的药理学抑制，主要由CCL3+促炎巨噬细胞和其他一些髓系亚簇表达的转录因子，可以显着减轻Dsg2mut/mut小鼠（ARVC小鼠模型）的右心室扩张和功能障碍。
结论：本研究以单细胞分辨率全面分析了ARVC患者血液和心肌的谱系特异性变化。药物抑制NLRP3可以预防ARVC小鼠右心室扩张和功能障碍。
方法：对来自8名研究参与者的血液和双心室心肌进行单细胞RNA测序（scRNA-seq），包括6例ARVC终末期心力衰竭患者和2例正常对照。然后对ScRNA-seq数据进行了深入分析，包括集群注释，细胞比例计算，以及细胞发育轨迹和相互作用的表征。对我们的单细胞数据和已发表的基于全基因组关联研究的数据的综合分析提供了对ARVC心律失常表型的细胞特异性贡献的见解。以Desmoglein2（Dsg2）mut/mut小鼠为ARVC模型，验证药物干预对已识别细胞簇的治疗作用。
结果：ARVC右心室富含CCL3+促炎巨噬细胞和TNMD+成纤维细胞。成纤维细胞优先在ARVC中受到影响，与ARVC相关的扰动与那些存在于与心律失常相关的遗传变异中的扰动重叠。促炎巨噬细胞与成纤维细胞强烈相互作用。Nod样受体蛋白3（NLRP3）的药理学抑制，主要由CCL3+促炎巨噬细胞和其他一些髓系亚簇表达的转录因子，可以显着减轻Dsg2mut/mut小鼠（ARVC小鼠模型）的右心室扩张和功能障碍。
结论：本研究以单细胞分辨率全面分析了ARVC患者血液和心肌的谱系特异性变化。药物抑制NLRP3可以预防ARVC小鼠右心室扩张和功能障碍。
