Human Tissue-Engineered Model of Myocardial Ischemia–Reperfusion Injury

Abstract

Ischemia–reperfusion injury (IRI) is a major, but potentially preventable contributor to the final tissue damage after an acute myocardial infarction. Many therapies have demonstrated successful reduction of IRI in preclinical settings, but none has shown improved outcomes in clinical studies. Part of the failure to translate new therapies to clinical settings can be attributed to the reliance on small animal models in preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not necessarily recapitulate human physiology. In this study, we utilized cardiac tissue engineering methods and cardiomyocytes derived from human induced pluripotent stem cells to establish a human tissue-engineered model of IRI. The resulting cardiac constructs were subjected to conditions that simulated ischemia–reperfusion. We demonstrated the presence of reperfusion injury and the ability to distinguish ischemic and reperfusion injury. We also demonstrated reductions in IRI following ischemic preconditioning, modification of reperfusion conditions, and addition of cardioprotective therapeutics. This study establishes the utility of a human tissue model for studying key aspects of IRI and the potential for improving translation of therapeutic strategies into the clinical setting.

Impact Statement

Reducing ischemia–reperfusion injury would significantly improve patient survival. Current preclinical models are inadequate because they rely on animals, which do not emulate human physiology and the clinical setting. We developed a human tissue platform that allowed us to assess the human cardiac response, and demonstrated the platform's utility by measuring injury during ischemia–reperfusion and the effects of cardioprotective strategies. The model provides a foundation for future studies on how patient-specific backgrounds may affect response to therapeutic strategies. These steps will be necessary to help translate therapies into the clinical setting.