Reductive stress in myocardial Ischemia: Mechanisms, pathophysiology, and therapeutic perspectives

Reductive stress (RS), characterized by excessive accumulation of reducing equivalents including NADH, NADPH, and glutathione, is increasingly recognized as a potential contributor to myocardial ischemic heart disease. Conventional models of ischemia reperfusion injury primarily focus on oxidative stress and reactive oxygen species (ROS) mediated damage; however, excessive reductive redox imbalance may also influence myocardial susceptibility to injury. During ischemia, metabolic disruption and accumulation of electron carriers constrain mitochondrial electron transport, promote reverse electron transport associated ROS generation during reperfusion, and lower the threshold for mitochondrial permeability transition pore opening. Together, these changes may increase vulnerability to reperfusion associated injury and maladaptive remodeling. This review presents RS as an ischemia associated metabolic priming state that influences mitochondrial redox biology and modifies the response to reperfusion in different metabolic settings. Evidence linking ischemia induced metabolic alterations with mitochondrial dysfunction, inflammatory signaling, and fibrosis is examined in the context of existing oxidative stress centered models. Therapeutic strategies aimed at restoring redox balance are also discussed, including mitochondria targeted antioxidants, NAD⁺ centered metabolic interventions, and modulation of Nrf2 and sirtuin signaling pathways. In addition, the review highlights the current absence of standardized biomarkers for RS and discusses the potential value of RS guided phenotyping for improving therapeutic precision in ischemic heart disease. This framework proposes experimentally testable concepts intended to support future mechanistic studies and biomarker development.