糖尿病心室-动脉耦联负荷、动脉生物力学特性改变及其机制研究

Diabetic cardiovascular disease, as the most common complication, is the most important fatal factor of diabetes. Therefore, understanding the key mechanism of diabetic angiopathy and early intervention are particularly important to reduce the morbidity and mortality of complications. In the pathophysiological process of diabetic angiopathy, arterial stiffness is the most critical one, and it seriously affects the ventricular-arterial coupling. Abnormal collagen metabolism plays a key role in the pathogenesis of arterial stiffness. Angiotensin - (1-7) is one of the members of RAS system, but it has absolutely different biological effects from Ang II, such as vasodilation, anti-myocardial cell proliferation and fibrosis, anti-smooth muscle cell proliferation, stabilization of endothelial cells and anti-inflammatory effects. Therefore, we hypothesize that angiotensin - (1-7) plays an important role in diabetic angiopathy. By changing the level of angiotensin - (1-7), we can improve the distribution and content of vascular collagen, improve the biological characteristics of arteries and ventricular-arterial coupling. The purpose of this study is to observe the changes of arterial biomechanical properties, cardiac reserve function and ventricular-arterial coupling reserve in diabetic patients without obvious complications through clinical experiments (including stress echocardiography) and animal experiments, and to clarify the correlation between pathological changes of diabetic vascular diseases and changes of arterial biomechanical properties, as well as the role of Ang-(1-7) in the correlation.

糖尿病心血管病变作为糖尿病最常见的并发症，是其最重要的致死因素。了解糖尿病血管病变的早期关键机制从而进行早期干预对于降低发病率和其所致死亡率尤为重要。在糖尿病血管病变的众多异常病生理过程中，动脉僵硬最为关键，同时也严重影响着心室-动脉耦联关系。而胶原代谢异常在动脉僵硬的病生理过程中起着关键作用。血管紧张素-(1-7) 具有舒张血管、抗心肌细胞增殖和纤维化、抗平滑肌细胞增殖等作用。因此，我们假设血管紧张素-(1-7)在糖尿病血管病变中扮演着重要角色，通过改变血管紧张素-(1-7)水平，可以改善血管胶原分布及含量，改善动脉生物学特性及心室-动脉耦联关系。本研究拟通过临床实验（含负荷超声心动图）及动物实验两部分观察无明显并发症的糖尿病患者动脉生物力学特性改变、心脏储备功能及心室-动脉耦联关系储备改变，明确糖尿病血管病变的病理改变与动脉生物力学特性改变的相关性及Ang-(1-7)在其中的作用。

糖尿病心血管病变对糖尿病患者的预后至关重要，本项目以糖尿病患者左室-动脉耦联关系为重点研究目标，通过临床实验（含运动负荷超声心动图）及动物实验两部分观察无明显并发症的糖尿病患者心脏储备功能及心室-动脉耦联关系储备改变，明确糖尿病血管病变的病理改变与动脉生物力学特性改变的相关性及Ang-(1-7)在其中的作用。在临床实验方面，通过负荷超声心动图建立了国人运动负荷后左室收缩储备功能的正常参考值，同时发现糖尿病患者血清NTproBNP水平、HbA1c、HOMA-IR（胰岛素抵抗指数）明显高于对照组，而糖尿病患者左室收缩储备△GLS、Ang-(1-7)明显低于对照组，多重线性回归分析显示，△GLS与Ang-(1-7)、HOMA-IR独立相关（值分别为0.573、-0.329，p均<0.05），因此，该研究结果显示糖尿病患者左室收缩储备功能受损，胰岛素抵抗降低心脏收缩功能储备，而Ang-(1-7)则对心脏收缩功能具有保护作用。通过对对照组及糖尿病组大鼠进行Ang-(1-7)干预前后血清学、超声及组织病理学检测发现：1、糖尿病组大鼠左室收缩及舒张功能明显减低，而Ang-(1-7)干预后，左室收缩及舒张功能明显改善；2、糖尿病组大鼠心肌组织内胶原纤维含量明显增加，而经过Ang-(1-7)干预后，胶原纤维含量减少，证明Ang-(1-7)可通过降低胶原纤维含量改善糖尿病大鼠心脏功能。提示Ang-(1-7)有望成为改善糖尿病患者心血管功能的潜在治疗药物。