Co-Administration of Inhibitors of HDAC6 and SGLT2 in Murine HFpEF Models Results in Additive Improvements in Cardiac Structural and Functional Measures

Background HFpEF is a form of heart failure characterized by diastolic dysfunction and associated with high morbidity, mortality and significant unmet need. Previously, we have demonstrated that selective inhibition of histone deacetylase 6 (HDAC6) has positive effects on diastolic dysfunction and left ventricular thickness of the heart, as well as overall improvements in systemic inflammation and metabolism, in a mouse model of HFpEF using a high-fat diet (HFD) and L-NAME. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor approved by the FDA for HFpEF patients, works as expected in this model, confirming the potential clinical translatability of results seen with HDAC6 inhibitors. In head-to-head studies, the beneficial effects of HDAC6 inhibition have been shown to be comparable to empagliflozin, while demonstrating a distinct mechanism of action in gene expression analysis. TN-301, a highly selective HDAC6 inhibitor has been advanced into clinical development for the potential treatment of HFpEF. Purpose In this study, we sought to investigate the additive or synergistic effects of combining HDAC6 and SGLT2 inhibition to improve cardiac function in a two-hit mouse model of HFpEF. Methods and Results Low doses of TYA-018 (a highly selective HDAC6 inhibitor) and empagliflozin were co-administered in our HFpEF model. We then assessed functional measures and cardiac gene expression in hearts from treated and control HFpEF mice. In our mouse model of HFpEF, pharmacological inhibition of TYA-018 results in extensive cardiac functional and structural improvements, including diastolic dysfunction and LV mass. Co-administration of TYA-018 and empagliflozin resulted in additive cardiac functional and structural measures vs. the single agents. Of note, multiple measures of diastolic dysfunction (e.g., E/e’) were returned to baseline values by combination treatment in HFpEF mice similar to those in WT mice. Gene expression analysis is being conducted using RNA-seq to elucidate the potential mechanisms underlying the efficacy of HDAC6 and SGLT2 inhibition by characterizing the pathway-level modulation by combination treatment compared to each therapy alone. Results of gene expression analysis comparing single-agent and combination activity are planned for inclusion at the time of presentation. Conclusion These studies demonstrate an additive benefit on diastolic dysfunction and elucidate key molecular mechanisms supporting the rationale for the potential use of HDAC6 inhibition as a single agent or in combination with SGLT2 inhibition for the treatment of HFpEF. HFpEF is a form of heart failure characterized by diastolic dysfunction and associated with high morbidity, mortality and significant unmet need. Previously, we have demonstrated that selective inhibition of histone deacetylase 6 (HDAC6) has positive effects on diastolic dysfunction and left ventricular thickness of the heart, as well as overall improvements in systemic inflammation and metabolism, in a mouse model of HFpEF using a high-fat diet (HFD) and L-NAME. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor approved by the FDA for HFpEF patients, works as expected in this model, confirming the potential clinical translatability of results seen with HDAC6 inhibitors. In head-to-head studies, the beneficial effects of HDAC6 inhibition have been shown to be comparable to empagliflozin, while demonstrating a distinct mechanism of action in gene expression analysis. TN-301, a highly selective HDAC6 inhibitor has been advanced into clinical development for the potential treatment of HFpEF. In this study, we sought to investigate the additive or synergistic effects of combining HDAC6 and SGLT2 inhibition to improve cardiac function in a two-hit mouse model of HFpEF. Low doses of TYA-018 (a highly selective HDAC6 inhibitor) and empagliflozin were co-administered in our HFpEF model. We then assessed functional measures and cardiac gene expression in hearts from treated and control HFpEF mice. In our mouse model of HFpEF, pharmacological inhibition of TYA-018 results in extensive cardiac functional and structural improvements, including diastolic dysfunction and LV mass. Co-administration of TYA-018 and empagliflozin resulted in additive cardiac functional and structural measures vs. the single agents. Of note, multiple measures of diastolic dysfunction (e.g., E/e’) were returned to baseline values by combination treatment in HFpEF mice similar to those in WT mice. Gene expression analysis is being conducted using RNA-seq to elucidate the potential mechanisms underlying the efficacy of HDAC6 and SGLT2 inhibition by characterizing the pathway-level modulation by combination treatment compared to each therapy alone. Results of gene expression analysis comparing single-agent and combination activity are planned for inclusion at the time of presentation. These studies demonstrate an additive benefit on diastolic dysfunction and elucidate key molecular mechanisms supporting the rationale for the potential use of HDAC6 inhibition as a single agent or in combination with SGLT2 inhibition for the treatment of HFpEF.