Multicellular crosstalk in diabetic cardiomyopathy – impact of SGLT2 inhibition on pathologic remodeling

Diabetic cardiomyopathy (DCM) is a common long-term complication among T2D patients with early manifestations of diastolic dysfunction, subsequent progression to systolic dysfunction and ultimately heart failure. majority with preserved ejection fraction (HFpEF). So far, no specific and effective therapies are currently available for HFpEF. Clinical studies of sodium-glucose co-transporter 2 (SGLT2) inhibitors as empagliflozin showed promising results with respect to the cardiovascular outcome of T2D patients at high cardiovascular risk. However, the mechanism underlying the cardioprotective effects of empagliflozin remains largely unknown. The aim of this project is to establish an in vitro model of diabetic cardiomyopathy using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and human ventricular fibroblasts (HVF). investigate the factors involved in the crosstalk between these cardiac cell types under diabetic conditions. Moreover, we will examine potential effects of empagliflozin on the metabolism of the single cell types and the factors contributing to multicellular crosstalk in diabetic cardiomyopathy.

First, hiPSC-CM cells are cultivated under normoglycaemic, hyperglycaemic or hyperglycaemic-hypertrophic conditions with prolonged cultivation period to ensure the progression into metabolic dysfunction. Aiming to find out whether a phenotype which meets key requirements of a DCM surrogate, we performed several experiments including the evaluation of hiPSC-CM contractility, cell viability readouts and gene expression studies.The recapitulation of important aspects of diabetic cardiomyopathy could be revealed in cells cultivated under hyperglycaemic-hypertrophic conditions. The iPSC-CM cultured under these conditions show functional differences such as increasing maximum contraction speed after 4 days of treatment, along with altered expression of metabolic genes GLUT1, GLUT4 and HK2 after 10 days. In line with these findings, the expression of hypertrophic markers such as NPPB and cytokines involved in inflammation like IL-6 were elevated under hyperglycaemic conditions, indicating a metabolic dysfunction in the cardiomyocytes.

Current experiments focus on the effect of empagliflozin and detailed characterization on these dysregulations. A special focus aims on the investigation of insulin resistance, cell viability and characterization of morphological changes under diabetic conditions. Taken together, these results will provide more detailed information about the effect of empagliflozin on pathways involved in remodeling and pathologic signalling in human cardiomyocytes and cardiac fibroblasts cultured under diabetic conditions.

Publications:

Enhanced structural maturation of human induced pluripotent stem cell-derived cardiomyocytes under a controlled microenvironment in a microfluidic system.  T.J. Kolanowski, M. Busek, M. Schubert, A. Dmitrieva, B. Binnewerg, J. Poche, K. Fisher, F. Schmieder, S. Grunzner, S. Hansen, A. Richter, A. El-Armouche, F. Sonntag, K. Guan. Acta Biomater. 2020;102:273-286.

Repurposing antidiabetic drugs for cardiovascular disease.  M. Schubert, S. Hansen, J. Leefmann, K. Guan. Front Physiol. 2020;11:568632.