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

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 gradeⅠ,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 AngⅡ 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 (all P> 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.