https://doi.org/10.1007/s00392-025-02625-4
1Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; 2University Medical Center Göttingen Department of Clinical Chemistry Göttingen, Deutschland; 3Universitätsklinikum Hamburg-Eppendorf Zentrum für Experimentelle Medizin, Experimentelle Herz-Kreislaufforschung Hamburg, Deutschland
Background: Mechanisms underlying low flow-low gradient severe aortic stenosis (LF-LG AS) are not well understood, creating significant challenges in its diagnosis and management. This complex subtype of aortic stenosis is defined by a combination of a reduced aortic valve area (AVA ≤1.0 cm²) and a low transvalvular pressure gradient (<40 mm Hg) associated with a reduced LV stroke volume index (SVi≤ 35mL/m2). LF-LG AS can present as classical LF-LG AS (CLF-LG AS), marked by reduced left ventricular ejection fraction (LV EF), or as paradoxical LF-LG AS (PLF-LG AS), defined by preserved LV EF despite severe stenosis. The paradoxical phenotype, in particular, remains enigmatic, complicating efforts to develop effective treatment strategies.
Objectives: The aim of this study is to identify the pathophysiological mechanisms driving these distinct phenotypes, with a focus on the paradoxical presentation, to advance targeted diagnostic and therapeutic approaches.
Methods: Left ventricular (LV) myocardial biopsies from patients with PLF-LG AS and CLF-LG AS, obtained during transcatheter aortic valve implantation (TAVI), were analyzed. The biopsies were subjected to detailed molecular analysis. In addition, human induced pluripotent stem cell (hiPSC) lines derived from PLF-LG AS and CLF-LG AS patients were utilized for further investigation of the underlying mechanisms.
Results: Molecular analysis revealed distinct differences in pressure overload induced calcium cycling and associated kinase activity between PLF-LG AS and CLF-LG AS. In contrast to CLF-LG AS, protein kinase A (PKA) activity appears to remain elevated in PLF-LG AS, as evidenced by increased phosphorylation of cardiac troponin I (cTnI) and phospholamban (PLN) at PKA-dependent sites, despite the chronic nature of the disease. Additionally, sustained nuclear PKA activity was detected in PLF-LG AS hiPSC-induced cardiomoycytes after stimulation with isoproterenol, a β1- and β2-adrenoreceptor agonist, compared to the CLF-LG AS. These findings suggest reduced desensitization of β-adrenergic receptors (β-AR) in PLF-LG AS.
Conclusion: Our study reveals distinct molecular differences between PLF-LG and CLF-LG aortic stenosis. Elevated PKA activity and reduced β-adrenergic receptor desensitization in PLF-LG AS suggest altered cellular signaling, indicating a unique pathogenesis compared to CLF-LG AS. Further investigation is warranted to identify potential targets for more effective diagnostic and therapeutic strategies in PLF-LG AS.