Early development and SGLT2 inhibitor-mediated reversal of coronary microvascular dysfunction in an isoprenaline-induced murine HFpEF model: Insights from multimodal in vivo imaging.

Abstract

BACKGROUND: Coronary microvascular dysfunction (CMD) is increasingly recognized as a mechanistically relevant contributor to HFpEF, yet the temporal and causal relationship between early functional CMD, coronary microvascular endothelial barrier injury, and fibrotic remodeling remains incompletely defined. The primary aim was to test whether CMD causally contributes to HFpEF-like remodeling and functional impairment in an isoprenaline (ISO) mouse model. A secondary aim was to determine whether empagliflozin (SGLT2i) or resolvin D2 modulates inflammatory and endothelial mechanisms of CMD. METHODS: Mice received Control, ISO, ISO + empagliflozin, or ISO + resolvin D2 (n = 5-6/group). ISO (100 mg·kg·day, s.c.) was given for 5 days. On days 7, 14, and 21 we assessed LV structure/function by cine-MRI, CFR by Doppler, diastolic indices by Doppler, and endothelial permeability/NO-dependent function by dynamic contrast-enhanced MRI (gadolinium-albumin) and L-NAME Tmapping. Treatments were given days 7-21. RESULTS: ISO caused hypertrophy with preserved ejection fraction, diastolic dysfunction, and reduced exercise capacity. Resting coronary flow increased by day 7 with preserved hyperemic flow, lowering CFR before fibrosis or endothelial barrier failure. By day 21, permeability rose with inflammatory activation, blunted NO-mediated response, and perivascular/interstitial fibrosis. Empagliflozin lowered resting flow, normalized CFR, reduced endothelial permeability and inflammatory signaling, limited fibrosis, and improved diastolic indices and LV strain. Resolvin D2 reduced inflammatory markers but did not consistently restore CFR, permeability, or diastolic indices. CONCLUSIONS: Short-term ISO causes progressive CMD, and empagliflozin reverses key CMD features, supporting direct coronary microvascular modulation as a mechanism of SGLT2i benefit in HFpEF in this animal model.