Abstract Body: Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired diastolic function with early abnormalities often undetectable under resting conditions. Assessment of cardiac reserve may uncover subclinical dysfunction during disease progression.
Aims: To determine if 12-week exposure to high-fat diet combined with nitric oxide synthase (NOS) inhibition induces early diastolic dysfunction detectable by stress echocardiography and speckle-tracking echocardiography (STE).
Methods: Male AKR/J mice (7–8 weeks) were fed low fat diet (LFD, n=12) or high-fat diet plus L-NAME (0.5 g/L) (HFD+L, n=8) for 12 weeks, constituting a two-hit HFpEF model. Cardiac structure and function were assessed by conventional echocardiography and STE at rest and during dobutamine stress (1 mg/kg IP).
Results: After 12 weeks, mice developed concentric LV remodeling characterized by increased relative wall thickness (HFD+L 0.70 ± 0.04 vs LFD 0.62 ± 0.07) and reduced LV internal diameter in diastole (HFD+L 3.47 ±0.26 mm vs LFD 3.76 ± 0.27 mm).
At rest, isovolumetric relaxation time was prolonged in HFD+L mice (13.3 ± 1.8 ms vs 12.1 ± 1.7 ms in LFD). EF remained preserved (HFD+L 77% vs LFD 70%).
During dobutamine stress, systolic reserve was largely preserved, although the increase in EF was attenuated in HFD+L mice (+21%) compared with LFD mice (+30%). STE demonstrated preserved augmentation of global longitudinal strain in both groups. In contrast, early diastolic radial and longitudinal strain were reduced in HFD+L mice at rest with blunted augmentation during stress (radial +173% vs +241%; longitudinal +100% vs +209%).
Despite reduced diastolic strain magnitude, early diastolic strain rate increased with dobutamine in HFD+L mice, revealing a magnitude-rate dissociation consistent with accelerated relaxation kinetics that remain mechanically constrained.
Conclusions: In a two-hit model of HFpEF, 12-week metabolic stress and NOS inhibition induced concentric remodeling with preserved systolic function but impaired relaxation and diastolic reserve. Dobutamine stress with STE unmasked abnormalities in myocardial relaxation not apparent at rest, identifying impaired diastolic reserve as an early functional signature of HFpEF.