Introduction
Patients with diabetes mellitus (DM) more frequently suffer from heart failure (HF), in particular heart failure with preserved ejection fraction (HFpEF), than individuals without DM (Seferovic et al. , 2018). Sodium glucose co-transporter 2 inhibitors (SGLT-2i’s), a novel class of glucose-lowering drugs, significantly reduce the risk of cardiovascular death and hospitalisation in patients with existing HF, regardless of the presence of DM (Zinman et al. , 2015; Nealet al. , 2017; Wiviott et al. , 2019; Packer et al. , 2020). Treatment with empagliflozin (EMPA) also reduces the combined outcome of worsening HF, rehospitalization of HF and death for HF in patients with acute HF (Damman et al. , 2020). Recently, the EMPEROR-Preserved phase III trial has established EMPA as the first potential therapy capable to improve cardiovascular outcome in patients suffering from HFpEF (Anker et al. , 2021). Until today, the exact mechanisms underlying these “off-target” effects of SGLT-2i’s remain largely unknown. Previous studies have highlighted the direct cardiac effects of SGLT-2i’s (Packer, 2020; Kleinbongard et al. , 2020), which are mediated by alleviation of oxidative stress, inflammation, apoptosis, and calcium (Ca2+) overload of cardiomyocytes (CMs) (Uthman et al. , 2018; Trum et al. , 2021).
The PROMIS-HFpEF trial has prospectively demonstrated a high prevalence of coronary microvascular disorder and systemic endothelial dysfunction in patients with HF (Shah et al. , 2018). Endothelial cells (ECs) form a monolayer over the inner surface of vessels (Kruger-Gengeet al. , 2019). In the adult human heart, ECs account for 12.2% of total cells within the arterial tissues and 7.8% within the ventricular regions (Litvinukova et al. , 2020). Physiologically, ECs serve to maintain cardiovascular function by ensuring the production of endothelium-derived vasoactive factors, preventing monocyte adhesion and platelet aggregation, regulating the proliferation of smooth muscle cells (SMCs) as well as the contraction and relaxation of CMs (Monteiroet al. , 2019). In patients with diabetes, hyperglycemia impairs endothelial function and ultimately causes the development of macro- and micro- vascular complications (Shi et al. , 2017). Thus, ECs might serve as a novel target to improve cardiac function of patients with HF.
Previous studies have shown that SGLT-2i’s directly ameliorate endothelial dysfunction in both euglycaemic and hyperglycaemic conditions (Alshnbari et al. , 2020; Durante et al. , 2021; Salvatore et al. , 2021) and that EMPA mitigates endothelial and cardiac dysfunction in patients with HFpEF via reducing inflammatory-oxidative pathways (Kolijn et al. , 2020). Our current manuscript focuses on the potential role of improved endothelial function as an indispensable contributor to the enhanced cardiac function in patients receiving SGLT-2i’s. We will review the current data and most recent progress in preclinical investigations concerning the direct effects of SGLT-2i’s on endothelial dysfunction, with the aim to improve the understanding of their compelling cardiovascular effect on patients with HF.