A heart attack, acute myocardial infarction (MI), is one of the leading causes of death and significantly affects the quality of life. In Hawai‘i, we have many cases of patients with acute MI due to multiple risk factors including diabetes and hypertension. The size of myocardial (heart muscle) scarring following acute MI – adverse left ventricular (LV) remodeling – is highly correlated with heart failure development. However, the mechanism underlying myocardial scarring following acute MI is not well characterized.
Though myocardial reperfusion therapies, such as primary percutaneous coronary intervention (PCI) using stents, reduce the initial infarct size in patients with acute MI, the process of reperfusion induces further injury in the myocardium, known as reperfusion injury. Previously we demonstrated that in a mouse model of ischemia-reperfusion injury, myocardial scarring extends specifically along myofibers that are formed from bundles of cardiomyocytes (heart cells). The unique distribution of myocardial scarring indicates cell-to-cell propagation of cardiomyocyte cell death along myofibers. The findings cannot be explained by the traditional concept, waterfront phenomenon, that states during acute MI, cardiomyocyte death starts from the insides of the LV wall and extends to the outside of LV wall following the path of coronary arteries that penetrate the LV wall.
Our recent paper displays two groups in ischemic heart disease within the silent teachers of JABSOM’s Willed Body Program; 1) the pathological pattern consistent with the wavefront phenomenon, and 2) the myocardial scarring pattern extending along myofibers that is consistent with mouse models of ischemia-reperfusion injury. We previously reported that ferroptosis, an iron-dependent form of regulated cell death, is a significant contributor to cell death in cardiomyocytes. To define whether ferroptosis is involved in the cell-to-cell propagation of cardiomyocyte cell death, we invented new methods using in vitro cell culture and ex vivo isolated heart system. We demonstrated for the first time that ferroptosis is a key pathological factor in propagating injury between cardiomyocytes that is observed in ischemia-reperfusion injury. Understanding this mechanism may lead to efficient therapeutic approaches to limit LV remodeling after ischemia-reperfusion injury and eventually reduce a risk of heart failure in a patient with acute MI.
Current and former graduate students at UH Mãnoa, Nicholas K. Kawasaki (DRB), Briana K. Shimada (CMB), Naaiko Yorichika (MBBE) and Jason K. Higa (CMB), serve as an author in this article. Jason K Higa, Assistant Professor of Anatomy, Biochemistry and Physiology, is currently a course director of MD4 at JABSOM. Takashi Matsui, Professor and Chair of Anatomy, Biochemistry and Physiology, serves as a corresponding author.
You can read the full paper in Life Sciences.
The role of ferroptosis in cell-to-cell propagation of cell death initiated from focal injury in cardiomyocytes. Life Sci. 2023;332:122113. doi: 10.1016/j.lfs.2023.122113
Kawasaki NK, Suhara T, Komai K, Shimada BK, Yorichika N, Kobayashi M, Baba Y, Higa JK, Matsui T.