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Phosphodiesterase 9a Inhibition in Mouse Models of Diastolic Dysfunction

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posted on 2023-03-22, 15:06 authored by Methajit MethawasinMethajit Methawasin, Joshua Strom, Tomasz Borkowski, Zaynab Hourani, Raymond B. Runyan, John E. Smith III, Henk L. Granzier

Background: Low myocardial cGMP-PKG activity has been associated with increased cardiomyocyte diastolic stiffness in HFpEF. cGMP is mainly hydrolyzed by phosphodiesterases (PDE) 5a and 9a. Importantly, PDE9a expression has been reported to be upregulated in human HFpEF myocardium and chronic administration of a PDE9a inhibitor reverses pre-established cardiac hypertrophy and systolic dysfunction in mice subjected to TAC (Transverse Aortic Constriction). We hypothesized that inhibiting PDE9a activity ameliorates diastolic dysfunction. 

Methods and Results: Two diastolic dysfunction mouse models were studied: 1) TAC-DOCA (deoxycorticosterone acetate) and 2) Leprdb/db, a metabolically induced diastolic dysfunction  model. The effect of acute PDE9a inhibition was investigated in intact cardiomyocytes isolated from TAC-DOCA mice; no acute cellular stiffness reduction was found. For chronic inhibition, mice were implanted with osmotic minipumps containing either PDE9a inhibitor or vehicle. PDE9a inhibition (5 and 8 mg/kg/day) resulted in reduced LV chamber stiffness in TAC-DOCA, but not in Leprdb/db mice. Passive cardiomyocyte stiffness was reduced by chronic PDE9a inhibition, with no differences in myocardial fibrosis or cardiac morphometry. PDE9a inhibition increased the ventricular-arterial (VA) coupling ratio, reflecting impaired systolic function. 

Conclusions: Chronic PDE9a inhibition lowers LV chamber stiffness in TAC-DOCA mice. However, the usefulness of PDE9a inhibition to treat high diastolic stiffness may be limited as the required PDE9a inhibitor dose also impairs systolic function, observed as a decline in ventricular-arterial coordination, in this model.



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Funding

Integrative studies of diastolic function of cardiomyocytes in health and disease.

American Heart Association

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National Heart Lung and Blood Institute

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Fondation Leducq

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