Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Biomed Pharmacother. 2022 Apr;148:112745. doi: 10.1016/j.biopha.2022.112745. Epub 2022 Feb 21.
Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS).
Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001).
Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.
心肾综合征（CRS）仍然是所有疾病实体住院患者死亡的主要原因。沙库巴曲缬沙坦（Sac/Val）治疗已被证明可改善心力衰竭或慢性肾病患者的预后。本研究检验了以下假设，即左西孟旦联合 Sac/Val 治疗优于单一疗法，可同时保护心脏和肾脏免受同时的心脏和肾脏缺血（I）（50 分钟）-再灌注（R）（7 天）（即双重 IR）损伤（定义为 CRS）。
成年雄性 Spraque-Dawley 大鼠（n=40）等分为第 1 组（假手术对照）、第 2 组（双重 IR）、第 3 组[双重 IR+左西孟旦（10mg/kg，于 30 分钟时腹腔内给药，继以 IR 术后每天 1 次）]、第 4 组[双重 IR+Sac/Val（10mg/kg，于 30 分钟时口服，继以 IR 术后每天 2 次）]和第 5 组（双重 IR+Sac/Val+左西孟旦）。在双重 IR 后第 7 天，左心室射血分数（LVEF）/左心室缩短分数（LVFS）在第 1 组最高，第 2 组最低，第 5 组明显高于第 3 组/第 4 组，但第 3 组/第 4 组之间无差异，而循环性心力衰竭（脑利钠肽）/促炎（肿瘤抑制因子 2）生物标志物、血尿素氮/肌酐和尿蛋白与肌酐比值（均 p<0.0001）在各组之间呈相反的 LVEF 模式。LV 心肌中炎症（肿瘤坏死因子-α/白细胞介素-1β/基质金属蛋白酶-9）/氧化应激（NOX-1/NOX-2/NOX-4）/凋亡（线粒体-Bax/半胱天冬酶-3/多聚（ADP-核糖）聚合酶）/纤维化（Smad3/转化生长因子-β）/线粒体损伤（胞质细胞色素-C）/心肌肥厚（β-MHC）生物标志物的蛋白表达在各组之间呈相反的 LVEF 模式（均 p<0.0001）。LV 心肌和肾脏中的炎症（CD68）/DNA 损伤（γ-H2AX）生物标志物的细胞表达和梗死/纤维化面积在各组之间呈相反的 LVEF 模式（均 p<0.0001）。
左西孟旦联合 Sac/Val 治疗优于单一疗法，可同时保护心脏和肾脏，防止双重 IR 损伤，保护其功能。
