Sudden death could be the first symptom of patients with arrhythmogenic cardiomyopathy (AC), a disease for which clinical indicators predicting adverse progression remain lacking. Recent findings suggest that metabolic dysregulation is present in AC. We performed this study to identify metabolic indicators that predicted major adverse cardiac events (MACEs) in patients with AC and their relatives. Comparing explanted hearts from patients with AC and healthy donors, we identified deregulated metabolic pathways using quantitative proteomics. Right ventricles (RVs) from patients with AC displayed elevated ketone metabolic enzymes, OXCT1 and HMGCS2, suggesting higher ketone metabolism in AC RVs. Analysis of matched coronary artery and sinus plasma suggested potential ketone body synthesis at early-stage AC, which was validated using patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in vitro. Targeted metabolomics analysis in RVs from end-stage AC revealed a "burned-out" state, with predominant medium-chain fatty acid rather than ketone body utilization. In an independent validation cohort, 65 probands with mostly non-heart failure manifestations of AC had higher plasma β-hydroxybutyrate (β-OHB) than 62 healthy volunteers (P < 0.001). Probands with AC with MACE had higher β-OHB than those without MACE (P < 0.001). Among 94 relatives of probands, higher plasma β-OHB distinguished 25 relatives having suspected AC from nonaffected relatives. This study demonstrates that elevated plasma β-OHB predicts MACE in probands and disease progression in patients with AC and their clinically asymptomatic relatives.

中文翻译：

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血浆β-羟基丁酸升高可预测心律失常性心肌病患者的不良结局和疾病进展。

猝死可能是心律失常性心肌病（AC）患者的第一个症状，该疾病尚缺乏可预测不良进展的临床指标。最近的发现表明，AC中存在代谢失调。我们进行了这项研究，以识别可预测AC患者及其亲属的主要不良心脏事件（MACE）的代谢指标。比较来自AC患者和健康供体的移植心脏，我们使用定量蛋白质组学鉴定了失控的代谢途径。患有AC的患者的右心室（RV）显示出较高的酮代谢酶OXCT1和HMGCS2，表明AC RV中的酮代谢较高。对匹配的冠状动脉和鼻窦血浆的分析表明，在早期AC中潜在的酮体合成，在体外使用患者来源的诱导多能干细胞来源的心肌细胞（iPSC-CM）进行了验证。对来自末期AC的RV的靶向代谢组学分析显示“倦怠”状态，主要是中链脂肪酸而不是酮体利用率。在一个独立的验证队列中，65位以AC为主的非心力衰竭表现的先证者的血浆β-羟基丁酸酯（β-OHB）高于62位健康志愿者（P <0.001）。有MACE的AC先证者的β-OHB高于没有MACE的先证者（P <0.001）。在先证者的94个亲戚中，较高的血浆β-OHB区分了25个疑似患有AC的亲戚和未受影响的亲戚。这项研究表明，血浆β-OHB升高可预测AC患者及其临床无症状亲属的先证者MACE和疾病进展。