摘要：突發性心跳停止經初步心肺復甦急救後，會因缺血再灌流引發之急性心肌功能失常而導致死亡，其中心臟及全身性代謝紊亂(metabolic crisis)是重要的原因，這些代謝物質的異常，與粒線體受損也息息相關。現行於恢復自發性循環後，亦即是再灌流階段進行之低溫治療已被確認為改善心臟功能失常及預後的有效方式，然而其最佳的治療溫度及施予模式仍未有定論，在預後的改善方面也未臻理想。若能於心跳停止，尚未恢復自發性循環此低度再灌流的時機，在施行心肺復甦術同時開始進行低溫治療(intra-arrest therapeutic hypothermia，IATH)，此突破性的做法，從機轉上來說可顯著減少再灌流傷害的發生，也有改善器官功能潛力，然其確定效果如何，以及是否透過快速穩定代謝路徑的紊亂(metabolic resuscitation)來達成仍未明。本研究計畫中，第一年將先確立 IATH 治療對心臟功能的保護效果，細胞及粒線體型態的維持及對氧化壓力傷害的減緩。第二年則是基於第一年結果，比較不同時間點及治療模式下，對於改善代謝產物的紊亂變化及治療的效果，並與粒線體功能的變化、細胞凋亡的進展比對，以釐清穩定代謝物質平衡與IATH 作用的機轉及潛在應用。第三年則是探討IATH 治療如何啟動保護機轉，將針對近來發現STAT-3 直接進入粒線體之重要路徑進行調控，以釐清其角色，並做為發展新治療的基礎。
Abstract: Myocardial dysfunction is a major cause of early mortality after sudden cardiac arrest andcardiopulmonary resuscitation. The global ischemia reperfusion injury causes the disturbance and imbalanceof metabolites which lead to metabolic crisis in post-cardiac arrest syndrome. The metabolic crisis causesmitochondria dysfunction and leads to myocardial dysfunction. Therapeutic hypothermia is the effectivetreatment for post-cardiac arrest myocardial dysfunction and can improve long-term outcomes. However,the optimal temperature and way of applying temperature controlling remains unclear. There is room forimprovement in outcome for cardiac arrest patient under current hypothermia treatment initiated after returnof spontaneous circulation (post-ROSC hypothermia) modality. The novel concept of intra-arrest therapeutichypothermia (IATH), i.e. starting cooling when performing chest compression before ROSC can minimizethe reperfusion injury. IATH commences the treatment in the low flow reperfusion status immediately afterending of ischemia and before complete reperfusion with occurrence of related injury when return ofspontaneous circulation achieved. The effects and mechanisms of metabolic resuscitation by stabilization ofmetabolic crisis remain unclear in IATH and deserve further investigation. Under IATH, how to initiate theprotection on mitochondria function and avoid metabolic crisis is not clear. Activation STAT-3 and relatedpathways induce the rapid translocation of STAT-3 into mitochondria and generate mitochondria protectioneffects after appropriate stimulation. The novel role of STAT-3 related pathway is different from thetraditional role of STAT-3 as a transcriptional factor into nucleus and regulating genes. Whether the IATHinitiates the novel pathway remains unclear and needs further studies.The study project includes 3 years planning for experiments. In the first year, we will establish thecardiac arrest and resuscitation model and measure the myocardial dysfunction in post-resuscitation period.The IATH will be applied and cardio-protection effects will be confirmed in the model. Treatment effects oncellular and mitochondrial morphology will be investigated and compared under various treatment policiesincluding IATH. The protective effects preventing from oxidative injury will be studied in the first year. Inthe second year, we will study and define the metabolic crisis by metabolic profiling the metabolicdisturbance after cardiac arrest and resuscitation and also the effects of maintaining metabolites balancesunder IATH. The difference of metabolite changes will be correlated to the effects on mitochondriadysfunction and anti-apoptosis under IATH to clarify its mechanisms and potential utilization. In the thirdyear, we will study the potential regulatory pathways for the cardioprotective effects of IATH. We willfigure out the roles and translocation of STAT-3 by inhibiting its activation in various treatment protocolsincluding IATH. The key hemodynamic effects, metabolic crisis and mitochondria changes defined in the 1stand 2nd year will be investigated under regulating the STAT-3 activities to clarify its role in the IATH relatedcardioprotection effects. The results can also be the basis of developing new therapeutic modality.
sudden cardiac arrest
intra-arrest therapeutic hypothermia
post-cardiac arrest syndrome