Bueto-Beni Carlos, Tafuni Alessandro, Chelko Stephen P, Sheppard Mary N, Field Ella, Tollit Jennifer, Heenan Imogen K, Barnes Annabelle, Taylor Matthew R, Mestroni Luisa, Kaski Juan Pablo, Saffitz Jeffrey E, Asimaki Angeliki
bioRxiv. 2023 Jul 27:2023.07.25.550526. doi: 10.1101/2023.07.25.550526.
We sought to determine if persistent innate immune signaling via NFκB occurs in cardiac myocytes in patients with arrhythmogenic cardiomyopathy and if this is associated with myocardial infiltration of pro-inflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NFκB signaling.
NFκB signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing CCR2-expressing macrophages which promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with arrhythmogenic cardiomyopathy.
We analyzed myocardium from arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NFκB signaling. We also counted myocardial CCR2-expressing cells.
NFκB signaling was seen in cardiac myocytes in 34 of 36 cases of arrhythmogenic cardiomyopathy but in none of 19 age-matched controls. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NFκB signaling. NFκB signaling also occurred in buccal cells in young subjects with active disease.
Patients with clinically active arrhythmogenic cardiomyopathy exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells reflecting an inflammatory process that fails to resolve. Such individuals may benefit from anti-inflammatory therapy.
NFκB signaling in cardiac myocytes causes arrhythmias and myocardial injury in a mouse model of arrhythmogenic cardiomyopathy by mobilizing pro-inflammatory CCR2-expressing macrophages to the heart. Based on these new mechanistic insights, we analyzed hearts of arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We observed active NFκB signaling in cardiac myocytes associated with marked infiltration of CCR2-expressing cells. We also observed NFκB signaling in buccal mucosa cells obtained from young subjects with active disease. Thus, anti-inflammatory therapy may be effective in arrhythmogenic cardiomyopathy. Screening buccal cells may be a reliable way to identify patients most likely to benefit.
Inflammation likely contributes to the pathogenesis of arrhythmogenic cardiomyopathy but the responsible mechanisms and the roles of specific classes of immune cells remain undefined.NFκB signaling in cardiac myocytes is sufficient to cause disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing injurious myeloid cells expressing CCR2 to the heart.Here, we provide evidence of persistent NFκB signaling in cardiac myocytes and increased CCR2-expressing cells in hearts of patients with arrhythmogenic cardiomyopathy. We observed a close correlation between the number of cardiac myocytes with active NFκB signaling and the number of CCR2-expressing cells in patient hearts.We also provide evidence of active NFκB signaling in buccal mucosa cells associated with initial onset of disease and/or disease progression in young subjects with arrhythmogenic cardiomyopathy alleles.
我们试图确定致心律失常性心肌病患者的心肌细胞中是否通过核因子κB（NFκB）发生持续的固有免疫信号传导，以及这是否与表达CCR2的促炎细胞的心肌浸润有关。我们还确定了携带遗传性疾病等位基因的年轻受试者的颊黏膜细胞是否表现出NFκB信号传导。
心肌细胞中的NFκB信号传导通过动员表达CCR2的巨噬细胞导致致心律失常性心肌病小鼠模型发病，这些巨噬细胞会促进心肌损伤和心律失常。颊黏膜细胞表现出与致心律失常性心肌病患者心肌细胞中所见相似的病理特征。
我们分析了猝死或需要心脏移植的致心律失常性心肌病患者的心肌。我们还分析了携带遗传性疾病等位基因的年轻受试者的颊黏膜细胞。心肌细胞和颊细胞细胞核中RelA/p65免疫反应性信号的存在被用作活跃NFκB信号传导的可靠指标。我们还对心肌中表达CCR2的细胞进行了计数。
在36例致心律失常性心肌病患者中，有34例的心肌细胞中可见NFκB信号传导，而19例年龄匹配的对照者中均未发现。患者心脏中表达CCR2的细胞数量增加，且与显示NFκB信号传导的心肌细胞数量直接相关。携带活跃疾病的年轻受试者的颊细胞中也出现了NFκB信号传导。
具有临床活动性致心律失常性心肌病的患者在心肌细胞和颊黏膜细胞中表现出持续的固有免疫反应，反映出炎症过程无法消退。这类患者可能从抗炎治疗中获益。
心肌细胞中的NFκB信号传导通过将表达促炎CCR2的巨噬细胞动员至心脏，在致心律失常性心肌病小鼠模型中导致心律失常和心肌损伤。基于这些新的机制见解，我们分析了猝死或需要心脏移植的致心律失常性心肌病患者的心脏。我们观察到心肌细胞中有活跃的NFκB信号传导，伴有表达CCR2的细胞明显浸润。我们还在携带活跃疾病的年轻受试者的颊黏膜细胞中观察到了NFκB信号传导。因此，抗炎治疗可能对致心律失常性心肌病有效。筛查颊细胞可能是识别最可能获益患者的可靠方法。
炎症可能促成致心律失常性心肌病的发病机制，但相关机制以及特定类型免疫细胞的作用仍不明确。心肌细胞中的NFκB信号传导足以通过将表达CCR2的损伤性髓样细胞动员至心脏，在致心律失常性心肌病小鼠模型中导致疾病。在此，我们提供了致心律失常性心肌病患者心肌细胞中持续NFκB信号传导以及心脏中表达CCR2细胞增加的证据。我们观察到患者心脏中具有活跃NFκB信号传导的心肌细胞数量与表达CCR2的细胞数量密切相关。我们还提供了携带致心律失常性心肌病等位基因的年轻受试者颊黏膜细胞中与疾病初始发作和/或疾病进展相关的活跃NFκB信号传导的证据。
