生理性缺血训练改善心衰的作用及自主神经调节机制

This newly proposed project by our research team is one of the series studies followed by the previous projects granted by the National Natural Science Foundation of China and Foundation of Jiangsu Province. Based on the results reported by our research team, physiological ischemia training (PIT) was demonstrated to launch protective effects on remote ischemic myocardium, in turn increase myocardial viability, and decrease the incidence of myocardial infarction and heart failure. However, the effectiveness of PIT on patients with heart failure due to myocardial infarction has not been well studied. Therefore, we hypothesized that PIT may improve autonomic nervous dysfunction via increasing the excitability of vagal nerve, in turn prevent myocardial remodeling and improve cardiac function. PIT was conducted on rat model of heart failure induced by myocardial infarction. Echocardiography and concentration of NT-proBNP in plasma were adopted to monitor the change of cardiac function. Level of Bcl-2/Bax and MMPs/TIMPs were measured by RT-PCR to evaluate myocardial remodeling. Rat models of heart failure with vagotomy or vagal stimulation, cholinergic receptor inhibitor or agonist were established to observe the effects of vagal nerve in the PIT precedure. The excitability of vagal nerve and autonomic nerve were reflected by several parameters monitored by PET and/or SPET, Karnovsky-roots histoehemistry stain, hydroxylase immunohistochemistry, ELISA and Ellman method. In addition, the optimal training protocol for PIT would be explored and the sensitive biological markers would be determined. In sum, this study was designed to develop a non-invasive and cost-effective rehab treatment for patients with heart failure.

本课题为数个国基金课题的延续，前期研究证实生理性缺血训练（PIT）可对远隔缺血心肌产生保护，心肌存活增加，心梗及心衰减少。病因为心梗的心衰患者临床是否可通过PIT产生的心脏保护作用改善心功能，目前报道较少。为此提出假说：PIT可通过持续提高迷走神经活性，调节自主神经失衡，抑制心肌重构，改善心衰心功能。为证明该假说，建立大鼠心梗后心衰模型，采用“袖带加压法”进行PIT。测定血流动力学；超声及血中NT-proBNP判定心功能；RT-PCR测定Bcl-2/Bax，MMPs/TIMPs判定心肌重塑。采用心衰加迷走神经阻断及刺激模型观察迷走传出活性在此过程中作用。迷走及交感活性通过核素心脏自主神经功能PET或SPET显像，Karnovsky-Roots组织化学法及酪氨酸羟化酶免疫组化法、ELISA及Ellman法测定。确定PIT改善心衰的最佳干预方案及敏感生物标志物。为心衰患者提供治疗新途径。

心力衰竭的发病率、再住院率、死亡率居高不下，心衰成为心血管治疗学上的难题。近年来多项研究发现运动训练可以改善心衰临床症状，降低死亡率及再住院率，提高生活质量，但对心衰患者而言常规运动训练存在较多禁忌症和局限性。本项目致力于探究生理性缺血训练（PIT）对心衰的改善作用及机制，因此提出假说即生理性缺血训练可以通过持续提高迷走神经活性，调节自主神经功能失衡，抑制心肌重构，改善心衰心脏功能。建立大鼠心梗后心衰模型，采用“袖带加压法”进行生理性缺血训练。测定PIT时血流动力学，通过超声心动图、生物学标志物检测等手段观察心肌重构、心功能、迷走神经活性等相关指标，探讨PIT对心衰的治疗作用及机制。研究发现：1.8周生理性缺血训练可以抑制心衰大鼠心肌重构，改善心功能；2.总时程8周，每天5个循环，每个循环为5min缺血/5min灌注的PIT方案对心衰大鼠心脏的远隔保护作用更显著，NT-proBNP可作为反映其保护作用的最佳生物学标志物；3.PIT通过提高迷走神经活性（表现为心肌乙酰胆碱酯酶活性提高及胆碱能神经密度增加，而心肌去甲肾上腺素含量与交感神经密度无明显改变）减轻心肌凋亡与间质纤维化，从而抑制心肌重构，改善心衰大鼠的心功能。这将为心衰患者的临床和康复治疗提供新途径，并为该途径的作用机制提供证据。