Chong Jun, Ho Andrew Fw, Yap Jonathan, Bulluck Heerajnarain, Hausenloy Derek J
Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom.
National Heart Centre Singapore, Singapore.
Cond Med. 2019 Oct;2(5):204-212.
Cardiac ischemia associated with chemotherapy has been linked to several anti-neoplastic agents and is multifactorial in etiology. Coronary artery vasospasm is one of the most commonly reported effects of cancer therapy that can lead to myocardial ischemia or infarction. The chemotherapy agent 5-fluorouracil (5-FU) or its oral pro-drug capecitabine can result in coronary vascular endothelial dysfunction causing coronary artery spasm, and possibly coronary thrombosis. These drugs have also been shown to be associated with myocardial infarction, malignant ventricular arrhythmias, heart failure, cardiogenic shock, and sudden death. The proposed mechanisms underlying cardiotoxicity induced by 5-FU are vascular endothelial damage followed by thrombus formation, ischemia secondary to coronary artery vasospasm, direct toxicity on myocardium, and thrombogenicity. There remains a pressing need to discover novel and effective therapies that can prevent or ameliorate 5-FU associated cardiotoxicity. To this point, promising overlap has been observed between proposed remote ischemic conditioning (RIC) cardioprotective mechanisms and 5FU-associated cardiotoxic cellular pathways. RIC, in which transient episodes of limb ischemia and reperfusion (induced by inflations and deflations of a pneumatic cuff placed on the upper arm or thigh), confer both cardioprotective and vasculoprotective effects, and may therefore prevent 5-FU coronary artery spasm/cardiotoxicity. In this review, we will be discussing the following potentially therapeutic aspects of RIC in ameliorating 5-FU associated cardiotoxicity: sequential phases of 5-FU cardiotoxicity as possible targets for dual windows of cardioprotection characteristic of RIC; protective effects of RIC on endothelial function and microvasculature in relation to 5-FU induced endothelial dysfunction/microvascular dysfunction; reduction in platelet activation by RIC in the context of 5-FU induced thrombogenicity; and the utility of improvement in mitochondrial function conferred by RIC in 5-FU induced cellular toxicity secondary to mitochondrial dysfunction.
化疗相关的心脏缺血与多种抗肿瘤药物有关，病因是多因素的。冠状动脉血管痉挛是癌症治疗最常报告的效应之一，可导致心肌缺血或梗死。化疗药物5-氟尿嘧啶（5-FU）或其口服前体药物卡培他滨可导致冠状动脉血管内皮功能障碍，引起冠状动脉痉挛，并可能导致冠状动脉血栓形成。这些药物还被证明与心肌梗死、恶性室性心律失常、心力衰竭、心源性休克和猝死有关。5-FU诱导心脏毒性的潜在机制包括血管内皮损伤继之以血栓形成、冠状动脉血管痉挛继发的缺血、对心肌的直接毒性以及血栓形成倾向。迫切需要发现能够预防或改善5-FU相关心脏毒性的新型有效疗法。至此，在提出的远程缺血预处理（RIC）心脏保护机制与5-FU相关心脏毒性细胞途径之间已观察到有前景的重叠。RIC通过在上臂或大腿上放置的气动袖带充气和放气诱导肢体缺血和再灌注的短暂发作，具有心脏保护和血管保护作用，因此可能预防5-FU冠状动脉痉挛/心脏毒性。在本综述中，我们将讨论RIC在改善5-FU相关心脏毒性方面的以下潜在治疗方面：5-FU心脏毒性的连续阶段作为RIC特有的双重心脏保护窗口的可能靶点；RIC对内皮功能和微血管的保护作用与5-FU诱导的内皮功能障碍/微血管功能障碍的关系；在5-FU诱导的血栓形成倾向背景下RIC对血小板活化的降低作用；以及RIC赋予的线粒体功能改善在5-FU诱导的继发于线粒体功能障碍的细胞毒性中的效用。
