沙库巴曲/缬沙坦对射血分数保留的心力衰竭兔心功能的影响

Effect of sacubitril/valsartan on cardiac function in heart failure rabbits with preserved ejection fraction

目的 探讨沙库巴曲/缬沙坦对射血分数保留的心力衰竭(HFpEF)兔心功能的影响.方法 健康成年雄性新西兰兔45只,采用随机数字表法分为假手术组(n=12)和模型组(n=33).模型组兔行腹主动脉缩窄术构建HFpEF模型.假手术组兔因麻醉意外死亡1只,模型组兔因急性左心衰竭死亡1只,建模8周时因未达模型建立成功标准排除3只.遂于建模8周时采用随机数字表法抽取并处死假手术组兔2只,模型组处死3只兔进行心肌组织学检查.最终,假手术组9只、模型组26只兔进入后续药物对照实验.进一步将模型组兔采用随机数字表法分为不治疗组8只、缬沙坦干预组9只和沙库巴曲/缬沙坦干预组9只,分别予以相应的药物灌胃干预.分别于药物干预后4、8周,通过对各组兔进食和运动活力情况行简单心功能分级评估;采用超声心动图检测各组兔心脏舒张期室间隔厚度(IVSd)、收缩期室间隔厚度(IVSs)、舒张期左心室后壁厚度(LVPWd)、左心室舒张末期内径(LVIDd)、左心室收缩末期内径(LVIDs),并计算左心室射血分数(LVEF),运用脉冲多普勒模式测量二尖瓣舒张早期最大流速度(E)/二尖瓣舒张晚期最大流速度(A)比值和心率;ELISA法测定各组兔血清N末端B型利钠肽原(NT-proBNP)、血管紧张素Ⅱ(Ang Ⅱ)及可溶性基质溶素2(sST2)含量.药物干预后8周,取各组兔心脏,称量全心质量和左心室质量,并计算心质量指数(HMI)和左心室质量指数(LVMI).结果 (1)心功能分级评估:缬沙坦组药物干预前心功能Ⅰ、Ⅱ、Ⅲ级的兔分别有2、5、2只,干预后8周分别有4、4、1只,心功能分级有改善的趋势,但差异无统计学意义(P>0.05).沙库巴曲/缬沙坦组兔药物干预前心功能Ⅰ、Ⅱ、Ⅲ级的兔分别有2、4、3只,干预后8周分别有7、2、0只,心功能分级明显改善(P<0.05).假手术组干预前及干预后8周Ⅰ、Ⅱ、Ⅲ级的兔均为9、0、0只,不治疗组分别有2、4、2和1、4、3只,心功能分级均无明显变化(P均>0.05).(2)超声心动图检测:药物干预后8周,不治疗组兔的IVSd、IVSs均明显高于假手术组,E/A比值明显低于假手术组(P均<0.01);缬沙坦组兔的IVSs明显高于假手术组,E/A比值明显低于假手术组(P均<0.01);沙库巴曲/缬沙坦组兔的E/A比值明显低于假手术组(P<0.01).缬沙坦组兔的IVSd、IVSs均明显低于不治疗组(P均<0.05),沙库巴曲/缬沙坦组兔的IVSd明显低于不治疗组(P<0.01).沙库巴曲/缬沙坦组兔的IVSd、IVSs、LVPWd、LVIDd、LVIDs、LVEF、E/A比值与缬沙坦组比较差异均无统计学意义(P均>0.05).各组兔心率差异无统计学意义((P>0.05).(3)血清NT-proBNP、AngⅡ及sST2含量:药物干预后4周,不治疗组、缬沙坦组、沙库巴曲/缬沙坦组兔外周血NT-proBNP含量均明显高于假手术组(P均<0.01);沙库巴曲/缬沙坦组兔外周血NT-proBNP含量明显低于不治疗组(P<0.01).药物干预后4周,不治疗组、缬沙坦组、沙库巴曲/缬沙坦组兔外周血AngⅡ含量均明显高于假手术组(P均<0.01),但上述各组间差异无统计学意义(P>0.05).药物干预后4周,不治疗组、缬沙坦组、沙库巴曲/缬沙坦组兔外周血sST2含量均明显高于假手术组(P均<0.01),缬沙坦组和沙库巴曲/缬沙坦组兔外周血sST2含量均明显低于不治疗组(P均<0.01);沙库巴曲/缬沙坦组兔外周血sST2含量明显低于缬沙坦组(P<0.01).药物干预后8周,不治疗组、缬沙坦组、沙库巴曲/缬沙坦组兔外周血NT-proBNP含量均明显高于假手术组(P均<0.01);缬沙坦组和沙库巴曲/缬沙坦组兔外周血NT-proBNP含量均明显低于不治疗组(P均<0.01);沙库巴曲/缬沙坦组兔外周血NT-proBNP含量明显低于缬沙坦组(P<0.01).药物干预后8周,不治疗组、缬沙坦组、沙库巴曲/缬沙坦组兔外周血AngⅡ含量均明显高于假手术组(P均<0.01);不治疗组和缬沙坦组兔外周血Ang Ⅱ含量较4周时均有增高趋势,沙库巴曲/缬沙坦组略有降低,但差异均无统计学意义(P均>0.05).药物干预后8周,不治疗组、缬沙坦组兔外周血sST2含量均明显高于假手术组(P均<0.01);沙库巴曲/缬沙坦组兔外周血sST2含量高于假手术组,但差异无统计学意义(P>0.05);缬沙坦组和沙库巴曲/缬沙坦组兔外周血sST2含量均明显低于不治疗组(P均<0.01);沙库巴曲/缬沙坦组兔外周血sST2含量明显低于缬沙坦组(P<0.01).(4)心脏大体标本:药物干预后8周,不治疗组兔全心质量、左心室质量、HMI和LVMI均明显高于假手术组(P均<0.01),缬沙坦组上述指标亦均明显高于假手术组(P均<0.05).缬沙坦组兔各指标虽较不治疗组低,但差异均无统计学意义(P均>0.05).沙库巴曲/缬沙坦组兔HMI、LVMI均较不治疗组低(P均<0.05).沙库巴曲/缬沙坦组兔上述指标均较缬沙坦组低,但差异均无统计学意义(P均>0.05).结论 沙库巴曲/缬沙坦改善HFpEF兔心功能的效果优于单独应用缬沙坦.

Objective To investigate the effect of sacubitril/valsartan on cardiac function in heart failure rabbits with preserved ejection fraction.Methods Forty-five healthy adult male New Zealand rabbits were divided into sham operation group (n=12) and model group (n=33) by random number table method.HFpEF model was constructed by abdominal aortic constriction in model group.In sham operation group,1 rabbit died due to anesthesia accident,and 1 rabbit in model group died of acute left heart failure.At 8 weeks of modeling,3 rabbits were excluded due to the failure to establish the successful model.At the 8th week of modeling,2 rabbits in sham operation group were selected and sacrificed by random number table method,and 3 rabbits in model group were selected and sacrificed for myocardial histological examination.Then,9 rabbits in sham operation group and 26 rabbits in model group entered the subsequent experiment.The model group was randomly divided into untreated group (n=8),valsartan intervention group (n=9),and sacubitril/valsartan intervention group (n=9),respectively,drugs were applied per gavage.The feeding and exercise activity of rabbits in each group were evaluated by simple cardiac function classification at baseline,4 and 8 weeks post intervention.Echocardiography was used to detect interventricular septal thickness at diastole(IVSd),interventricular septal thickness at systolic(IVSs),left ventricular posterior wall of diastolic(LVPWd),left ventricular internal diameter at diastolic(LVIDd),left ventricular internal diameter at systolic(LVIDs),and calculate the left ventricular ejection fraction(LVEF),mitral valve's early diastolic flow velocity(E)/late mitral diastolic maximum flow rate ratio(A) and heart rate at baseline,4 and 8 weeks post intervention.Serum N terminal B-type natriuretic peptide (NT-proBNP) and angiotensin (Ang) Ⅱ and soluble matrix lysin 2(sST2) content was determined by ELISA at baseline,4 and 8 weeks post intervention.Eight weeks after intervention,the hearts of rabbits were taken and weighed,and heart mass index (HMI) and left ventricular mass index (LVMI) were calculated.Results (1) Evaluation results of cardiac function:there were 2,5,and 2 rabbits with cardiac function grade Ⅰ,Ⅱ and Ⅲ before the drug intervention,and 4,4,and 1 rabbits with respective cardiac function grade after 8 weeks of intervention in valsartan group (P>0.05).There were 2,4,and 3 rabbits with heart function grade Ⅰ,Ⅱ and Ⅲ before the drug intervention,and 7,2,and 0 rabbits with respective heart function grade after 8 weeks of intervention in sacubitril/valsartan group(P<0.05).(2) Echocardiographic results:at 8 weeks after drug intervention,IVSd and IVSs of rabbits in untreated group were significantly higher than those in sham operation group,and the ratio of E/A was significantly lower than that in sham operation group(all P<0.01).IVSs of the valsartan group was significantly higher than that of sham operation group,and the ratio of E/A was significantly lower than that of sham operation group(all P<0.01).The E/A ratio in the sacubitril/valsartan group was significantly lower than that in sham operation group(P<0.01).IVSd and IVSs in valsartan group were significantly lower than those in untreated group(all P<0.05),and IVSd in sacubitril/valsartan group was significantly lower than that in untreated group(P<0.01).The IVSd,IVSs,LVPWd,LVIDd,LVIDs,LVEF,E/A ratios were similar between sacubitril/valsartan group and valsartan group(all P>0.05).There was no significant difference in heart rate between the groups(P>0.05).(3) Serum NT-proBNP,Ang Ⅱ and sST2 levels:4 weeks after drug intervention,untreated group,valsartan group,and sacubitril/valsartan group's serum NT-proBNP levels were significantly higher than that of sham operation group(all P<0.01);serum NT-proBNP was significantly lower in sacubitril/valsartan group than that in untreated group(P<0.01).Four weeks after intervention,serum Ang Ⅱ levels were significantly higher in untreated group,valsartan group,sacubitril/valsartan group than in sham group(all P<0.01),but there was no statistically significant difference between the modeling groups(P>0.05).Four weeks after drug intervention,the serum sST2 contents in untreated group,valsartan group,and sacubitril/valsartan group were significantly higher than in sham operation group(all P<0.01),and which was significantly lower in valsartan group and sacubitril/valsartan group than in untreated group(all P<0.01),which were significantly lower in sacubitril/valsartan group than in valsartan group(P<0.01).Eight weeks after drug intervention,serum NT-proBNP levels were significantly higher in untreated group,valsartan group,and sacubitril/valsartan group than in sham operation group(all P<0.01),which were significantly lower in valsartan group and sacubitril/valsartan group than in untreated group(all P<0.01),which were significantly lower in valsartan group than in sacubitril/valsartan group(P< 0.01).Eight weeks after drug intervention,Ang Ⅱ levels were significantly higher in valsartan group and sacubitril/valsartan group than in untreated group(all P<0.01),which tended to be higher in untreated group and valsartan group,tended to be lower in sacubitril/valsartan compared to value at 4 weeks(all P>0.05).Eight weeks after drug intervention,serum sST2 was significantly higher in untreated group and valsartan group than in sham operation group(all P<0.01),which tended to be higher in sacubitril/valsartan group compared to sham operation group(P>0.05),which were significantly lower in valsartan group and sacubitril/valsartan group than in untreated group(all P<0.01),which was significantly lower in sacubitril/valsartan group than in valsartan group(P<0.01).(4) Comparison of whole-heart mass,left ventricular mass,HMI and LVMI:8 weeks after drug intervention,the whole-heart mass,left ventricular mass,HMI and LVMI were significantly higher in untreated group than in sham operation group(all P<0.01),and the above indexes were also significantly higher in valsartan group than in sham operation group(all P<0.05),tended to be lower in valsartan group compared to untreated group (allP>0.05).HMI and LVMI were lower in sacubitril/valsartan group than in untreated group(all P<0.05).All the above indexes tended to be lower in sacubitril/valsartan group than in valsartan group(all P>0.05).Conclusion Sacubitril/valsartan is superior to valsartan alone on improving cardiac function in HFpEF rabbits.