Go big or go home - Translational approaches to target ischemic heart failure

PhD thesis, Evelyne Demkes

With the increased incidence of ischemia-induced heart failure and the high disease burden associated with this, novel therapeutics that protect the heart from developing heart failure are desired. Direct post-ischemic remodeling is essential for clearance of cellular debris and proper scar formation but long-term adverse cardiac remodeling drives progression to heart failure.
Accordingly, the main objective of the research in this thesis is to target processes critically contributing to cardiac remodeling, namely, excessive cell death, acute and chronic inflammatory responses, and excessive fibrosis formation in search for new interventions and therapies for future clinical testing. To accomplish this, we made use of a clinically relevant large animal model, a crucial link in the translation of basic science to first-in-man trials.

In part I, we aimed to reduce inflammatory-associated myocardial damage after myocardial infarction by studying the effect of a novel NLRP3-inflammasome inhibitor in a porcine model of ischemia/reperfusion.

In part II, we aimed to prevent extensive cardiomyocyte death and limit cardiac fibrosis by using a combined treatment with a glucagonlike peptide-1 receptor agonists and a mineralocorticoid receptor antagonists in a pig model of severe ischemia/reperfusion and a mouse model of permanent myocardial infarction.

In part III, we aimed for replacement of lost cardiac tissue during progression towards heart failure by transplanting microtissues. In addition, we provided recommendations with respect to immunosuppressive regimens in preclinical cardiac cell-replacement studies and we designed an immunosuppression regimen for xeno-cell transplantation studies that can be used in porcine animal models.