Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome.
Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome.
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DOI：
10.1016/j.cardfail.2020.08.009
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发表时间：
2020-11
影响因子：
6
通讯作者：
Singh-Gupta V
中科院分区：
文献类型：
--
作者：
Sabbah HN;Zhang K;Gupta RC;Xu J;Singh-Gupta V
沙库巴曲/缬沙坦（Sac/瓦尔）是一种血管紧张素II受体阻滞剂（瓦尔）和脑啡肽酶抑制剂（Sac）的组合，摩尔比为1：1，已显示可降低心力衰竭（HF）患者心血管死亡或HF住院的风险，并降低LV射血分数（EF）。本研究检测了Sac/瓦尔对实验性心肾综合征（CRS）犬左室结构、功能和生物能量学以及肾损伤和肾功能生物标志物的影响。将14只CRS（冠状动脉微栓塞诱导的HF和肾功能不全）犬随机分配至3个月Sac/瓦尔治疗组（100 mg，每日一次，n=7）或无治疗组（对照组，n=7）。在治疗前和治疗结束时测量LV EF和肌钙蛋白I（TnI）以及肾损伤/功能的生物标志物，包括血清肌酐（sCr）和尿肾损伤分子-1（KIM-1），并计算变化（治疗效应Δ）。在治疗结束时，在分离的心肌细胞中测量线粒体功能测量，包括ATP合成的最大速率（ATPsyn）。在Sac/瓦尔犬中，与对照组相比，EF增加（6.9±1.4 vs. 0.7± 0.6%，p<0.002），而ΔTnI降低（−0.16±0.03 vs. −0.03±0.02 ng/ml，p<0.001）。与对照组相比，Sac/瓦尔治疗组犬的尿液ΔKIM-1降低（−17.2±7.9 vs. 7.7±3.0 mg/ml，p<0.007），而sCr无显著差异。与对照相比，用Sac/瓦尔处理增加了ATPsyn（3，240 ±121对986±84 RLU/μg蛋白，p<0.05）。在CRS犬中，Sac/瓦尔可改善LV收缩功能，改善线粒体功能，并降低心脏和肾脏损伤的生物标志物。这些结果为Sac/瓦尔在肾功能受损的HF中的获益提供了机制性见解。
Sacubitril/Valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to reduce the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced LV ejection fraction (EF). This study examined the effects of Sac/Val on LV structure, function and bioenergetics and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome (CRS). 14 dogs with CRS (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n=7) or no therapy (control, n=7). LV EF and troponin-I (TnI) as well as biomarkers of kidney injury/function including serum creatinine (sCr) and urinary kidney injury molecule-1 (KIM-1) were measured before and at end of therapy and the change (treatment effect Δ) calculated. Mitochondrial function measures including maximum rate of ATP synthesis (ATPsyn) were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, EF increased compared to controls (6.9±1.4 vs. 0.7±0.6 %, p<0.002) while ΔTnI decreased (−0.16±0.03 vs. −0.03±0.02 ng/ml, p<0.001). Urinary ΔKIM-1 decreased in Sac/Val treated dogs compared to controls (−17.2±7.9 vs. 7.7±3.0 mg/ml, p<0.007) whereas sCr was not significantly different. Treatment with Sac/Val increased ATPsyn compared to control (3,240±121 vs. 986±84 RLU/μg protein, p<0.05). In dogs with CRS, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.
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