Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernandez Almagro, 3. 28029 Madrid, Spain.
Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Spain.
Cardiovasc Res. 2021 Mar 21;117(4):1132-1143. doi: 10.1093/cvr/cvaa181.
Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC.
Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs.
In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
蒽环类药物诱导的心脏毒性（AIC）是癌症患者的一种严重不良反应。AIC 的一个中心机制是不可逆的线粒体损伤。尽管付出了巨大努力，但目前尚无有效的疗法能够预防 AIC。
纳入 40 头大白猪。在研究 1 中，20 头猪随机 1:1 分为远程缺血预处理（RIPC，3 个周期的 5 分钟腿部缺血，然后再灌注 5 分钟）或无预处理。RIPC 在每周 0、2、4、6 和 8 给予阿霉素（0.45mg/kg）的每个冠状动脉内注射之前立即进行。一组 10 头未接触阿霉素的猪作为健康对照。猪在基线和第 6、8、12 和 16 周进行了一系列心脏磁共振（CMR）检查，然后进行了安乐死。在研究 2 中，10 头新猪接受了 3 次阿霉素注射（有无 RIPC 预处理），并在第 6 周进行了安乐死。在研究 1 中，接受 RIPC 预处理的阿霉素（RIPC-Doxo）动物的左心室射血分数（LVEF）下降得到缓解，其在第 16 周的 LVEF 明显高于未接受预处理的阿霉素治疗猪（Untreated-Doxo）（41.5±9.1%对 32.5±8.7%，P=0.04）。这主要是由于局部收缩功能的保持。在研究 2 中，第 6 周的透射电子显微镜（TEM）显示，在未接受 Doxo 治疗的猪中，线粒体出现碎片化，形态异常严重，同时分裂和自噬蛋白上调。在为期 16 周的研究 1 方案结束时，TEM 显示未接受 Doxo 治疗的猪出现明显的线粒体碎片化和结构碎片化，而 RIPC+Doxo 猪的间质纤维化程度较轻。
在可转化的大型动物 AIC 模型中，阿霉素注射前立即应用 RIPC 可导致心脏收缩力保持，LVEF 长期显著升高，心脏纤维化程度降低。RIPC 可预防 AIC 早期的线粒体碎片化和调节失常的自噬。RIPC 是一种有前途的干预措施，可在 AIC 的临床试验中进行测试。
