Dual Angiotensin Receptor-Neprilysin Inhibition With Sacubitril/Valsartan Attenuates Systolic Dysfunction in Experimental Doxorubicin-Induced Cardiotoxicity

• Published in: JACC CardioOncology Vol. 2; no. 5; pp. 774 - 787
• Main Authors: Boutagy, Nabil E., Feher, Attila, Pfau, Daniel, Liu, Zhao, Guerrera, Nicole M., Freeburg, Lisa A., Womack, Sydney J., Hoenes, Abigail C., Zeiss, Caroline, Young, Lawrence H., Spinale, Francis G., Sinusas, Albert J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2020; Elsevier
• Subjects: anthracycline; echocardiography; Original Research; preclinical study; treatment; Val; treatment; echocardiography; RAAS; LVEF; LV; preclinical study; DOX; ARB; MMP; anthracycline; SAC; AIC; TIMP
• ISSN: 2666-0873; 2666-0873
• DOI: 10.1016/j.jaccao.2020.09.007

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. [Display omitted]