SCS结合FNS治疗心功能衰竭对心脏功能和心肌力学影响及其机制的实验研究

Despite recent advances in reperfusion therapy for acute myocardial infarction (MI) and pharmacotherapy for post-MI left ventricular (LV) remodeling, the incidence and mortality of post-MI heart failure (HF) are increasing. About 30% of patients develop intractable HF after acute MI. It is estimated that there are globally more than 15 million patients with HF. This has become a major clinical and public health challenge because of the aging population. There is, thus, tremendous interest in the discovery of novel therapies for post-MI LV remodeling and dysfunction..Sympathetic-parasympathetic interaction plays a critical role in the physiological and pathophysiological control of the heart. In HF, dysregulation of the autonomic nervous system with increased sympathetic tone and decreased parasympathetic tone are observed. This imbalance is associated with progression of HF and increased mortality. Although suppression of the sympathetic nervous system with β-blockers alone has reduced HF mortality by up to 35%, a significant proportion of patients with HF are intolerant to such therapy. No pharmacological therapy can directly enhance the parasympathetic nervous system. Thus, a novel therapeutic approach that modulates the autonomic nervous system to restore this imbalance between the sympathetic and parasympathetic nervous system may improve symptoms and/or clinical outcome. Spinal cord stimulation (SCS) with an implantable device has been used clinically to relieve symptoms in patients with refractory angina and chronic pain syndrome. Our project team has studied acute SCS treat a porcine model of ischemic HF induced by MI and rapid ventricular pacing, although the mechanisms by which SCS exerts its effects remain unclear, prior studies have suggested that acute SCS improves global and regional LV contractile function, suppresses peripheral sympathetic tone by modulation of the intrinsic afferent sensory cardiac neurons related to sympathetic excitation. But in the chronic experiments, we can see a large variation in traits. SCS may, thus, offer a novel therapeutic approach to treat HF, but there are lots of contents need to be studied further. Fastigial nucleus stimulation(FNS) has been proved to have cardioprotective effects, got more attention on curing cardiovascular diseases. The aim of this study is to investigate the effect of acute SCS combined use of FNS on LV contractile cardiac contractile function, myocardial mechanics and cardiac remodeling using invasive hemodynamic assessment, detailed noninvasive echocardiographic measurements,myocardium microvessel density(MVD) and serum BNP in a porcine model of ischemic HF.

脊髓电刺激（SCS）治疗是国际公认治疗顽固性疼痛的方法，也是缓解顽固性心绞痛和改善心肌缺血的有效方法，目前国际个别研究团队开始探索将其作为治疗急性心肌梗死（AMI）后心功能衰竭（HF）的方法，我们研究团队三年前开始该领域的研究，前期急性实验证明SCS能明显提高AMI后HF的心功能，但在慢性实验中该方法存在较大的变异性，本项目根据小脑顶核电刺激（FNS）能启动预防及治疗中枢神经源性保护的机制，对心脑等重要脏器产生缺血性保护，制定SCS结合FNS的治疗新方案，使交感神经和副交感神经达到新的平衡，增进心脏功能，降低恶性心室重构和室性心律失常的发生，为AMI后HF的患者开辟新的治疗方法。本研究方案采用现代超声最新技术实施心功能、心肌力学特性、心脏机械重构及心肌血流灌注的评价，结合心肌微血管密度计数和血浆BNP的测定，综合评价疗效，实验手段和评价方法有明显的先进性和可行性。

脊髓电刺激治疗（SCS）是国际公认治疗顽固性疼痛的方法，通过向脊髓硬膜外间隙植入电极，发放电刺激，缓解疼痛和改善心肌缺血。我们研究团队于2008年开始承担美国St.Jude公司的科技公关项目，进行SCS治疗急性心肌梗死（AMI）后心功能衰竭的实验研究，前期急性和慢性实验证明SCS能增进和保存多数AMI后心功能衰竭患者的心功能，降低室性心律失常发生，为AMI后心功能衰竭的患者开辟新的治疗方法。但是，SCS刺激对心交感神经具体作用机制和心交感神经元的电活动一直不清楚，该问题是国际心血管病专家困惑和我们研究团队一直思索和亟待解决的问题。本研究成功建立AMI后心功能衰竭兔动物模型后，对心交感神经在SCS刺激后电活动调节变化进行研究，研究结果显示低频（5HZ）、中频（50HZ）及高频（500HZ）刺激后，AMI后心功能衰竭组和正常对照组心交感神经纤维复合动作电位下降，交感神经元放电频率下降。其中，以AMI后心功能衰竭组的变化尤为明显，下降幅度表现为中频＞高频＞低频，呈现递减趋势。SCS抑制心交感神经放电活动，交感神经纤维复合动作电位下降，心交感神经活性降低，去甲肾上腺素水平下降，心功能改善，钠尿肽水平下降。本实验补充完善前期实验SCS治疗AMI后心功能衰竭的作用机制，为SCS实验的进一步深入开展提供循证学依据和理论机制。