Dual Angiotensin Receptor-Neprilysin Inhibition With Sacubitril/Valsartan Attenuates Systolic Dysfunction in Experimental Doxorubicin-Induced Cardiotoxicity.
Dual Angiotensin Receptor-Neprilysin Inhibition With Sacubitril/Valsartan Attenuates Systolic Dysfunction in Experimental Doxorubicin-Induced Cardiotoxicity.
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DOI：
10.1016/j.jaccao.2020.09.007
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Sinusas AJ
中科院分区：
文献类型：
--
作者：
Boutagy NE;Feher A;Pfau D;Liu Z;Guerrera NM;Freeburg LA;Womack SJ;Hoenes AC;Zeiss C;Young LH;Spinale FG;Sinusas AJ
阿霉素（DOX）通过激活基质金属蛋白酶（MMPs）诱导心脏毒性。沙库巴曲/缬沙坦（Sac/瓦尔）在心肌梗死临床前模型和心力衰竭患者中发挥的心脏保护作用超过了肾素-血管紧张素-醛固酮抑制剂。我们假设Sac/瓦尔比瓦尔在进行性DOX诱导的心脏毒性的啮齿动物模型中具有更好的心脏保护作用，并且这种益处与MMP活化的调节相关。我们试图研究Sac/瓦尔治疗蒽环类药物引起的心脏毒性的有效性。雄性Wistar大鼠在3周内腹膜内接受DOX（累积15 mg/kg）或盐水。在第一次治疗后，对照动物每天管饲水（n = 25），而DOX治疗的动物每天管饲水（n = 25）、瓦尔（31 mg/kg; n = 25）或Sac/瓦尔（68 mg/kg; n = 25），持续4或6周。超声心动图在基线时和DOX开始后4周和6周进行。此外，心肌MMP活性与99 mTc-RP 805进行了评估，心脏毒性的严重程度进行了评估，在这些时间点在一个亚组的动物。在6周时，DOX和DOX +瓦尔大鼠的左心室射血分数降低了10%（均p < 0.05），而这种降低在DOX + Sac/瓦尔大鼠中减弱。MMP活性在6周时在单独DOX的大鼠中增加76%，并且在DOX +瓦尔大鼠中倾向于增加（36%; p = 0.051），但是与时间匹配的对照动物相比，在DOX + Sac/瓦尔大鼠中是相似的。两种疗法都减弱了细胞毒性和纤维化的组织学证据（p < 0.05）。在进行性DOX诱导的心脏毒性啮齿动物模型中，与标准血管紧张素受体阻滞剂治疗相比，Sac/瓦尔对左心室重塑和功能障碍提供了更好的保护。
Doxorubicin (DOX) induces cardiotoxicity in part by activation of matrix metalloproteinases (MMPs). Sacubitril/valsartan (Sac/Val) exerts additive cardioprotective actions over renin-angiotensin-aldosterone inhibitors in preclinical models of myocardial infarction and in heart failure patients. We hypothesized that Sac/Val would be more cardioprotective than Val in a rodent model of progressive DOX-induced cardiotoxicity, and this benefit would be associated with modulation of MMP activation. We sought to investigate the efficacy of Sac/Val for the treatment of anthracycline-induced cardiotoxicity. Male Wistar rats received DOX intraperitoneally (15 mg/kg cumulative) or saline over 3 weeks. Following the first treatment, control animals were gavaged daily with water (n = 25), while DOX-treated animals were gavaged daily with water (n = 25), Val (31 mg/kg; n = 25) or Sac/Val (68 mg/kg; n = 25) for either 4 or 6 weeks. Echocardiography was performed at baseline, and 4 and 6 weeks after DOX initiation. In addition, myocardial MMP activity was assessed with 99mTc-RP805, and cardiotoxicity severity was assessed by histology at these time points in a subgroup of animals. Left ventricular ejection fraction decreased by 10% at 6 weeks in DOX and DOX + Val rats (both p < 0.05), while this reduction was attenuated in DOX + Sac/Val rats. MMP activity was increased at 6 weeks by 76% in DOX-alone rats, and tended to increase in DOX + Val rats (36%; p = 0.051) but was similar in DOX + Sac/Val rats as compared with time-matched control animals. Both therapies attenuated histological evidence of cellular toxicity and fibrosis (p < 0.05). Sac/Val offers greater protection against left ventricular remodeling and dysfunction compared with standard angiotensin receptor blocker therapy in a rodent model of progressive DOX-induced cardiotoxicity.
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影响因子：
1.9
作者：
Akolkar G;Bhullar N;Bews H;Shaikh B;Premecz S;Bordun KA;Cheung DY;Goyal V;Sharma AK;Garber P;Singal PK;Jassal DS
通讯作者：
Jassal DS
影响因子：
2.4
作者：
Russell, Raymond R.;Alexander, Jonathan;Schwartz, Ronald G.
通讯作者：
Schwartz, Ronald G.
影响因子：
4.8
作者：
Cadeddu, Christian;Piras, Alessandra;Mercuro, Giuseppe
通讯作者：
Mercuro, Giuseppe
影响因子：
45.3
作者：
Silber, JH;Cnaan, A;Zhao, HQ
通讯作者：
Zhao, HQ
影响因子：
9.7
作者：
Boutagy, Nabil E.;Wu, Jing;Sinusas, Albert J.
通讯作者：
Sinusas, Albert J.