<b>Epigenetic signatures of treatment with intravenous furosemide plus hypertonic saline solution in decompensated heart failure patients: A Randomized Controlled Trial ( RCT)</b>

In a randomised controlled trial (RCT) , we compared the effects of treatment with furosemide + small volumes of hypertonic saline solution (HSS) to furosemide alone in patients with decompensated heart failure (HF) and evaluated the effects after administration of an acute saline bolus on inflammatory and remodelling markers and epigenetic signatures.Methods: All consecutive patients with acute decompensated heart failure (ADHF) due to heart failure with reduced ejection fraction (HFrEF) were enrolled. Patients were randomly assigned to treatment with i.v. furosemide plus HSS or i.v. furosemide alone. Patients were evaluated at T0 (admission), T1 (after treatment), and T2 (after a saline bolus) to determinate serum concentrations of NT-proBNP, hsTnT, s-ST2, galectin-3, IL-6, and CRP and to evaluate some selected miRNA concentrations.Results: We enrolled 200 subjects, 107 randomized to the furosemide plus HSS, and 93 to furosemide alone. At T1, patients treated with high-dose furosemide + HSS had higher absolute delta values of IL-6, hsTnT, NT-proBNP and galectin-3. At T2, after acute administration of a saline bolus, patients treated with i.v. furosemide + HSS showed significantly lower increases in the serum concentrations of IL-6, hsTNT, sST2, galectin-3 and NT-proBNP. In terms of differentially expressed miRNAs, we observed a decrease in the expression of miR181b in subjects treated with i.v. furosemide plus HSS in comparison to patients treated with i.v. furosemide alone and a more significant reduction of miRNA181b expression in subjects treated with furosemide plus HSS. Intragroup analysis revealed significant differences in the expression of miR214, miR1505p, and miR125a5p at T0 <i>vs.</i> T1 and of miR214, miR365, miR181b, miR1505p, and miR125a5p at T1 <i>vs.</i> T2.Conclusions: Our findings revealed that in subjects with ADHF , treatment with i.v. furosemide plus HSS significantly decreased the serum levels of IL-6, sST2, hsTnT, galectin-3, and NT-proBNP and modulated some miRNA expression.本项随机对照试验（randomised controlled trial, RCT）对比了呋塞米（furosemide）联合小容量高渗盐水溶液（hypertonic saline solution, HSS）与单用呋塞米治疗失代偿性心力衰竭（decompensated heart failure, HF）患者的疗效，并评估了急性生理盐水推注给药后对炎症与重塑标志物及表观遗传特征的影响。 方法：本研究纳入所有因射血分数降低型心力衰竭（heart failure with reduced ejection fraction, HFrEF）所致急性失代偿性心力衰竭（acute decompensated heart failure, ADHF）的连续入组患者。将患者随机分配至静脉内呋塞米联合HSS治疗组，或单用静脉内呋塞米治疗组。分别于T0（入院时）、T1（治疗后）及T2（生理盐水推注后）三个时间点对患者进行评估，检测血清N末端B型利钠肽原（NT-proBNP）、高敏肌钙蛋白T（hsTnT）、可溶性ST2（s-ST2）、半乳糖凝集素-3（galectin-3）、白细胞介素-6（IL-6）、C反应蛋白（CRP）浓度，并测定部分选定的微小RNA（microRNA, miRNA）表达水平。 结果：本研究共纳入200例受试者，其中107例被随机分配至呋塞米联合HSS治疗组，93例分配至单用呋塞米治疗组。在T1时间点，接受大剂量呋塞米+HSS治疗的患者其IL-6、hsTnT、NT-proBNP及半乳糖凝集素-3的绝对变化值更高。在T2时间点，即急性生理盐水推注给药后，接受静脉内呋塞米+HSS治疗的患者其血清IL-6、hsTNT、sST2、半乳糖凝集素-3及NT-proBNP浓度的升高幅度显著更低。在差异表达微小RNA方面，与单用静脉内呋塞米治疗的患者相比，接受静脉内呋塞米联合HSS治疗的受试者中miR181b的表达水平出现下降，且该组受试者的miR181b表达水平降低更为显著。组内分析显示，在T0 vs. T1时间点，miR214、miR1505p及miR125a5p的表达水平存在显著差异；在T1 vs. T2时间点，miR214、miR365、miR181b、miR1505p及miR125a5p的表达水平存在显著差异。 结论：本研究结果显示，在急性失代偿性心力衰竭患者中，静脉内呋塞米联合HSS治疗可显著降低血清IL-6、sST2、hsTnT、半乳糖凝集素-3及NT-proBNP水平，并可调控部分微小RNA的表达。