血管紧张素受体脑啡肽酶抑制剂在实验性心肌梗死后提供比血管紧张素转换酶抑制剂更优越的心脏保护作用。
Angiotensin receptor neprilysin inhibition provides superior cardioprotection compared to angiotensin converting enzyme inhibition after experimental myocardial infarction.
机构信息
Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Department of Stomatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
出版信息
Int J Cardiol. 2018 May 1;258:192-198. doi: 10.1016/j.ijcard.2018.01.077.
BACKGROUND
Angiotensin receptor neprilysin inhibitor (ARNi) enhances beneficial natriuretic peptides by inhibiting their breakdown through neprilysin. Although the first-in-class ARNi sacubitril/valsartan (LCZ696) reduced mortality and morbidity in heart failure (HF) with reduced ejection fraction (EF) compared to angiotensin converting enzyme inhibitor (ACEi), mechanistic data on ARNi are scarce. ARNi may be superior to ACEi in attenuating adverse cardiac remodeling and dysfunction post-myocardial infarction (MI).
METHODS
Rats randomized at 1 week post-MI were administered LCZ696 (60 mg/kg, N = 12), the ACEi perindopril (2 mg/kg, N = 11) or vehicle (corn oil, N = 13), orally for 4 weeks. Sham rats received vehicle (corn oil, N = 9). Echocardiography was assessed before and after treatment, prior to invasive hemodynamics using pressure-volume analysis. Hypertrophy and fibrosis was evaluated by histochemical staining, and analysis of myocardial gene and protein expression using real-time quantitative PCR and Western blot.
RESULTS
Compared to Sham, MI groups had large infarcts (>40%) and reduced left ventricular (LV) EF. LCZ696 improved LVEF and end systolic pressure-volume relationship compared to perindopril (P < 0.05). LCZ696 but not perindopril reduced lung weight and LV filling pressures post-MI. Reductions in cardiac hypertrophy and fibrosis were similar, however gene expression of hypertrophic markers, ANP and βMHC were reduced with LCZ696 versus perindopril. LCZ696 versus perindopril reduced myocardial TIMP2 gene expression with a trend (P = 0.067) to lowering collagen I.
CONCLUSION
LCZ696 attenuated adverse cardiac remodeling and dysfunction and reduced pulmonary congestion and hypertrophic markers after MI compared to perindopril. This study supports clinical evaluation of ARNi versus ACEi in targeting post-MI cardiac dysfunction and remodeling.
背景
血管紧张素受体脑啡肽酶抑制剂（ARNi）通过抑制脑啡肽酶分解利钠肽来增强其有益作用。尽管首个 ARNi 沙库巴曲缬沙坦（LCZ696）与血管紧张素转换酶抑制剂（ACEi）相比，可降低射血分数降低的心力衰竭（HF）患者的死亡率和发病率，但 ARNi 的机制数据仍很有限。ARNi 可能在减轻心肌梗死后（MI）的不良心脏重构和功能障碍方面优于 ACEi。
方法
MI 后 1 周随机分组的大鼠分别给予 LCZ696（60mg/kg，N=12）、ACEi 培哚普利（2mg/kg，N=11）或载体（玉米油，N=13），连续口服 4 周。假手术大鼠给予载体（玉米油，N=9）。治疗前后进行超声心动图评估，在使用压力-容积分析进行侵入性血流动力学评估之前。通过组织化学染色以及实时定量 PCR 和 Western blot 分析心肌基因和蛋白表达来评估心肌肥厚和纤维化。
结果
与 Sham 相比，MI 组有较大的梗死（>40%）和左心室（LV）射血分数降低。与培哚普利相比，LCZ696 改善了 LVEF 和收缩末期压力-容积关系（P<0.05）。LCZ696 而非培哚普利降低了 MI 后肺重和 LV 充盈压。心肌肥厚和纤维化的减少相似，但 LCZ696 与培哚普利相比，心脏肥厚标志物、ANP 和βMHC 的基因表达降低。LCZ696 与培哚普利相比，降低了心肌 TIMP2 基因表达，有降低趋势（P=0.067）。
结论
与培哚普利相比，LCZ696 可减轻 MI 后不良的心脏重构和功能障碍，并减少肺充血和肥厚标志物。本研究支持在针对 MI 后心脏功能障碍和重构方面，对 ARNi 与 ACEi 进行临床评估。
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