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.