缺血性心力衰竭心室整体复极离散与跨壁复极离散的三维单向动作电位研究

Malignant ventricular tachyarrhythmia (MVT) is one of the major causes of death in patients with chronic ischemic heart failure. Increased dispersion of ventriuclar repolarization has been reported to be highly associated with the MVT. However, little is known about the ?trial fibrillation (AF) is the most common arrhythmia and is associated with significant mortality, principally through heart failure and stroke. The incidence of AF increases with age; a prevalence of 0.1% in adults younger than 55 years increases to 9% in adults older than 80 years. In the Framingham Heart Study, the lifetime risk for developing AF was one in four in men and women aged 40 years or above..The mechanism of atrial fibrillation is complicated, which is a result of continuous remodelling of the atria, which involves electrical and structural transformation, altered metabolism, and autonomic changes secondary to ageing, progression of underlying heart disease, and genetic and environmental factors. There are many possible causes of AF, and the risk of AF increases with age; however, the majority (>70%) of patients have some form of structural heart disease. .Among different risk factors, hypertension is one of the important independent risk factors for the development of AF. In the Cardiovascular Health Study of subjects older than 65 years of age, the risk for developing new-onset AF was higher in hypertensive patients was 1.11. In patients with AF, up to 60% have a history of hypertension. In combination, AF and hypertension are associated with an 8-fold increased risk of stroke, and in a high-risk hypertensive population, preexisting or new-onset AF is associated with increased mortality..In patients with hypertension, several mechanisms may contribute to the development of AF. First, the hemodynamic changes in atria caused by hypertension could be account for the atria vulnerability to AF. Previous studies have shown that increased LA (left atrial) pressure due to impaired LV relaxation in the hypertensive heart will eventually lead to LA enlargement. The consequent distention and stretching of the atria related to hypertension can alter atrial electrophysiological properties, including shortening of the effective refractory period and increased dispersion of refractoriness with subsequent increased vulnerability to AF. Second, the Renin-angiotensin-aldosterone system(RAAS) has been well demonstrated that activation of the RAAS occurs in patients with hypertension and is strongly implicated in the development of AF. .The special electrophysiological characteristics of pulmonary veins (PVs) are highly correlated with the incidence of AF. The observation that ectopic beats from the PVs play a major role in the initiation of AF has led to the development of catheter ablation circumferential PV isolation (CPVI) as an accepted treatment for AF. To date, the CPVI has been demonstrated to be effective in many patients with paroxysmal AF. However, hypertension is

室性恶性心律失常所致心源性猝死是慢性缺血性心衰患者死亡的主要原因。心室复极离散增加与恶性心律失常的发生明确相关，但目前在体进行心室整体复极离散与跨壁复极离散的相关性研究较少，对于缺血性心衰研究更加有限。本课题采用三维单向动作电位标测技术，对比正常猪、慢性缺血性心力衰竭猪模型，及该模型右室心内膜、左室心外膜、双心室起搏等不同起搏程序下的心室整体三维单向动作电位标测；继之在体标测其心内膜、心室中间层、心外膜心室跨壁复极离散变化。评价各情况下心室复极与除极的关系；心室整体复极离散与跨壁复极离散的差异及相关性；并结合程序刺激辅助判断各情况下发生恶性室性心律失常的风险。其后，对照研究心衰猪离体心室灌注模型心室各层跨壁复极离散特点，并对比研究缝隙连接蛋白(Cx43) 在心室中的表达。同时，观察不同情况下心室整体及跨壁复极离散与心电图T 波终末时间的关系，以助T 波形成机制的理解。

心力衰竭作为各种心脏病的终末期表现之一，死亡率较高。其中，心源性猝死是该类患者主要的死亡原因，而这种心源性猝死主要与恶性室性心律失常相关。但是，不同病因所导致的心力衰竭特点不同，导致猝死的电生理机制也不尽相同。本课题组前一课题针对右室心尖部起搏致心衰模型的心源性猝死机制进行了深入研究，而缺血性心脏病作为导致心力衰竭的常见原因之一，其发生心源性猝死的机制也不尽相同，因此这类心衰患者发生心源性猝死的机制仍需要深入研究。心力衰竭发生猝死的主要原因是恶性室性心律失常，针对引起猝死的主要病因，如心肌肥厚、高血压病、急性心肌梗死等，课题组从大动物试验，基因组学、蛋白组学等层面开展了相关研究，取得了以下研究结果：（1）在心衰犬中研究发现，左室心外膜起搏显著增加心室复极离散度。在人体观察实验中，高位间隔起搏明显优于流出道和心尖部起搏.而流出道起搏略优于心尖部起搏，提示不同部位起搏对血流动力学也存在一定的影响。同时观察了不同部位起搏时心电图的变化，提示心力衰竭发生时室内传导不同步增加了心室复极离散程度，增加恶性心律失常的发生；（2）证实了骨髓来源CXCR2因子参与高血压及血管功能障碍的调节，文章发表在Ciruclation杂志；还发现NADPH因子能够促进血管损伤及高血压形成，推测可能对心肌重构产生影响；（3）动物实验中证实microRNA Let-7i对心肌炎症及纤维化起到保护作用；（4）发现诊断急性心肌梗死的新的生物标记物E3，诊 及敏感性均优于肌钙蛋白；（5）下调ATRAP水平能够促进血管紧张素II诱导的心肌肥厚；（6）通过抑制AKT/mTOR, ERK1/2, NF-κB及Ca信号通路能够促进心肌肥厚的发生。（7）AGGF1通过抑制心肌细胞凋亡和调节再生能够保护心肌缺血再灌注损伤。课题组通过动物实验、细胞试验等取得的研究成果从心肌肥厚、心肌梗死、心力衰竭等角度阐述了心肌细胞凋亡、离子通道改变等潜在诱发恶性心律失常的机制。