Vasohibin Inhibition Improves Myocardial Relaxation In A Rodent Model Of Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection (HFpEF) is a complex syndrome with few therapies available to patients. Diastolic dysfunction is a common clinical feature among HFpEF patients, and strategies to mitigate impaired relaxation may have a therapeutic benefit. Recognizing that increased stabilization of the microtubule network induced by detyrosination of α-tubulin contributes to increased cardiomyocyte stiffness ex vivo , we explored if inhibition of detyrosination with a small molecule vasohibin inhibitor (VASHi) could improve in vivo diastolic function in obese/hypertensive (ob) ZSF1 rats, compared to lean/hypertensive ZSF1 and non-hypertensive Wistar Kyoto (Wky) rats as controls. Animals received two intravenous injections of VASHi (6.6mg/kg) or vehicle (veh) at 30 weeks old, when ob have a HFpEF phenotype. Echocardiography and invasive hemodynamics were performed after the first and second injection, respectively. Compared to ob veh-treated animals, ob VASHi-treated animals had a significant improvement in invasively measured time constant of early LV relaxation, tau (veh: 14.73ms ± 0.73 vs. VASHi: 11.02ms ± 0.45; P < 0.05) and echo-derived deceleration time of early LV filling, indicative of improved early relaxation (Fig. A, B). VASHi improved early relaxation in cardiomyocytes isolated from non-failing (NF, N=3) and failing (HF, N=4) human hearts (Fig. C), providing the first evidence of small molecule VASHi improving human myocyte function. These studies indicate that excess detyrosination contributes to impaired early myocyte and myocardial relaxation in a clinically relevant HFpEF model and supports a potential therapeutic role for VASHi in HFpEF.