Thorac Cardiovasc Surg 2020; 68(S 01): S1-S72
DOI: 10.1055/s-0040-1705428
Oral Presentations
Tuesday, March 3rd, 2020
Cardiovascular Basic Sciences
Georg Thieme Verlag KG Stuttgart · New York

Endothelial and Cardiomyocyte Dysfunction in Heart Failure with Preserved Ejection Fraction Is Attenuated via PDE9A Inhibition

N. Hamdani
1   Bochum, Germany
,
D. Kolijn
1   Bochum, Germany
,
M. Lodi
1   Bochum, Germany
,
M. Herwig
1   Bochum, Germany
,
Á. Kovács
1   Bochum, Germany
,
S. Van Linthout
2   Berlin, Germany
,
Z. Bagi
3   Augusta, United States
,
A. Mügge
1   Bochum, Germany
,
J. Strauch
1   Bochum, Germany
,
P. Haldenwang
1   Bochum, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
13 February 2020 (online)

 

    Objectives: Left ventricular diastolic dysfunction (LVDD) with impaired relaxation is characteristic of heart failure with preserved ejection fraction (HFpEF). Evidence suggests that comorbidities common to HFpEF promote a systemic inflammatory state that contributes to endothelial dysfunction. We hypothesize that oxidative stress and inflammation affect HFpEF pathophysiology by modulation of LV stiffness at least partly by changing the myocardial cGMP-PKG pathway aiming to assess specific treatment strategies in an attempt to develop tailored HFpEF therapy.

    Methods: Endothelial function, cardiomyocyte function, proinflammatory cytokines, oxidation stress level, protein expression and phosphorylation were measured in human HFpEF samples and in ZSF1 obese rat model. Phosphodiesterase 9A (PDE9A) inhibitor PF04447943 (3 mg/kg) or vehicle was administered to 18-week old HFpEF rats by daily oral gavage. At the age of 20 weeks, HFpEF rats developed LVDD, which was assessed by transthoracic echocardiography and vasodilation was examined in coronary arteries using videomicroscopy.

    Results: HFpEF patients and rats showed lower coronary artery vasodilation compared to control groups. Proinflammatory cytokines (vascular cell adhesion molecule-1, IL6 and TNF-α) as well as oxidative stress parameters (3-Nitrotyrosine, lipid peroxidase and hydrogen peroxidase) were increased in HFpEF patients and HFpEF rats compared to control groups. Phosphorylation of myofilament proteins such as myosin light chain, troponin I, myosin binding protein C was lower in HFpEF compared to controls. In HFpEF rats, LV relaxation, coronary artery dilation to acetylcholine (Ach), and sodium nitroprusside (SNP) were significantly reduced in the 20-week-old vehicle-treated HFpEF rats compared to controls. PDEA9A inhibitor-treated rats showed improved LV relaxation, and coronary artery dilations to ACh and SNP. Ex vivo exposure of coronary arteries to the PDE9A inhibitor (18 nmol/L) for 30 minutes augmented vasodilation to Ach and SNP.

    Conclusion: Increased inflammation and oxidative stress in HFpEF caused endothelial and cardiomyocyte dysfunction. Chronic stimulation of the cGMP/PKG signaling pathway with PDE9A inhibition decreased LV passive stiffness and improved global LV performance via improved endothelial function. The effect of PDE9A treatment on the whole signaling cascade, from the upstream pathway of inflammation/oxidative stress to the downstream targets is still being investigated.


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    No conflict of interest has been declared by the author(s).