Sacubitril/Valsartan Improves Left Atrial and Left Atrial Appendage Function in Patients With Atrial Fibrillation and in Pressure Overload-Induced Mice
Sacubitril/Valsartan Improves Left Atrial and Left Atrial Appendage Function in Patients With Atrial Fibrillation and in Pressure Overload-Induced Mice
复制标题
沙库巴曲/缬沙坦改善心房颤动患者和压力过载诱导小鼠的左心房和左心耳功能
DOI：
10.3389/fphar.2019.01285
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发表时间：
2019-10-29
影响因子：
5.6
通讯作者：
Li, Guangping
中科院分区：
文献类型：
--
作者：
Suo, Ya;Yuan, Meng;Li, Guangping
LCZ 696（沙库巴曲/缬沙坦）是一种血管紧张素受体-脑啡肽酶抑制剂，对心力衰竭患者具有有益作用。然而，LCZ 696是否能防止左心房（LA）和左心耳（LAA）功能障碍仍不清楚。本研究旨在评估LCZ 696改善LA和LAA功能的疗效。我们进行了一项回顾性研究，比较LCZ 696与血管紧张素受体阻滞剂（ARB），以评估LCZ 696在房颤患者中的疗效，并在压力超负荷小鼠模型中进行了动物研究。与ARB相比，LCZ 696组患者的LA收缩期峰值应变、LAA排空流速和LAA射血分数（LAAEF）显著增加（分别为p = 0.024、p = 0.036、p = 0.026）。LCZ 696使用者的自发超声心动图造影发生率较低（p = 0.040）。然后，将患者分为两组（LAAEF ≤ 20%和> 20%）。LAAEF > 20%患者的LCZ 696给药频率高于LAAEF ≤ 20%患者（p = 0.032）。即使在控制LAA功能障碍相关风险因素后（年龄、房颤类型、陈旧性心肌梗死、高血压、充血性心力衰竭和既往卒中或短暂性脑缺血发作），使用LCZ 696与LAAEF ≤ 20%的概率降低显著相关[比值比= 0.011; 95%置信区间（0.000-0.533），p = 0.023]。为了进一步证实LCZ 696对LA功能的影响，我们在小鼠中构建了横主动脉缩窄后模型。LCZ 696处理的小鼠与载体或缬沙坦处理的小鼠相比显示出较低的LA尺寸和较高的左心室射血分数和LAA排空流速。同时，与溶剂或缬沙坦相比，LCZ 696显著降低小鼠LA纤维化。总之，我们提供的证据表明，LCZ 696在改善人类和小鼠的LA和LAA功能方面可能比ARB更有效，这表明LCZ 696可能被评估为心房重构和AF的直接治疗剂。
LCZ696 (sacubitril/valsartan) is an angiotensin receptor-neprilysin inhibitor and has shown beneficial effects in patients with heart failure. However, whether LCZ696 protects against left atrial (LA) and LA appendage (LAA) dysfunction is still unclear. The present study aimed to assess the efficacy of LCZ696 for improving the function of LA and LAA. We performed both a retrospective study comparing LCZ696 with angiotensin receptor blockers (ARBs) to assess the efficacy of LCZ696 in patients with atrial fibrillation and an animal study in a mouse model with pressure overload. LA peak systolic strain, LAA emptying flow velocity, and LAA ejection fraction (LAAEF) were significantly increased in patients with LCZ696 as compared with ARBs (p = 0.024, p = 0.036, p = 0.026, respectively). Users of LCZ696 had a lower incidence of spontaneous echocardiography contrast (p = 0.040). Next, patients were divided into two groups (LAAEF ≤ 20% and > 20%). Administration of LCZ696 in patients with LAAEF > 20% was more frequent than LAAEF ≤ 20% (p = 0.032). Even after controlling for LAA dysfunction-related risk factors (age, atrial fibrillation type, old myocardial infarction, hypertension, congestive heart failure, and prior stroke or transient ischemic attack), use of LCZ696 remained significantly associated with reduced probability of LAAEF ≤ 20% [odds ratio = 0.011; 95% confidence interval (0.000–0.533), p = 0.023]. To further confirmed effect of LCZ696 in LA function, we constructed a post-transverse aortic constriction model in mice. Mice with LCZ696 treatment showed lower LA dimension and higher left ventricular ejection fraction and LAA emptying flow velocity as compared with mice with vehicle or valsartan treatment. Meanwhile, as compared with vehicle or valsartan, LCZ696 significantly decreased LA fibrosis in mice. In summary, we provide evidence that LCZ696 may be more effective in improving LA and LAA function than ARBs in both humans and mice, which suggests that LCZ696 might be evaluated as a direct therapeutic for atrial remodeling and AF.