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，可引起严重的心脏毒性副作用，最终导致充血性心力衰竭 (HF)。目前没有临床成像技术或生物标志物可用于在功能下降之前检测 DOX 心脏毒性。线粒体功能障碍被认为是导致功能下降的关键因素，尽管实时代谢通量从未在 DOX 心脏毒性中进行过评估。超极化磁共振成像 (MRI) 可以评估体内的实时代谢通量。在这里，我们表明，在临床相关的 DOX-HF 大鼠模型中，心脏功能下降之前是通过超极化 MRI 测量的氧化线粒体碳水化合物代谢的变化。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，而不是像迄今为止普遍认为的那样，氧化应激。由于超极化 MRI 已成功转化为临床试验，这开辟了测试接受 DOX 的癌症患者心脏毒性早期迹象的潜力。