Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy
Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy
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DOI：
10.1126/scitranslmed.aay8329
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发表时间：
2020-02-12
影响因子：
17.1
通讯作者：
Hu, Sheng-Shou
中科院分区：
文献类型：
--
作者：
Song, Jiang-Ping;Chen, Liang;Hu, Sheng-Shou
猝死可能是致瘤性心肌病（AC）患者的首发症状，这种疾病仍然缺乏预测不良进展的临床指标。最近的研究结果表明，代谢失调是目前在AC。我们进行这项研究，以确定预测AC患者及其亲属主要不良心脏事件（MACE）的代谢指标。比较AC患者和健康供体的心脏，我们使用定量蛋白质组学鉴定了失调的代谢途径。AC患者的右心室（RV）显示酮代谢酶OXCT 1和HMGCS 2升高，表明AC RV的酮代谢较高。匹配的冠状动脉和窦血浆的分析表明，在早期AC时可能有酮体合成，这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。对来自终末期AC的RV进行的靶向代谢组学分析显示了一种“耗尽”状态，主要是中链脂肪酸而不是酮体利用。在一个独立的验证队列中，65名AC先证者的血浆β-羟基丁酸（β-OHB）水平高于62名健康志愿者（P < 0.001）。AC先证者中有MACE者β-OHB明显高于无MACE者（P < 0.001）。在94名先证者亲属中，较高的血浆β-OHB将25名疑似AC的亲属与未受影响的亲属区分开来。这项研究表明，血浆β-OHB升高可预测先证者的MACE和AC患者及其临床无症状亲属的疾病进展。
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 beta-hydroxybutyrate (beta-OHB) than 62 healthy volunteers (P < 0.001). Probands with AC with MACE had higher beta-OHB than those without MACE (P < 0.001). Among 94 relatives of probands, higher plasma beta-OHB distinguished 25 relatives having suspected AC from nonaffected relatives. This study demonstrates that elevated plasma beta-OHB predicts MACE in probands and disease progression in patients with AC and their clinically asymptomatic relatives.