Dysregulation of cardiomyocyte active relaxation in heart failure with preserved ejection fraction -a mechanistic study

• Applicants: Professor Dr. Martin Falcke; Professor Dr. Frank Heinzel, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470514310

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with increasing prevalene and without therapeutic approach to improve prognosis. HFpEF is triggered by clinical factors (e.g. arterial hypertension, age, diabetes, kidney disease) and characterized by myocardial remodeling with diastolic dysfunction. The cellular mechanisms are not well understood. We and others could show that slowed active (Ca2+-depdendent) relaxation contributes to HFpEF. The diastolic Ca concentration in cardiomyocytes is influenced by the sarcolemmal Na/Ca exchanger (NCX) which during the cardiac cycle mainly works in forward mode (Ca out) but also in reverse mode (Ca in). The NCX connects Ca to Na homeostasis. We could show in an animal model of HFPEF that chronic specific inhibition of the NCX improves cardiomyocyte relaxation and cardiac function. This is likely a result of a complex adaptation of the highly controlled intracellular Na and Ca homeostasis, but the mechanims are not well understood. In the planned project we combine comprehensive experimental characterization of cardiomyocyte function and (sub)cellular structures (Heinzel) with multi-scale modeling of ion signaling based on an adapted mathematical model (Falcke), to allow quantification of the interdependence of the Ca- and Na-handling proteins. We use an established HFpEF model (subtotal nephrectomy + salt rat) for electrophysiological quantification of cellular regulation without and with specific NCX inhibition. In addition, we perform proteome and phosphoproteome analyses and quantification of subcellular structures (confocal, STORM) to characterize in depth the adaptation of excitation contraction coupling. The mathematical simulations adapted based on the experimental data use reaction diffusion parital differential equations and finite elements methods taking into account the local control of Ca2+ homeostasis in intracellular microdomains (e.g. dyads). In an additional approach the experimental and mechanistic results and concepts are validated in human ventricular cardiomyocytes obtained from excess myocardial samples from HFpEF patients scheduled for elective heart surgery. The results from this combined approach are expected to assess the relevant steps and targets involved in the maladaptation of cardiomyocyte Na+ and Ca2+ homeostasis in HFpEF without and with NCX inhibition and to identify potential new targets to improve Ca2+dependent contractile function.

• DFG Programme: Research Grants