Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes

Aims/hypothesis Empagliflozin (EMPA), an inhibitor of the renal sodium–glucose cotransporter (SGLT) 2, reduces the risk of cardiovascular death in patients with type 2 diabetes. The underlying mechanism of this effect is unknown. Elevated cardiac cytoplasmic Na+ ([Na+]c) and Ca2+ ([Ca2+]c) concentrations and decreased mitochondrial Ca2+ concentration ([Ca2+]m) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify [Na+]c, [Ca2+]c and [Ca2+]m in cardiomyocytes. Methods [Na+]c, [Ca2+]c, [Ca 2+]m and Na+/H+ exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and rats. Results An increase in extracellular glucose, from 5.5 mmol/l to 11 mmol/l, resulted in increased [Na+]c and [Ca2+]c levels. EMPA treatment directly inhibited NHE flux, caused a reduction in [Na+]c and [Ca2+]c and increased [Ca2+]m. After pretreatment with the NHE inhibitor, Cariporide, these effects of EMPA were strongly reduced. EMPA also affected [Na+]c and NHE flux in the absence of extracellular glucose. Conclusions/interpretation The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial [Na+]c and [Ca2+]c and enhancing [Ca2+]m, through impairment of myocardial NHE flux, independent of SGLT2 activity. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4134-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

QT dispersion was originally proposed to measure spatial dispersion of ventricular recovery times. Later, it was shown that QT dispersion does not directly reflect the dispersion of recovery times and that it results mainly from variations in the T loop morphology and the error of QT measurement. The reliability of both automatic and manual measurement of QT dispersion is low and significantly lower than that of the QT interval. The measurement error is of the order of the differences between different patient groups. The agreement between automatic and manual measurement is poor. There is little to choose between various QT dispersion indices, as well as between different lead systems for their measurement. Reported values of QT dispersion vary widely, e.g., normal values from 10 to 71 ms. Although QT dispersion is increased in cardiac patients compared with healthy subjects and prognostic value of QT dispersion has been reported, values are largely overlapping, both between healthy subjects and cardiac patients and between patients with and without adverse outcome. In reality, QT dispersion is a crude and approximate measure of abnormality of the complete course of repolarization. Probably only grossly abnormal values (e.g. > or =100 ms), outside the range of measurement error may potentially have practical value by pointing to a grossly abnormal repolarization. Efforts should be directed toward established as well as new methods for assessment and quantification of repolarization abnormalities, such as principal component analysis of the T wave, T loop descriptors, and T wave morphology and wavefront direction descriptors.