Effects of 6-mercaptopurine in pressure overload induced right heart failure

BackgroundSeveral antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB).MethodsMale Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses.ResultsPTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats.ConclusionTreatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.

背景：已有多种抗肿瘤药物被提议作为肺动脉高压（pulmonary arterial hypertension）治疗的新型候选化合物，但其中多数存在心脏毒性副作用。化疗药物6-巯基嘌呤（6-mercaptopurine）或可用于肺动脉高压的治疗，但与此同时，由于其与心肌细胞内多条下游信号通路存在相互作用，其对右心室后负荷适应的影响难以预测。本研究旨在探究6-巯基嘌呤对由肺动脉干环扎术（pulmonary trunk banding, PTB）诱导的孤立性右心衰竭大鼠的直接心脏作用。
方法：将雄性Wistar断奶大鼠（体重112±2g）随机分为假手术组（sham组，n=10）与肺动脉干环扎术组。后者再进一步随机分为安慰剂对照组（PTB-control组，n=10）以及6-巯基嘌呤干预组：其中干预于肺动脉干环扎术前启动（PTB-prevention组，n=10），或于术后两周启动（PTB-reversal组，n=10）。通过超声心动图、心脏磁共振成像、有创压力-容积测量以及组织学与分子生物学分析，对右心室效应进行评估。
结果：肺动脉干环扎术可升高右心室后负荷，诱导右心室肥厚与衰竭。与安慰剂对照组大鼠相比，无论是术前预防干预还是术后逆转干预，6-巯基嘌呤均未改善右心室功能，亦未减轻右心室重构。
结论：6-巯基嘌呤给药对右心室功能与重构无任何有益或有害影响。本研究数据表明，采用6-巯基嘌呤治疗肺动脉高压，不会对衰竭的右心室造成损伤。