Targeting PDE9A Restores Coronary Microvasculature in a Rat Model of HfpEF

Fopiano KA, Zhazykbayeva S, El-Battrawy I, Buncha V, Pearson WM, Hardell DJ, Lang L, Hamdani N, Bagi Z. PDE9A inhibition improves coronary microvascular rarefaction and left ventricular diastolic dysfunction in the ZSF1 rat model of HFpEF. Microcirculation 2024;31(8):e12888. doi: 10.1111/micc.12888.

Background: Heart failure with preserved ejection fraction (HFpEF) is frequently driven by comorbidities such as hypertension, obesity and diabetes, leading to left ventricular (LV) diastolic dysfunction associated with coronary microvascular disease. Excessive oxidative stress and reduced nitric oxide availability contribute to vascular dysfunction and microvascular rarefaction. Phosphodiesterase 9A (PDE9A) has been implicated in HFpEF pathogenesis, and its inhibition may improve cardiac and vascular outcomes by restoring cGMP signaling.

Hypothesis: This study hypothesized that inhibition of PDE9A would attenuate coronary microvascular rarefaction and improve LV diastolic dysfunction in the ZSF1 rat model of HFpEF through mechanisms involving reduced oxidative stress and enhanced antioxidant defense.

Methods: The authors used obese ZSF1 rats treated for two weeks with the PDE9A inhibitor PF04447943 or vehicle. Echocardiography was performed to assess LV function, and coronary microvascular networks were reconstructed in three dimensions using Vesselucida and analyzed with Vesselucida Explorer. Oxidative and nitrosative stress markers, proteomic profiles and antioxidant protein levels were quantified by biochemical assays, liquid chromatography–mass spectrometry and western blotting.

Results: PDE9A inhibition improved LV diastolic function without affecting systolic performance or hypertrophy. It mitigated coronary microvascular rarefaction by increasing the number of branching nodes, decreased myocardial hydrogen peroxide and 3-nitrotyrosine levels, and upregulated peroxiredoxin-5 expression identified through proteomic and immunoblot analyses.

Conclusions: PDE9A inhibition ameliorated coronary microvascular rarefaction and LV diastolic dysfunction in HFpEF rats, likely through enhancement of peroxiredoxin-dependent antioxidant mechanisms, suggesting a potential therapeutic strategy for cardiometabolic heart failure.