Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w

New insights into mechanisms underlying paradoxical low flow-low gradient aortic stenosis

M. El Kenani1, M. Schnelle2, B. A. Mohamed1, M. Mayr3, G. Hasenfuß4, K. Toischer1, for the study group: DZHK

1Department of Cardiology and Pneumology, University Medical Center Goettingen, Goettingen; 2Clinical Chemistry, University Medical Center Goettingen, Goettingen; 3The James Black Centre, King´s College London, London, UK; 4Herzzentrum, Klinik für Kardiologie und Pneumologie, Universitätsmedizin Göttingen, Göttingen;

Background: Low flow-low gradient severe aortic stenosis (LFLGs-AS) is a subtype of AS that is highly challenging in terms of diagnosis and therapeutic management. It combines small aortic valve area (AVA <1.0 cm2) and low gradient (<40 mm Hg). This entity may occur in patients with reduced left ventricular ejection fraction (LV EF), so-called classical LFLGs-AS or with preserved LV EF, resulting in a paradoxical LFLGs-AS phenotype. The pathology that defines the disease remains yet to be clarified. Objectives: This study was designed to identify pathophysiological mechanisms underlying LFLGs-AS with a particular focus on the paradoxical LFLGs-AS entity. Therefore, (i) we established a mouse model that shows the major clinical features of the paradoxical LFLGs-AS disease with subsequent mechanistic assessment, and (ii) we investigated the alteration in the LV proteomic portrait of patients with paradoxical LFLGs-AS in comparison to classical-AS patients, using state-of-the-art mass spectrometry. Methods: (i) Induction of chronic pressure overload (PO) in an experimental mouse model through transverse aortic constriction (TAC) surgery to mimic the state of AS in human. (ii) Human biopsies from paradoxical LFLGs-AS patients (n=5) vs. classical-AS (n=6) undergoing trans-catheter aortic valve implantation (TAVI) for proteomics and standard molecular analyses. Results: We found that mice from the FVB/N background, subjected to chronic PO, developed a paradoxical LFLGs-AS like phenotype with preserved EF, but reduced stroke volume (SV), diastolic dysfunction and absence of LV dilation. In contrast, C57Bl/6J mice captured the major clinical characteristics of classical LFLGs-AS patients following chronic TAC with LV dilation and severe LV dysfunction with low SV. On the molecular level, both TAC groups showed enhanced activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII). In FVB/N-TAC mice, additional signalling kinases were activated, including the protein kinase B (Akt) and the protein kinase A (PKA), associated with an increased SR Ca2+ leak and a high proportion of arrhythmic events, which may explain the relatively high mortality seen in these mice compared to C57Bl/6J-TAC mice (25 % vs. 13.8 %). Moreover, we found that the Raf kinase inhibitor protein (RKIP), a beta-adrenergic receptor (β-ARs) activator, and an upstream regulator for PKA and Akt dependent signalling pathways, was upregulated in FVB/N-TAC but not in C57Bl/6J-TAC hearts. RKIP was shown to induce positive inotropic and lusitropic effects in pressure overloaded-hearts through simultaneous activation of the β1-AR, and was sufficient to attenuate adverse cardiac remodelling through simultaneous β2-AR activation. Abundance of RKIP protein in FVB/N-TAC hearts is consistent with our proteomic results obtained from TAVI samples, which revealed upregulation of RKIP protein levels in paradoxical LFLGs-AS myocardial protein extracts compared to classical-AS. This further links our mouse model to the paradoxical LFLGs-AS disease. Conclusion: This study provides the first insight into the cardiac proteomic profile of paradoxical LFLGs-AS, as well as an experimental mouse model that exhibits the characteristics of the paradoxical LFLGs-AS disease. Increased RKIP activity may have a crucial pathophysiological role by (i) preventing cardiac dilatation, (ii) inducing arrhythmias, and (iii) increased mortality. These findings may contribute to a better understanding of the underlying disease pathogenesis as well as the development of more selective therapeutic approaches for the paradoxical LFLGs-AS entity.

https://dgk.org/kongress_programme/jt2021/aP613.html