Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart

Rationale: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of remodeling on cardiac cells during failure (HF) is essential prevent adverse ventricular and restore organ functionality in affected patients. Objectives: We aimed (1) identify consistent modifications structure mechanics that contribute HF (2) determine underlying mechanisms. Methods Results: first performed decellularization human murine (decellularized ECM) then analyzed pathological changes occurring decellularized by atomic force microscopy, 2-photon high-resolution 3-dimensional image analysis, computational fluid dynamics simulation. functional assays patient-derived fibroblasts based YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity collagen contraction assays. The analysis resulting from ischemic or dilated cardiomyopathy, as well mouse infarcted tissue, identified common pattern their topography. As compared with healthy heart, exhibited aligned, flat, compact fiber bundles, reduced elasticity organizational complexity. At level, RNA sequencing highlighted overrepresentation dysregulated genes involved organization, being connected TGF?1 (transforming growth factor ?1), interleukin-1, TNF-?, BDNF signaling pathways. Functional tests pointed at mechanosensor key player diseased via transcriptional activation focal adhesion assembly. Finally, vitro experiments clarified prevents cell homing, thus further hints possible window action for therapy diseases. Conclusions: Our multiparametric approach has repercussions fibroblast activation, protein expression hyperactivated HF.