干预陈旧性心肌梗死瘢痕区成纤维细胞上的缝隙连接功能对梗死后室性心动过速影响的实验研究

The mortalityof myocardial infarction is up to 15% in the first year, the vast majority of it relates to post- infarct ventricular tachycardia. To find a new treatment of ventricular tachycardia is very important since it is easy to lead to sudden death and the effects of the existing treatment methods is not satisfactory. The happening of ventricular tachycardia is supposed to relate to post-infact scar tissue. The traditional idea is a large quantity of fibroblasts accumulated in scar tissue. They are the barrier of electrical conduction that will lead to the formation of reentry loop. Recently, some evidence suggests that fibroblasts also have the ability of electrical conduction, and they can couple to other fibroblast and myocytes via gap junctions － the high efficiency channel for electrical conduction, but the function and the effects of them to electrical conduction in scar are not known. Whether the gap junctions are beneficial is still controversial. In theory, on one hand, they could bridge the heathy myocardium with the survival myocardium through fibroblasts and provide a mechanism for electrical communication, but on the other hand, the change of electrical property and the slow conduction, which occurs across fibroblast inserts, could be arrhythmogenic. This research is to investigate the function of gap junctions on the fibroblasts. To evaluate whether an incease or reduction in coupling should be favored. This study aims to explore the role of gap junctions in electrical property and conduction in scar tissue to find a new treatment of old myocardial ventricular tachycardia by investigating if reduction of the coupling could block the slow conduction path to terminate the reentry exciting like medicine ablation, or enhancement of the coupling could increase the synchronization of excitable tissue to avoid ventricular tachycardia happening.

心梗后一年内死亡率高达15%，其中绝大部分与心梗后室速有关，后果严重而疗效欠佳，故找到新的治疗途径极为重要。心梗后室速的发生与瘢痕组织有关，传统观点认为瘢痕处成纤维细胞大量聚集，对心肌电传导起阻隔作用，易于形成折返环路。而近年研究提示，成纤维细胞虽电阻大但也具有电传导性能，且成纤维细胞之间及与心肌细胞之间可能存在电传导的高速通路- - 缝隙连接，但其功能状态和对瘢痕区电传导的影响尚不明确。从理论上讲虽有利于通过成纤维细胞建立正常心肌与梗死区存活心肌之间的电联系，但也可能由于成纤维细胞的介入导致电学特性改变和电传导延缓而引起折返性室速，有益还是有害尚无定论。本课题旨在研究成纤维细胞上缝隙连接在瘢痕区电激动和电传导中的地位，观察阻滞其功能是否能起到阻断瘢痕区缓慢传导通路以达到药物消融的目的；或激动其功能是否可以增加心脏电传导的整体性，减少室速的发生，以找到治疗陈旧性心肌梗死室性心动过速的新途径。

心梗后一年内死亡率高达15%，其中绝大部分与心梗后室速有关，后果严重而疗效欠佳，故找到新的治疗途径极为重要。心梗后室速的发生与瘢痕组织有关，传统观点认为瘢痕处成纤维细胞大量聚集，对心肌电传导起物理性阻隔作用，易于形成折返环路。而近年研究提示，成纤维细胞上也可能存在电传导的高速通路——缝隙连接，但其对瘢痕区电传导的影响尚不明确。本课题采用小型猪为动物模型，制造心肌梗死模型，观察给予缝隙连接激动剂APP－10前后对室性心动过速的影响。在免疫荧光实验中发现，在心肌梗死区域成纤维细胞增生明显，而成纤维细胞上Cx43平均光密度下降，心肌细胞减少，而Cx43平均光密度代偿性增加，总体梗死区Cx43水平较正常区域下降，而较梗死过渡缺血区有所上升。在电生理实验中发现，APP－10能增加心肌梗死区域电传导速度和局部电压值。血清学研究中发现，APP－10能降低急性心肌梗死后血浆中多巴胺及肾上腺素水平。在室速诱发试验中发现APP－10在急性和慢性心肌梗死模型中均能有效减少室速的发生。实验结果表明，陈旧性心肌梗死区域成纤维细胞增加，细胞上缝隙连接的数量减少，这与心梗后局部电传导受阻易于发生室速有关。梗死区心肌细胞间缝隙连接数量增加可能是机体的一种代偿性行为，加强局部缝隙连接的传导后即加强这种代偿行为后发现局部的电压值升高，室速的诱发减少。说明缝隙连接在陈旧性心肌梗死室速的发生中可能具有重要的地位，这种地位可能与缝隙连接在电传导中的作用有关，也有可能与其降低交感神经递质水平有关。