Aims Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). We aim to study clinical parameters and long-term outcomes related to the TTNtv genotype and determine the related molecular changes at tissue level in TTNtv DCM patients. Methods and results A total of 303 consecutive and extensively phenotyped DCM patients (including cardiac imaging, Holter monitoring, and endomyocardial biopsy) underwent DNA sequencing of 47 cardiomyopathy-associated genes including TTN, yielding 38 TTNtv positive (13%) patients. At long-term follow-up (median of 45 months, up to 12 years), TTNtv DCM patients had increased ventricular arrhythmias compared to other DCM, but a similar survival. Arrhythmias are especially prominent in TTNtv patients with an additional environmental trigger (i.e. virus infection, cardiac inflammation, systemic disease, toxic exposure). Importantly, cardiac mass is reduced in TTNtv patients, despite similar cardiac function and dimensions at cardiac magnetic resonance. These enhanced life-threatening arrhythmias and decreased cardiac mass in TTNtv DCM patients go along with significant cardiac energetic and matrix alterations. All components of the mitochondrial electron transport chain are significantly upregulated in TTNtv hearts at RNA-sequencing. Also, interstitial fibrosis was augmented in TTNtv patients at histological and transcript level. Conclusion Truncating titin variants lead to pronounced cardiac alterations in mitochondrial function, with increased interstitial fibrosis and reduced hypertrophy. Those structural and metabolic alterations in TTNtv hearts go along with increased ventricular arrhythmias at long-term follow-up, with a similar survival and overall cardiac function.

中文翻译：

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Titin 心肌病导致线粒体能量改变、纤维化增加和长期危及生命的心律失常

目的 截断肌联蛋白变异 (TTNtv) 是扩张型心肌病 (DCM) 最常见的遗传原因。我们旨在研究与 TTNtv 基因型相关的临床参数和长期结果，并确定 TTNtv DCM 患者组织水平的相关分子变化。方法和结果 共有 303 名连续和广泛表型的 DCM 患者（包括心脏成像、动态心电图监测和心内膜心肌活检）接受了包括 TTN 在内的 47 个心肌病相关基因的 DNA 测序，产生 38 名 TTNtv 阳性（13%）患者。在长期随访中（中位数为 45 个月，长达 12 年），与其他 DCM 相比，TTNtv DCM 患者的室性心律失常增加，但生存率相似。心律失常在具有额外环境触发因素（即病毒感染、心脏炎症、全身性疾病、毒性暴露）。重要的是，尽管心脏磁共振的心脏功能和尺寸相似，但 TTNtv 患者的心脏质量减少。在 TTNtv DCM 患者中，这些增强的危及生命的心律失常和减少的心脏质量伴随着显着的心脏能量和基质改变。线粒体电子传递链的所有成分在 RNA 测序时在 TTNtv 心脏中显着上调。此外，在组织学和转录水平上，TTNtv 患者的间质纤维化增加。结论 截断肌联蛋白变异导致线粒体功能的明显心脏改变，间质纤维化增加和肥大减少。