Abstract 15707: Histone Deacetylase Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling

Abstract

Introduction: Diastolic dysfunction is associated with the development of heart failure with preserved ejection fraction and other cardiac maladies, including atrial fibrillation. Inhibition of histone deacetylase (HDAC) activity has previously been shown to prevent diastolic dysfunction by enhancing myofibril relaxation. Here, we further addressed the therapeutic potential of HDAC inhibition in a model of established diastolic dysfunction with preserved ejection fraction. Methods: Four weeks following uninephrectomy (UNX) and implantation with deoxycorticosterone acetate (DOCA) pellets, when diastolic dysfunction was clearly evident, one cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Serial echocardiography, blood pressure measurements, and endpoint invasive hemodynamic analyses were performed, along with the evaluation of pathological cardiac fibrosis and remodeling. Results: HDAC inhibition completely normalized diastolic function without lowering blood pressure in this model of systemic hypertension. Cardiac fibrosis was not evident in any mouse cohorts based on picrosirius red staining or second harmonic generation 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 atomic force microscopy. Remarkably, ITF2357/Givinostat treatment entirely blocked ECM expansions 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 diastolic dysfunction, 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’ cardiac fibrosis that is below the limit of detection of histochemical stains, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.