Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
J Transl Med. 2019 Jul 19;17(1):229. doi: 10.1186/s12967-019-1978-0.
Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy.
Male Wistar rats (n = 7-11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro.
The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis.
For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment.
化疗引起的左心室功能障碍是一个主要的临床问题，通常只有在晚期才被发现，此时支持治疗无效。虽然早期心力衰竭治疗可以积极影响健康状况和临床结果，但对于大多数没有心血管病史的患者，在接受潜在的心脏毒性化疗之前，仍然没有常规预防性心脏保护的证据。在这项研究中，我们旨在研究与常规心力衰竭治疗相比，预防性心脏保护治疗是否更有效地预防阿霉素（DOX）诱导的心肌病的心脏毒性。
雄性 Wistar 大鼠（每组 7-11 只）分为 4 个亚组，即接受静脉内生理盐水（CON）的阴性对照、接受静脉内 DOX（6 个周期；D-CON）的阳性对照，以及接受预防性（PRE，在 DOX 前 1 周开始）或常规应用（POST，在 DOX 后 1 个月开始）联合心力衰竭治疗的口服比索洛尔、培哚普利和依普利酮的 DOX 处理动物。在体内监测血压、心率、体重和超声心动图参数，而心肌纤维化、毛细血管化、超微结构、肌丝功能、细胞凋亡、氧化应激和线粒体生物发生在体外进行研究。
与 D-CON 相比，PRE 组的存活率显著提高（p=0.0207）。DOX 增加了动物的心率（p=0.0193），而 PRE 组的血压（p≤0.0105）和心率（p=0.0029）与 D-CON 和 POST 相比显著降低。与 D-CON 或 POST 相比，PRE 组的射血分数保持不变（p≤0.0237），而任何治疗都不能预防 DOX 诱导的等容舒张时间增加。DOX 降低了肌球蛋白交叉桥循环的速度，无论应用何种治疗（p≤0.0433）。D-CON 和 POST 动物的心肌显示出明显的超微结构损伤，而 PRE 组则没有（p≤0.033）。虽然 DOX 诱导的细胞凋亡活性可以在 PRE 和 POST 组中降低（p≤0.0433），但没有一种治疗能够预防纤维化重塑或受损的线粒体生物发生。
为了减轻 DOX 引起的心肌不良影响，预防性心脏保护与晚期应用治疗相比具有许多优势。
