Abstract Body (Do not enter title and authors here): Introduction: Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome that accounts for >50% of heart failure but has limited treatment options. HFpEF is associated with left ventricular hypertrophy and impaired diastolic function. Increased post-translational detyrosination of α-tubulin (dT), mediated by vasohibins (VASH1/2), occurs in all forms of human heart failure including those with diastolic dysfunction and contributes to left ventricular stiffness and impaired relaxation. We have recently shown that a new class of small molecule VASH inhibitors (VASHi) are capable of acutely improving myocardial relaxation in a rat model of HFpEF. The implications of prolonged dosing are unknown but crucial to defining the efficacy of VASHi for the treatment of HFpEF.

Hypothesis: Sustained treatment with VASHi improves relaxation and prevents adverse remodeling in the ZSF1 rat model of HFpEF.

Methods: ZSF1 obese rats, a well-validated model of cardiometabolic HFpEF, were treated either with an oral formulation of VASHi 200 mg/kg daily for 8 weeks (N=14, age 12-14 to 20-22 weeks) or with a vehicle control (N=14). They were compared to Wistar-Kyoto (WKY) wild-type control rats (N=13). Both males and females were studied. Animals were assessed by serial echocardiography over the course of treatment and by invasive hemodynamics at endpoint, then assessed for extent of dT reduction.

Results: Sustained VASH inhibition normalized detyrosinated microtubule levels in male ZSF1 obese rats. This was associated with improvements in diastolic function as evidenced by reduced left ventricular end-diastolic pressure (LVEDP) and tau, the time constant of relaxation. Notably, systolic function remained normal (Average LVEF±SEM, WKY: 68.1±2.1%, Vehicle: 68.8±2.0%, VASHi: 70.2±1.4%). At endpoint, hearts of male VASHi treated animals had lower heart weight per tibia length with no difference in blood pressures between the ZSF1 obese groups (Average±SEM, Vehicle: 175±4/125±3 mmHg vs. VASHi: 177±5/126±3 mmHg, systolic BP p=0.78, diastolic BP p=0.70).

Conclusions: Daily oral dosing of VASHi in ZSF1 obese rats improved diastolic function and blunted adverse structural remodeling, suggestive of a blood pressure-independent reduction in myocardial hypertrophy. These data support VASH inhibition as a therapeutic target for HFpEF.