PDF(Pubmed)
Abstract：
The objective of this study was to determine associations of paraoxonase-1 (PON-1) with development of cancer therapy-related cardiac dysfunction (CTRCD). PON-1 is a cardioprotective enzyme associated with high-density lipoprotein that prevents oxidized low-density lipoprotein formation. Given the role of oxidative stress in doxorubicin-induced cardiotoxicity, PON-1 activity may have relevance for the prediction of CTRCD. In 225 patients with breast cancer receiving doxorubicin with or without trastuzumab, we quantified PON-1 activity through its paraoxonase (Pon) and arylesterase (Aryl) enzymatic activity at baseline, during, and after doxorubicin completion. Echocardiograms were performed at baseline, during therapy, and annually. CTRCD was defined as a decrease in left ventricular ejection fraction by ≥10% from baseline to <50%. Associations between baseline biomarkers and clinical variables were determined using multivariable linear regression. Associations between changes in biomarker activity and time to CTRCD were evaluated using Cox regression. Pon was directly associated with Black race and inversely associated with Stage 2 cancer. Aryl was inversely associated with body mass index. After doxorubicin completion, activity levels of Pon and Aryl were significantly decreased (median ratio compared with baseline for Pon: 0.95 [Q1-Q3: 0.81-1.07, P < 0.001]; for Aryl: 0.97 [Q1-Q3: 0.85-1.08, P = 0.010]). A total of 184 patients had an available quantitated echocardiogram at baseline and at least 1 follow-up visit. Increases from baseline in Pon at doxorubicin completion were independently associated with increased CTRCD risk (per 10% increase: hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05-1.39; P = 0.007). Associations between increases in Aryl and CTRCD tended in the same direction but were of borderline statistical significance (HR: 1.17; 95% CI: 0.99-1.38; P = 0.071). In patients with breast cancer treated with doxorubicin with or without trastuzumab, increases in the Pon enzymatic activity level of PON-1 were associated with increased CTRCD risk. PON-1 activity may be relevant to mechanistic risk prediction of cardiotoxicity with anthracyclines.
摘要：
这项研究的目的是确定对氧磷酶-1（PON-1）与癌症治疗相关的心脏功能障碍（CTRCD）发展的关系。PON-1是与高密度脂蛋白相关的心脏保护酶，可防止氧化低密度脂蛋白形成。鉴于氧化应激在阿霉素诱导的心脏毒性中的作用，PON-1活性可能与CTRCD的预测相关。在225例接受阿霉素联合或不联合曲妥珠单抗的乳腺癌患者中，我们通过基线时的对氧磷酶（Pon）和芳基酯酶（Aryl）酶活性定量PON-1的活性，during,阿霉素完成后。在基线时进行超声心动图检查，治疗期间,和每年。CTRCD定义为左心室射血分数从基线下降≥10%至<50%。使用多变量线性回归确定基线生物标志物与临床变量之间的关联。使用Cox回归评估生物标志物活性变化与CTRCD时间之间的关联。Pon与黑人种族直接相关，与2期癌症成反比。芳基与体重指数呈负相关。阿霉素完成后，Pon和芳基的活性水平显著降低(Pon与基线相比的中位数:0.95[Q1-Q3:0.81-1.07,P<0.001];芳基:0.97[Q1-Q3:0.85-1.08,P=0.010]).总共184名患者在基线和至少1次随访时进行了定量超声心动图检查。完成多柔比星时Pon的基线增加与CTRCD风险增加独立相关（每增加10％：风险比[HR]：1.21;95％置信区间[CI]：1.05-1.39;P=0.007）。芳基和CTRCD的增加之间的关联趋于相同方向，但具有临界统计学意义（HR：1.17；95％CI：0.99-1.38；P=0.071）。在多柔比星联合或不联合曲妥珠单抗治疗的乳腺癌患者中，PON-1的Pon酶活性水平增加与CTRCD风险增加相关.PON-1活性可能与蒽环类药物心脏毒性的机制风险预测有关。
