Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro-adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low-density lipoprotein (oxLDL)-dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient-derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock-out mice through high-fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies.

中文翻译：

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氧化低密度脂蛋白依赖性途径是致心律失常性心肌病的新致病触发因素

致心律失常性心肌病（ACM）的特点是心室纤维脂肪形成改变，导致心功能障碍和心律失常。尽管 ACM 表型是由基因决定的（例如PKP2突变），但其差异很大。等待更多关于表型调节剂、临床预测和病因治疗的数据。我们假设氧化低密度脂蛋白 (oxLDL) 依赖性 PPARγ 激活（ACM 脂肪生成的公认效应物）有助于疾病发病机制。血浆 oxLDL 浓度高的 ACM 患者在脂肪浸润、心室功能障碍和主要心律失常事件风险方面表现出严重的临床表型。在 ACM 患者来源的心肌细胞中，我们证明 oxLDL 是脂肪生成的主要辅助因子。从机制上讲，脂质积累的增加是由 oxLDL 细胞通过 CD36 内化介导的，最终导致 PPARγ 上调。通过高脂饮食喂养来提高Pkp2杂合基因敲除小鼠的 oxLDL ，我们在体内证实了心脏脂肪生成和右心室收缩损伤的氧化脂质依赖性，而阿托伐他汀治疗可以抵消这种依赖性。氧化脂质对 ACM 脂肪生成的调节作用已在细胞、小鼠和患者水平上得到证实，代表了一种新的风险分层工具和 ACM 药理学策略的目标。