Translational studies to understand myocardial stunning in acute myocardial infarction

Abstract

Myocardial stunning is a reversible contractile dysfunction that persists despite the resolution of myocardial ischemia. It is commonly associated with acute myocardial infarction. However, myocardial stunning also occurs in other acute cardiomyopathies, including Takotsubo syndrome (TS), triggered by severe emotional or physical stress. While the pathophysiology remains incompletely understood, oxidative stress and disruptions in intracellular calcium homeostasis are key mechanisms that impair the cellular contractile apparatus following ischemia. Despite its clinical relevance, the natural temporal progression of myocardial stunning during ischemia and reperfusion, along with factors influencing recovery, remains poorly characterized. The overarching aim of this thesis is to investigate the natural course of myocardial stunning using a translational approach. In Paper I, we demonstrated that circulating levels of cardiac injury biomarkers troponin I and T increase after brief myocardial ischemia without overt infarction, suggesting that troponin release is not specific for myocardial cells death. However, longer ischemic durations resulting in significant myocardial infarction led to an increased troponin I/troponin T ratio, in both rats and humans. In Paper II, we showed that ischemic preconditioning (IPC), in addition to reducing infarct size, modified phosphosites critical for contractile function and enhanced myocardial stunning after experimental ischemia-reperfusion injury. In Paper III, we developed and validated a novel method to quantify cardiac dysfunction in patients with STEMI and TS using transthoracic echocardiography. In Paper IV, we compared the severity and temporal recovery of cardiac dysfunction after STEMI between sexes, highlighting potential sex-specific differences in myocardial stunning. Together, these studies advance our understanding of the mechanisms, assessment, and recovery of myocardial stunning.