Multi-Omics Profiling of Myocardial Stunning and Necrosis across Experimental and Clinical Settings

Abstract

This thesis investigates the molecular basis of ischemic preconditioning (IPC)-induced cardioprotection and the mechanisms behind the reversible post-ischemic dysfunction (termed myocardial stunning) and irreversible myocardial necrosis seen after myocardial ischemia-reperfusion (I/R) injury. Using an experimental in vivo rat model and a multi-omics approach, this work explored molecular responses following IPC and I/R. IPC was associated with reduced infarct size and a greater tendency toward reversible post-ischemic dysfunction. This effect was accompanied by early changes in phosphorylation of proteins involved in the sarcomere, Z-disc, cytoskeleton, and actin binding structures, consistent with rapid adjustment of contractile machinery during ischemic stress.

Beyond these early phosphorylation-dependent changes, IPC was associated with a temporal proteomic response. Early adaptive pathways were activated, whereas proteins linked to inflammation, complement, coagulation, and remodeling were attenuated during reperfusion, suggesting a more favorable post-ischemic myocardial environment. At the level of gene regulation, IPC was associated with transcriptional and epigenetic reprogramming, including reduced global DNA methyltransferase activity and selective promoter methylation changes in genes involved in inflammation, stress signaling, and DNA repair. These changes were consistent with suppression of maladaptive responses and activation of protective molecular programs. In addition, plasma profiling in women identified differences in inflammatory and stress-response protein signatures in patients with Takotsubo syndrome compared to ST-elevation myocardial infarction. The findings of this thesis are consistent with the concept of myocardial stunning as a biologically regulated and potentially adaptive state.