Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02087-y

Untangling the stress and metabolic pathways associated with inflammation and oxidative stress in right and left ventricles of heart failure with preserved ejection fraction

H. Budde1, Á. Kovács1, M. Herwig1, M. Sieme1, S. Delatat1, N. Mostafi1, L. Van Heerebeek2, C. Tschöpe3, S. Van Linthout3, A. Mügge4, N. Hamdani1

1Molekulare und Experimentelle Kardiologie, Ruhr-Universität Bochum, Bochum; 2Department of Cardiology, Onze Lieve Vrouw Gasthuis Amsterdam, Amsterdam, NL; 3Department of Cardiology and Pneumology, Charité, University Medicine Berlin, Berlin; 4Medizinische Klinik II, Kardiologie, Klinikum der Ruhr-Universität Bochum, Bochum;

The prevalence of HF with preserved ejection fraction (HFpEF) is increasing, and this rise correlates with the increased prevalence of metabolic disorders such as obesity, metabolic syndrome, Typ 2 Diabetes Mellitus (T2D) and salt-sensitive arterial hypertension. All previous attention has centred on the left ventricle (LV) dysfunction in HFpEF; however, the prevalent RV dysfunction is associated with increased mortality in HFpEF patients, but no study has characterized long-term changes in RV structure and function within the same patient. Since anatomic and hemodynamic factors in the RV are different from those in the LV, it could well be that mechanosensing is also differentially regulated in the RV vs. LV during the development of HF. Accordingly, we will examine if the intracellular signaling modulation and thereby cardiomyocyte function differ between LV and RV in HFpEF. We found that in HFpEF human biopsies, Ca2+ sensitivity was higher in LV and lower in RV compared to controls with also a distinct mechanical regulation of cardiomyocyte stiffness in both ventricles compared to controls. We found that CaMKII and PKG could restore the passive stiffness of failing cardiomyocytes, with distinct effects as CaMKII-dependent phosphorylation has a specific stiffness-lowering effect only in the RV, whereas PKG-dependent phosphorylation has a beneficial stiffness-lowering effect in both ventricles. Our data emphasizes the high importance of how each ventricle can be individually treated based on the diagnostic of HFpEF.

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