Abstract
Empagliflozin, a sodium-glucose co-transporter (SGLT) inhibitor, reduces heart failure and sudden cardiac death but the underlying mechanisms remain elusive. In cardiomyocytes, SGLT1 and SGLT2 expression is upregulated in diabetes mellitus, heart failure, and myocardial infarction. We hypothesise that empagliflozin exerts direct effects on cardiomyocytes that attenuate diabetic cardiomyopathy. To test this hypothesis, cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) were used to test the potential effects of empagliflozin on neutralization of cardiac dysfunction induced by diabetic-like cultures. Our results indicated that insulin-free high glucose culture significantly increased the size of and NPPB, SGLT1 and SGLT2 expression of hiPSC-derived cardiomyocytes. In addition, high glucose-treated hiPSC-derived cardiomyocytes exhibited reduced contractility regardless of the increased calcium transient capacity. Interestingly, application of empagliflozin before or after high glucose treatment effectively reduced the high glucose-induced cardiac abnormalities. Since application of empagliflozin did not significantly alter viability or glycolytic capacity of the hiPSC-derived cardiomyocytes, it is plausible that empagliflozin exerts its effects via the down-regulation of SGLT1, SGLT2 and GLUT1 expression. These observations provide supportive evidence that may help explain its unexpected benefit observed in the EMPA-REG trial.
Highlights
Factors such as HbA1c, blood pressure, or weight loss achieved with empagliflozin cannot be attributed to such a magnitude of improvement in cardiovascular outcomes
To recreate the diabetogenic environment, human induced pluripotent stem cells (hiPSCs) (Line KS1)-derived cardiomyocytes were exposed to a high glucose (HG) environment by supplementing standard culture medium with 22 mM glucose for 14 days (Fig. 2A)
Exposure to a HG environment increased the expression of NPPB, which encodes the brain-type natriuretic peptide (BNP), in hiPSC-derived cardiomyocytes (Fig. 2G)
Summary
Factors such as HbA1c, blood pressure, or weight loss achieved with empagliflozin cannot be attributed to such a magnitude of improvement in cardiovascular outcomes In concordance with this notion, the very early separation of cumulative incidence curves for cardiovascular mortality and heart failure-related hospitalization within a few weeks of randomization likewise could not be explained by the modification of atherosclerosis progression. Myocardial expression of SGLT1 is up-regulated in type II diabetes mellitus, myocardial ischemia, and severe heart failure[4]. This up-regulation in these conditions can theoretically increase sodium as well as glucose entry into cardiomyocytes. Intracellular calcium overload in cardiomyocytes impairs excitation-contraction coupling and relaxation mechanisms, leads to electrical instability, and activates a calcium sensitive hypertrophic signaling pathway. Empagliflozin abolished hyperglycemia-induced hypertrophic changes, alleviated the abnormal calcium-handling, and restored contractility of high glucose (HG)-treated hiPSC-derived cardiomyocytes
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