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

尽管收缩功能正常的单纯舒张性心力衰竭频繁发生，但由于尚未建立单纯舒张性心力衰竭的动物模型，我们对其病理生理机制的了解有限。7周龄高盐饮食的Dahl-Iwai(Dahl-S)大鼠在13周龄时出现高血压，13周时出现代偿性左室肥厚，19周时出现单纯舒张性心力衰竭。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。我们通过长期应用血管紧张素II 1型受体(AT1-R)拮抗剂坎地沙坦酯对左心形态和功能的影响，进一步研究局部肾素-血管紧张素系统(RAS)是否与单纯性舒张性心力衰竭的转变有关。将Dahl-S大鼠置于高盐饲料中，同时或不给予坎地沙坦酯(1 mg/kg/d)灌胃。在13周时，治疗组大鼠左室质量/体重的增加与未治疗组相当，但此后仅在未治疗组大鼠中观察到进一步的增加。19周时，未治疗的大鼠出现LVEDP升高和心肌纤维化，坎地沙坦酯可阻止这些变化。因此，AT1-R拮抗剂Candesartan Cilexate不能抑制最初的适应性LVH直到代偿期，但可以预防此后的非适应性过度LVH和心肌纤维化，从而有利于停止或至少延缓向失代偿期的过渡。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过度左室肥厚和心肌纤维化方面发挥了重要作用。

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.