Saxagliptin and tadalafil differentially alter left ventricular mechanics in a translational miniature swine model of heart failure with preserved ejection fraction (652.15)

We previously demonstrated pathological cardiac remodeling in a swine model of heart failure with preserved ejection fraction (HFpEF) was associated with altered left ventricular (LV) mechanics. The inhibitory effect of cGMP (cyclic guanosine 3',5'‐monophosphate) on pathological hypertrophic signaling is well established. Reduced cGMP signaling in HFpEF may occur as a result of dysfunctional production or enhanced catabolism via increased phosphodiesterase (PDE) activity. We hypothesized preservation of cGMP expression would attenuate pathological remodeling and improve LV mechanics in HFpEF. Thus, the purpose of this study was to promote cGMP signaling via two mechanisms: 1) the DPP4 inhibitor saxagliptin; and 2) the PDE5 inhibitor tadalafil. We assessed LV mechanics with 2D strain echocardiography 1 and 3 months post‐aortic banding in mini‐swine divided into four groups (n=5); control non‐banded (CON), HFpEF (HF), HFpEF saxagliptin‐treated (HF‐SAX) and HFpEF tadalafil‐treated (HF‐TAD). Tadalafil attenuated compensatory increases in systolic strain and early diastolic strain rate observed in the HF and HF‐SAX groups. In contrast, saxagliptin prevented increases in late diastolic strain rate associated with enhanced atrial systole observed in HF and HF‐TAD animals. Saxagliptin increased torsion transiently (1 mo.), although at 3 mo. both apical and early diastolic rotation rate were increased only in the HF‐TAD group. In conclusion, LV mechanics were distinctly altered in response to separate methods of pharmacological cGMP regulation. Our results suggest the mechanism by which cGMP signaling is promoted may play a role in LV mechanical adaptations to developing HFpEF.