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Examination of the mechanism of the transition to isolated diastolic heart failure

向孤立性舒张性心力衰竭转变的机制研究

基本信息

批准号：
10670653
负责人：
MASUYAMA Tohru
金额：
$ 2.05万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670653/
关键词：
isolated diastolic heart failure hypertension hypertrophy fibrosis renin-angiotensin system

项目摘要

In spite of frequent occurrence of isolated diastolic heart failure with preserved systolic function, our understanding of its pathophysiology is limited because an animal model for isolated diastolic heart failure has not been established. We have demonstrated that Dahl-Iwai salt-sensitive (Dahl-S) rats fed on high salt diet from 7 weeks old develop hypertension followed by compensated LV hypertrophy (LVH) at 13 weeks and isolated diastolic heart failure at 19 weeks. At the failing stage in this model (19 weeks), progressive fibrosis and an increase in LV ACE mRNA were observed. We further studied whether the local renin-angiotensin system (RAS) was associated with transition to isolated diastolic heart failure by studying effects of chronic administration Angiotensin II type 1 receptor (AT1-R) antagonist (Candesartan Cilexetil) on LV geometry and function. Dahl-S rats were placed on high salt diet with or without oral administration Candesartan Cilexetil (1mg/kg/day). An increase in the LV mass/weight in the treated rats at 13 weeks was comparable to that in the untreated rats, but a further increase thereafter was observed only in the untreated rats. At 19 weeks, the elevation of LVEDP and myocardial fibrosis were observed in the untreated rats, and Candesartan Cilexetil prevented these changes. Thus, AT1-R antagonist Candesartan Cilexetil did not restrain initial adaptive LVH up to compensated stage, but prevented non-adaptive excessive LVH thereafter and myocardial fibrosis, which benefited in stopping or at least in delaying the transition to decompensation. In conclusion, cardiac RAS seems to play an important role in facilitating excessive LV hypertrophy and myocardial fibrosis that closely link to isolated diastolic heart failure.

尽管经常发生的孤立性舒张性心力衰竭与保留收缩功能，我们的理解是有限的，因为孤立性舒张性心力衰竭的动物模型尚未建立。我们已经证明，Dahl-Iwai盐敏感（Dahl-S）大鼠从7周龄开始高盐饮食喂养，在13周时发生高血压，随后发生代偿性左心室肥大（LVH），在19周时发生孤立性舒张性心力衰竭。在该模型的失败阶段（19周），观察到进行性纤维化和LV ACE mRNA的增加。我们进一步研究了局部肾素-血管紧张素系统（RAS）是否与转变为孤立的舒张性心力衰竭，通过研究慢性给药血管紧张素II 1型受体（AT 1-R）拮抗剂（坎地沙坦酯）对左室几何形状和功能的影响。将Dahl-S大鼠置于高盐饮食中，经口给予或不给予坎地沙坦酯（1 mg/kg/天）。第13周时，给药大鼠的LV质量/重量增加与未给药大鼠相当，但此后仅在未给药大鼠中观察到进一步增加。19周时，未治疗组大鼠出现LVEDP升高和心肌纤维化，坎地沙坦酯可预防这些变化。因此，AT 1-R拮抗剂坎地沙坦西酯并不能抑制最初的适应性LVH直至代偿期，但可以预防此后的非适应性过度LVH和心肌纤维化，这有利于阻止或至少延迟向失代偿的过渡。总之，心脏RAS似乎在促进与单纯舒张性心力衰竭密切相关的LV过度肥大和心肌纤维化中起重要作用。