Abstract 176 Prevention of diastolic dysfunction in a pre-HFpEF hypertensive model via reducing inflammation, oxidative and metabolic stress signals

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02087-y
Prevention of diastolic dysfunction in a pre-HFpEF hypertensive model via reducing inflammation, oxidative and metabolic stress signals
S. Delatat¹, Á. Kovács², M. Herwig¹, A. B. Gevaert³, M. Sieme¹, D. Kolijn¹, S. Zhazykbayeva¹, A. J. Leloup³, P. Fransen³, G. A. Fülöp², M. Lódi¹, D. Czuriga⁴, Z. F. Kisvárday⁵, L. Van Heerebeek⁶, P. Sandner⁷, Z. Papp², S. Van Linthout⁸, C. Tschöpe⁸, A. Mügge¹, G. W. De Keulenaer⁹, W. A. Linke¹⁰, N. Hamdani¹
¹Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Bochum; ²Department of Cardiology, University of Debrecen, Debrecen, HU; ³Laboratory of Physiopharmacology, University of Antwerp, Antwerp, BE; ⁴Division of Cardiology, University of Debrecen, Debrecen, HU; ⁵Department of Anatomy, Histology and Embryology, University of Debrecen, Debrecen, Ungarn; ⁶Department of Cardiology, Onze Lieve Vrouw Gasthuis Amsterdam, Amsterdam, NL; ⁷Drug Discovery Cardiology, Bayer AG, Wuppertal; ⁸BIH Center für regenerative Therapien (BCRT), Charité - Universitätsmedizin Berlin, Berlin; ⁹Department of Pharmaceutical Science, University of Antwerp, Antwerp, Antwerp, BE; ¹⁰Institut für Physiologie II, Universitätsklinikum Münster, Münster;
Introduction and aims: Heart failure (HF) with preserved ejection fraction (pEF) is a prevalent and deadly disease with lack of effective treatments, therefore, preventive strategies focused on at-risk individuals with comorbidities are needed. Aim: To prevent HFpEF development via enhancing the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling pathway using the sGC stimulator BAY 41-8543 in a pre-HFpEF model with hypertension and assess the effect on the modulation of left ventricular (LV) diastolic function. Methods and Results: Chronic (4 weeks) pharmacological stimulation of sGC was studied in 15-week-old male Dahl/salt-sensitive with diastolic dysfunction (DD) and control rats (n=8-12/group). For the preventive study design high-salt diet and sGC treatment were initiated in parallel. Acute, ex-vivo stimulation of sGC was investigated in endomyocardial biopsies of HFpEF patients. The pre-HFpEF model was characterized with high blood pressure, increased LV end-diastolic pressure and stiffness parameters, impaired arterial elastance, arterial stiffening and endothelial dysfunction, all of which were improved upon chronic sGC stimulation in DD compared to control rats. Immunohistochemistry showed diffuse sGC distribution in unstimulated DD rats, but sarcomere association of the enzyme after sGC stimulation. Treatment with sGC reduced fibrosis, collagen gene expression, high oxidative stress and inflammation observed in DD, and this corrected the low NO bioavailability level, cGMP concentration, PKG activity, and stress as well as metabolic pathways. PKG-mediated hypophosphorylation of titin in DD was significantly improved, correlating with the reduction of high cardiomyocyte stiffness in DD after sGC stimulation. In addition, acute sGC stimulation in LV biopsy tissue from HFpEF patients improved cardiomyocyte stiffness via increased titin phosphorylation and reduced oxidative stress in cardiomyocytes. Conclusion: We show that chronic stimulation with sGC is able to prevent the development of hallmarks of tissue remodeling in HFpEF and maintain LV diastolic function. KEYWORDSheart failure, pre-HFpEF, prevention, sGC stimulator, diastolic dysfunction, cardiomyocyte, endothelial cells, extracellular matrix, titin, oxidative stress, inflammation, signaling pathways
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