Abstract Body (Do not enter title and authors here): Background: Cardiac remodeling among individuals with heart failure with preserved ejection fraction (HFpEF) and its risk factors is incompletely understood. Non-invasive cardiac imaging can reliably assess myocardial oxidative metabolism, perfusion, fibrosis, systolic and diastolic function. Nevertheless, the interrelationships between these, particularly with oxidative metabolism, remain unresolved from health to HFpEF as most human studies lack complementary multi-modality imaging.

Methods: We performed a cross-sectional study using multi-modality cardiovascular imaging in healthy individuals (n=17), those with hypertension (n=15), and patients with HFpEF (n=8). We quantified myocardial oxidative metabolism (K_mono) with ¹¹C-acetate positron emission tomography (PET), coronary flow reserve (CFR) with ¹³N-ammonia PET, fibrosis (extracellular volume [ECV], LVEF and mass with magnetic resonance imaging (MRI), and LV diastolic filling pressure (E/e’) by echocardiography. The associations between myocardial oxidative metabolism, perfusion, and fibrosis across clinical status (health, hypertension, and HFpEF) were examined in multivariable models.
Results: From health to HFpEF, we found significant graded declines in oxidative metabolism indexed to workload (K_mono/RPP) (β = -1.66 x 10^-6 [95%CI: -3.12 x 10^-6 to -2.10 x 10^-6]; p = 0.027) and CFR (β = -0.76 [95% CI: -1.36 to -0.16]; p = 0.021), along with increased fibrosis (ECV) (β = 2.12% [95% CI: 0.10 to 4.14%]; p = 0.041), independent of LVEF, LV mass, E/e’, age, sex, and body mass index. The decline in oxidative metabolism from health to HFpEF was also independent of ECV and CFR (β = -2.98 x 10^-6 [95% CI: -5.62 x 10^-6 to -3.41 x 10^-6], p = 0.015). In contrast, the decline in CFR from health to HFpEF was no longer significant (p = 0.30) with further adjustment for ECV.

Conclusions: HFpEF and its development involves progressive declines in myocardial oxidative metabolism and perfusion reserve with increase in fibrosis. The decline in myocardial oxidative metabolism from health to HFpEF is independent of fibrosis and perfusion reserve, suggesting oxidative metabolism may be a target for the prevention and treatment of HFpEF.