心梗后心衰变时功能不全的频率干预对预防猝死的作用及机制的研究

Chronotropic incompetence (CI), which is a prevalent concomitant disease in patients with heart failure, serves as a significant independent risk factor for Sudden Cardiac Death (SCD). The efficacy and possible mechanism of CI intervention for SCD prevention is poorly elucidated. Based on previous researches and up-to-date perspectives, we bring forward for the first time the hypothesis that risk of SCD in heart failure caused by Myocardial Infarction (MI) would probably be reduced by the intervention of concomitant CI. The mechanism mainly includes: 1) Upregulation of β1 AR and β2 AR ; 2) Upregulation of transcription factor MEIS1 and its down-stream pathway. A cell experiment will be conducted concerning the influence of hypoxia on MEIS1,β1 AR and β2 AR. The following three objectives would be tested on post-MI heart failure canine model: 1) The evolving mechanism of CI; 2) the correlation between MEIS1 down-regulation and SCD; 3) the efficacy and mechanism of CI intervention in SCD prevention. And a clinical follow-up will also be conducted concerning the influence of CI intervention on SCD and other clinical outcomes, which would in turn clarify the significance of CI in rescuing SCD in post-MI heart failure patients and spot a new breakthrough in SCD prevention.

心脏变时功能不全在心衰患者中发病率高，同时也是心脏性猝死的独立高危因素。通过频率干预改善心脏变时功能不全能否预防心梗后心衰患者SCD的发生及机制尚不清楚。本课题申请人在前期工作的基础上，结合最新的研究进展，首次提出：对心梗后心衰CI的频率干预很可能预防SCD，相关机制包括1）支配心脏的交感神经受体上调；2）通过上调MEIS1基因表达水平影响及其下游分子通路。本实验拟从细胞实验、动物和临床三方面探讨：（1）细胞实验水平模拟缺氧环境，探讨缺氧与MEIS1基因及交感神经受体的影响；（2）探索在心梗后心衰犬模型上应用频率应答起搏干预CI防治SCD的可行性及可能机制；（3）在临床上通过长期随访，进一步探索长期应用频率应答起搏干预CI防治SCD的可行性及对其他临床结局的影响，明确CI的频率干预的价值。本研究将为临床上SCD的防治提供了科学的突破口。

心脏变时功能不全在心衰患者中发病率高，同时也是心脏性猝死的独立高危因素。通过频率干预改善心脏变时功能不全能否预防心梗后心衰患者SCD的发生及机制尚不清楚。本课题申请人在前期工作的基础上，结合最新的研究进展，首次提出：对心梗后心衰CI的频率干预很可能预防SCD，相关机制包括1）支配心脏的交感神经受体上调；2）通过上调MEIS1基因表达水平影响及其下游分子通路。本实验拟从细胞实验、动物和临床三方面探讨：（1）细胞实验水平模拟缺氧环境，探讨缺氧与MEIS1基因及交感神经受体的影响；（2）探索在心梗后心衰犬模型上应用频率应答起搏干预CI防治SCD的可行性及可能机制；（3）在临床上通过长期随访，进一步探索长期应用频率应答起搏干预CI防治SCD的可行性及对其他临床结局的影响，明确CI的频率干预的价值。本研究将为临床上SCD的防治提供了科学的突破口。