Background

Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a condition that is complex and heterogeneous. These include metabolic alterations, which have previously been associated with the development of HFpEF. Despite advances in clinical assessment, current recommendations and therapeutic to this common complication of HF remain suboptimal, with current guidelines advocating to treat underlying disease or comorbidities and no therapeutics approved for treatment by the Food and Drug Administration.

The beta-3 adrenergic receptor (β3AR) has been previously reported to affect metabolic dysregulation and beneficial effects for cardiac function and remodeling. Our preliminary data indicate that the β3AR agonist mirabegron reduces right ventricular systolic pressure (RVSP), an estimate of pulmonary artery pressure, in a dose-dependent fashion. To confirm the role of the β3AR in HFpEF-PH, we aim to test SR59230A, a selective β3AR antagonist, as well as other medications that improve metabolic dysfunction. These data may provide novel therapeutic targets for PH.

Animal Model

A previously developed mouse model involving AKR/J mice induced with left heart failure (HF-PH) that we successfully replicated will be used for this project. This model involves feeding the mice with a high-fat diet (HFD, 60% lipids/kcal) for 16-20 weeks. After this period, the mice have been shown to develop HFpEF, which progresses to PH. This recapitulates key clinical markers known to be present in patients with HFpEF-PH, including preserved ejection fraction, elevated end-diastolic pressure, right ventricular systolic pressure, and biventricular hypertrophy.

Treatment

The primary agents used in the course of the experiments will be SR59230A, dapagliflozin, metformin, and a placebo vehicle. All agents have been used in vivo, and a well-tolerated, clinically-relevant dose will be administered. These agents all have metabolic effects but via different mechanisms. The experimental agents will be delivered through ALZET osmotic pumps, implanted subcutaneously in the mice's subscapular region. This allows for controlled, chronic delivery of test compounds to the mice for a period of 4 weeks.

Experimental Design

The β3AR antagonist will be administered to explicate the mechanism of β3AR in HF- PH further. We hypothesize the β3AR antagonist will worsen the prognosis of the disease compared to control mice. We will also administer an SGLT2 inhibitor and metformin to determine if our previously observed PH-mitigating effects with β3AR agonism were specific to that receptor or if metabolic effects due to varying mechanisms improve PH. To evaluate HF-PH progression, the mice will undergo cardiac catheterization to measure right heart pressure and estimate pulmonary pressures for PH status. The mice will be euthanized after the procedure. Blood and tissue will be harvested immediately after euthanasia.