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

尽管孤立性舒张性心力衰竭时有发生，但由于孤立性舒张性心力衰竭的动物模型尚未建立，我们对其病理生理学的了解有限。我们已经证明，从7周龄开始饲喂高盐饮食的Dahl-Iwai盐敏感（Dahl-S）大鼠在13周龄出现代偿性左室肥厚（LVH）， 19周龄出现孤立性舒张性心力衰竭。在模型衰竭期（19周），观察到进行性纤维化和左室ACE mRNA升高。我们通过研究慢性给药血管紧张素II型1受体（AT1-R）拮抗剂（坎地沙坦西列蒂尔）对左室几何和功能的影响，进一步研究局部肾素-血管紧张素系统（RAS）是否与过渡到孤立性舒张性心力衰竭有关。将Dahl-S大鼠置于高盐饮食中，同时口服或不口服坎地沙坦西列西汀（1mg/kg/天）。治疗组大鼠在13周时左室质量/重量的增加与未治疗组大鼠相当，但此后仅在未治疗组大鼠中观察到进一步增加。在第19周时，观察到未经治疗的大鼠LVEDP升高和心肌纤维化，坎地沙坦西列西地尔阻止了这些变化。因此，AT1-R拮抗剂坎地沙坦西列西地尔并不能抑制初始适应性LVH直至代偿期，但可以阻止此后的非适应性过度LVH和心肌纤维化，这有利于停止或至少延缓向代偿期的过渡。总之，心脏RAS似乎在促进左室过度肥大和心肌纤维化中起重要作用，这与孤立性舒张性心力衰竭密切相关。

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.