Timm Kerstin N, Perera Charith, Ball Vicky, Henry John A, Miller Jack J, Kerr Matthew, West James A, Sharma Eshita, Broxholme John, Logan Angela, Savic Dragana, Dodd Michael S, Griffin Julian L, Murphy Michael P, Heather Lisa C, Tyler Damian J
Department of Physiology Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK.
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
Commun Biol. 2020 Nov 19;3(1):692. doi: 10.1038/s42003-020-01440-z.
Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects culminating in congestive heart failure (HF). There are currently no clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline. Mitochondrial dysfunction is thought to be a key factor driving functional decline, though real-time metabolic fluxes have never been assessed in DOX-cardiotoxicity. Hyperpolarized magnetic resonance imaging (MRI) can assess real-time metabolic fluxes in vivo. Here we show that cardiac functional decline in a clinically relevant rat-model of DOX-HF is preceded by a change in oxidative mitochondrial carbohydrate metabolism, measured by hyperpolarized MRI. The decreased metabolic fluxes were predominantly due to mitochondrial loss and additional mitochondrial dysfunction, and not, as widely assumed hitherto, to oxidative stress. Since hyperpolarized MRI has been successfully translated into clinical trials this opens up the potential to test cancer patients receiving DOX for early signs of cardiotoxicity.
阿霉素（DOX）是一种广泛使用的化疗药物，可导致严重的心脏毒性副作用，最终发展为充血性心力衰竭（HF）。目前尚无临床成像技术或生物标志物可在功能衰退前检测出DOX心脏毒性。线粒体功能障碍被认为是导致功能衰退的关键因素，不过尚未在DOX心脏毒性中评估实时代谢通量。超极化磁共振成像（MRI）可以在体内评估实时代谢通量。在此我们表明，在一个与临床相关的DOX-HF大鼠模型中，心脏功能衰退之前会出现氧化线粒体碳水化合物代谢的变化，这是通过超极化MRI测量得出的。代谢通量降低主要是由于线粒体丢失和额外的线粒体功能障碍，而不是像迄今广泛假设的那样，是由于氧化应激。由于超极化MRI已成功转化为临床试验，这为检测接受DOX治疗的癌症患者心脏毒性的早期迹象开辟了可能性。
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