Establishment Of Animal Model And Therapy Of Metoprolol On Diastolic Heart Failure Induced By Pressure Overload

Background: Diastolic heart failure(DHF) is a kind of clinical syndrome characterizing clinical manifestation of congestive heart failure(CHF), preserved ejection fraction(EF) and injured diastolic function, In clinic, 25-40% patients of CHF belong to DHF. However, there is no an effective animal model of DHF yet, and EF is not sensitive to early change of systolic function. Large scale clinical trials indicate that P-receptor blocker can lower mortality of CHF, but study on its effect on DHF animal is poor. In the study, New-Zealand rabbits were performed constriction at the abdominal aorta(above renal artery). Myocardial systolic and diastolic function were detected by echocardiography and systemic hemodynamics, and change of pathology, neuroendocrine system and renal function were combined together to explore the establishment method of DHF induced by pressure overload. At the same time, Metoprolol was administered in the early stage of hypertension, and its therapeutic effect on DHF rabbits was observed.Methods: 1)75 male New-Zealand rabbits were randomly assigned to three groups: constriction was performed at the abdominal aorta 1 cm just above right renal artery in operated group 1 (n=45, external diameter decreases 35-40% ) and operated group 2(n=15, external diameter decreases 50-60%). Left ventricle catheter was used to measure hemodynamics before operation and sacrifice. At the time point of pre-operation, 2 weeks, 4 weeks, 5 weeks after operation, echocardiography was executated. In the 6 hours after every echocardiography, blood was drawn from ear central artery and serum was separated. Indices of hemodynamics included LVSP, LVEDP, +dp/dt_max, -dp/dt_min andτ. LAV was measured by 2D echo. IVSD, LVPWD, LVEDV, LVESV, EF, and Vp were measured by M mode echo. Pulse Doppler was used to detect E, A, PVa, andPVaD. Tissue doppler imaging was used to detect Sm and Em. E/Em and E/Vp were calculated. ELISA was used to measure change of AngII, ET-1, NE, NT-proBNP in serum and myocardium, and correlation analysis was executed between NT-proBNP and EF, Sm, Em, E/Em, E/Vp. Urease method was used to measure BUN and Cr. 2) 30 male New-Zealand rabbits were randomly assigned to three groups: operation was performed in operated group(n=12) and operated therapy group(n=12) according to operation group 1. Metoprolol was administered from the first day after operation in operated therapy group (25mg, 2/d), and then following 4 weeks, indices were measured ibid. 3) The software of SPSS 13.0 was used to perform statistical analysis, and statistical difference was considered to exist when P<0.05.Results: 1) In the operated group 1, there were 22 rabbits showing manifestation of CHF such as dpression, inappetence, dysponea 26-30 days after operation. In the operated group 2, 6 rabbits died of acute pulmonary edema 6-10 days after operation. 2) In the operated group 1, 2 weeks after operation, IV SD and LVPWD increased (P<0.000 ) . LAV and LVEDV augmented (P<0.01) . Sm(P<0.05 ) , Em (P<0.05 ) and Vp (P<0.000 ) decreased, and E/Em (P<0.01 ) , and E/Vp (P<0.05 ) increased. 4 weeks after operation, changes of these indices were more obvious, however, EF was preserved. LVEDP andτrose markedly (P<0.000 ), and -dp/dt_min declined (P<0.01) . In the serum and myocardium, level of AngII , ET-1, NE, NT-proBNP(P<0.000, P<0.01 ) increased. BUN and Cr(P<0.000) also rose. 3)In the operated group 2, LAV (P<0.000) , LVEDV(P<0.05 ), LVESV(P<0.000)augmented markedly. Sm( P<0.000 ), Em( P<0.01), Vp (P<0.000 ), E/Em (P<0.05 ) and E/Vp (P<0.01 ) occorrenced notable change, and EF declined to below 50 % (P<0.000). LVEDP, τ, -dp/dt_min and +dp/dt_max also changed markedly (P<0.000) . Indices of serum and myocardium changed more obviously. 4) Good correlation existed between NT-proBNP and Sm, Em, E/Em , and E/Vp (P<0.000) , however, its correlation with EF was poor(r=-0.395). 5)In the Metoprolol therapy group, only 1 rabbit occurrenced DHF. In the rest, LVEDP(P<0.000) ,τ (P<0.000) ,LAV (P<0.01 ) IVSD (P<0.05) , Em (P<0.05) and E/Em( P<0.05 )ameliorated; AngII and ET-1 (P<0.01 )in the serum, and NE NT-proBNP (P<0.01, P<0.05 ) both in the serum and myocardium all declined. However, BUN and Cr (P<0.01) was kept no change.Conclusions: 1)Through constriction of the abdominal aorta above right renal artery(external diameter decreases 35-40%), New-Zealand rabbit can show manifestation of CHF after 26-30 day. -dp/dt_min , Vp and Em decline, and LVEDP, τ, E/Em and E/Vp increase markedly but EF is preserved, so it can be taken as a model of DHF resulting from hypertention. 2)After constriction of abdominal aorta, Sm declines which indicates that injure of systolic function participates in DHF possiblely. 3)Activiation of circular and myocardial local neuroendocrine system is a possible important mechanism of DHF. 4)NT-proBNP correlates well with Sm, Em, E/Em and E/Vp, however, there is poor correlation between it and EF. 5)In the DHF rabbit, Metoprolol can lessen myocardium hypertrophy, dilatation of chambers and injure of diastolic and systolic function, and inhibit activiation of neuroendocrine system.