Human induced pluripotent stem cell-derived cardiomyocytes to study inflammation-induced diastolic dysfunction

Abstract

AbstractHeart failure with preserved ejection fraction (HFpEF) is commonly found in persons living with HIV (PLWH) even when antiretroviral therapy (ART) suppresses HIV viremia. However, studying this condition has been challenging because an appropriate animal model is not available. In this paper, we study the relaxation function of human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) in culture to simulate HFpEF and to assess whether various drugs have an effect. We show that treatment of hiPSC-CMs with inflammatory cytokines (such as interferon-γ or TNF-α) impair their relaxation and that SGLT2 inhibitors, clinically proven as effective for HFpEF, reverse this effect.Additionally, treatment with mitochondrial antioxidants (like mito-Tempo) and certain antiretrovirals resulted in the reversal of the effects of these cytokines on cardiomyocyte relaxation. Finally, incubation of hiPSC-CMs with serum from HIV patients with and without diastolic dysfunction (DD) did not alter their relaxation, indicating that short exposure to the serum of these patients is not sufficient to induce DDin vitro. Together, our results indicate that hiPSC-CMs can be used as a model to study molecular mechanisms of inflammation-mediated abnormal cardiomyocyte relaxation and screen for potential new interventions.