Biological Mechanisms of the Infarct Borderzone

ABSTRACT Ischemic heart disease, the most common cause of death in the world, is a spatially heterogeneous injury. Between areas of cell death and distant normal cells lies the borderzone (BZ), a complex and dynamic region of cells that plays a critical role in infarct expansion and pathologic remodeling. Historically, it was challenging to study the BZ because of reliance on bulk measurement techniques that combine it with infarct and remote zones in uncontrolled proportions. However, our recently published work shows that the BZ can be redefined based on gene expression using single cell/nuclei, spatial transcriptomics, and multiplexed FISH. This led to the Loss of Neighbor Hypothesis, which proposes that the biology of the BZ is mechanically induced as a result of destabilizing forces resulting from large areas of ischemic cell death. We propose that this secondary mechanical injury is central to infarct expansion and precipitates nuclear envelope rupture and repair, which underlies infarct expansion, pathologic remodeling, and development of heart failure. Aim 1 will investigate the relationship between nuclear rupture, DNA damage, and cell fate at the infarct BZ. Aim 2 will delineate cell-type-specific roles in initiation and propagation of the BZ during infarct expansion. Aim 3 will develop a therapeutic strategy to modulate borderzone biology and limit infarct expansion. Success in this project will advance our understanding of multiscale mechanisms in the BZ and reveal new opportunities for therapy to break the links between myocardial infarction and development of chronic progressive heart failure.