Gerçek Mustafa, Gerçek Muhammed, Kant Sebastian, Simsekyilmaz Sakine, Kassner Astrid, Milting Hendrik, Liehn Elisa A, Leube Rudolf E, Krusche Claudia A
Institutes for Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
Institute of Pharmacology and Clinical Pharmacology, Heinrich Heine University, Düsseldorf, Germany.
Am J Pathol. 2017 Apr;187(4):752-766. doi: 10.1016/j.ajpath.2016.12.018. Epub 2017 Feb 7.
Arrhythmogenic cardiomyopathy (AC) is a hereditary disease leading to sudden cardiac death or heart failure. AC pathology is characterized by cardiomyocyte loss and replacement fibrosis. Our goal was to determine whether cardiomyocytes respond to AC progression by pathological hypertrophy. To this end, we examined tissue samples from AC patients with end-stage heart failure and tissue samples that were collected at different disease stages from desmoglein 2-mutant mice, a well characterized AC model. We find that cardiomyocyte diameters are significantly increased in right ventricles of AC patients. Increased mRNA expression of the cardiac stress marker natriuretic peptide B is also observed in the right ventricle of AC patients. Elevated myosin heavy chain 7 mRNA expression is detected in left ventricles. In desmoglein 2-mutant mice, cardiomyocyte diameters are normal during the concealed disease phase but increase significantly after acute disease onset on cardiomyocyte death and fibrotic myocardial remodeling. Hypertrophy progresses further during the chronic disease stage. In parallel, mRNA expression of myosin heavy chain 7 and natriuretic peptide B is up-regulated in both ventricles with right ventricular preference. Calcineurin/nuclear factor of activated T cells (Nfat) signaling, which is linked to pathological hypertrophy, is observed during AC progression, as evidenced by Nfatc2 and Nfatc3 mRNA in cardiomyocytes and increased mRNA of the Nfat target regulator of calcineurin 1. Taken together, we demonstrate that pathological hypertrophy occurs in AC and is secondary to cardiomyocyte loss and cardiac remodeling.
致心律失常性心肌病（AC）是一种导致心源性猝死或心力衰竭的遗传性疾病。AC的病理学特征是心肌细胞丢失和替代性纤维化。我们的目标是确定心肌细胞是否通过病理性肥大对AC进展做出反应。为此，我们检查了晚期心力衰竭AC患者的组织样本以及从桥粒芯糖蛋白2突变小鼠（一种特征明确的AC模型）在不同疾病阶段收集的组织样本。我们发现AC患者右心室的心肌细胞直径显著增加。在AC患者的右心室中还观察到心脏应激标志物利钠肽B的mRNA表达增加。在左心室中检测到肌球蛋白重链7的mRNA表达升高。在桥粒芯糖蛋白2突变小鼠中，在隐匿性疾病阶段心肌细胞直径正常，但在急性疾病发作导致心肌细胞死亡和纤维化心肌重塑后显著增加。在慢性疾病阶段肥大进一步进展。同时，肌球蛋白重链7和利钠肽B的mRNA表达在两个心室中均上调，以右心室为主。在AC进展过程中观察到与病理性肥大相关的钙调神经磷酸酶/活化T细胞核因子（Nfat）信号传导，心肌细胞中的Nfatc2和Nfatc3 mRNA以及钙调神经磷酸酶1的Nfat靶标调节因子的mRNA增加证明了这一点。综上所述，我们证明病理性肥大发生在AC中，并且是心肌细胞丢失和心脏重塑的继发结果。
