Background: Diastolic dysfunction (DD) is associated with the development of heart failure (HF) and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation (AF). Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. Here, we addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction (EF). Methods: Four weeks following uninephrectomy (UNX) and implantation with deoxycorticosterone acetate (DOCA) pellets, when DD was clearly evident, one cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and endpoint invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed ex vivo. Cardiac fibrosis was evaluated by picrosirius red (PSR) staining and second harmonic generation (SHG) microscopy of left ventricular (LV) sections, RNA-sequencing of LV mRNA, mass spectrometry-based evaluation of decellularized LV biopsies, and atomic force microscopy (AFM) determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts. Results: HDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. Surprisingly, in contrast to prior models, myofibril relaxation was unimpaired in UNX/DOCA mice. Furthermore, cardiac fibrosis was not evident in any mouse cohorts based on PSR staining or SHG microscopy. However, mass spectrometry revealed induction in the expression of more than one hundred extracellular matrix (ECM) proteins in LVs of UNX/DOCA mice, which correlated with profound tissue stiffening based on AFM. Remarkably, ITF2357/Givinostat treatment blocked ECM expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the pro-fibrotic chromatin reader protein, BRD4, to key gene regulatory elements. Conclusions: These findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD, and establish blockade of ECM remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Additionally, our data reveal the existence of pathophysiologically relevant 'covert' or 'hidden' cardiac fibrosis that is below the limit of detection of histochemical stains such as PSR, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.

End stage heart failure is a major cause of death in the US. At present, organ transplant and left-ventricular assist devices remain the only viable treatments for these patients. Cardiac tissue engineering presents the possibility of a new option. Nanomaterials such as gold nanorods (AuNRs) and carbon nanotubes (CNTs) present unique properties that are beneficial for cardiac tissue engineering approaches. In particular, these nanomaterials can modulate electrical conductivity, hardness, and roughness of bulk materials to improve tissue functionality. Moreover, they can deliver bioactive cargo to affect cell phenotypes. This review covers recent advances in the use of nanomaterials for cardiac tissue engineering.

Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT). RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with ephrinB2 FC protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy. Significance: Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease. See related commentary by Garcia Garcia et al., p. 3158