Mechano-biological phenotype in post-infarction cardiac remodeling

Abstract

Ischemic heart disease is one of the leading cause of death in developed countries. In 30% of patients with heart infarction, inadequate cardiac fibrosis leads to terminal failure. We believe that local mechanical forces (inherent to the pump function of the heart) after cardiac infarction play a key role in the outcome of cardiac remodeling, in particular by modifying the response of microvascular endothelial cells (MECs), main players accompanying myocardial healing processes. Dynamic data, accessible by ultrasound, are however not widely used in the clinic, and could help to understand why patients remain refractory to treatments for heart failure. We aimed at studying the mechano-biological coupling that exists between mechanical stress applied to ischemic lesions, and the local biological response of cardiac cells. Using a mouse model of myocardial infarction (coronary artery ligation), we analyzed heart deformation using dynamic ultrasound imaging 1 month post-infarction (speckle tracking, VevoLabs). Mice were then sacrificed, and the hearts were harvested and processed for immunohistochemical analysis. Multiparametric mechanical maps (strain, displacement and velocity) were obtained using a morphometry program developed in the laboratory, and compared to a spatial transcriptomic analysis in the corresponding section planes (Visium, 10X genomics), in 4 infarcted heart of various size and localization. The transcriptomic data were validated in situ by immunofluorescence, in contiguous mouse heart sections ( Fig. 1 ). Generated big data highlight a panel of transcripts which expression highly correlates with radial strain and displacement of the heart wall. Among these factors, neuregulin-1 (involved in cardiac remodeling), and TRPC6 or PECAM-1 (sensors of mechanical forces) were found highly expressed in the mouse heart sections (immunofluorescence). Neuregulin-1 and TRPC6 strongly co-localized with MECs and coronary artery SMCs bordering the infarcted area, while PECAM-1 activation (phosphorylation) in MECs was found highly correlated with radial strain. These results support a mechano-biological coupling in infarcted hearts, modulating the expression of factors involved in its repair. Understanding the biology associated with mechanical stress could improve the management of patients after a heart attack, on the sole basis of dynamic imaging.