Mastoor Yusuf, Murphy Elizabeth, Roman Barbara
J Clin Invest. 2025 Jan 2;135(1):e184134. doi: 10.1172/JCI184134.
Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a "drug cocktail" approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.
急性心肌梗死（MI）是全球主要的死亡原因之一。尽管采用目前的治疗方法，MI的急性死亡率较低，但与MI相关的心肌损伤和重塑是导致后续心力衰竭的原因。减少与急性MI相关的细胞死亡将降低与心力衰竭相关的死亡率。尽管进行了大量研究，但缺血再灌注（I/R）触发细胞死亡的确切机制仍未完全了解。在本综述中，我们总结了I/R损伤期间发生的变化，重点关注那些可能引发细胞死亡的变化，如钙超载和氧化应激。我们回顾了细胞死亡途径和途径间的相互作用，并讨论了心脏保护方法，以便深入了解可作为治疗干预靶点的机制。最后，我们回顾了心脏保护临床试验，重点关注它们未成功的可能原因。心脏保护主要集中在抑制单一细胞死亡途径或一种死亡触发机制（钙或活性氧）。在治疗其他疾病（如癌症）时，采用“药物鸡尾酒”方法靶向多种途径的益处已得到证实。鉴于细胞死亡途径之间的相互作用，应考虑靶向多种心脏死亡机制。
