Empagliflozin Reverses Late Na
            <sup>+</sup>
            Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murine Model of Heart Failure With Preserved Ejection Fraction

Hegyi, Bence; Hernández, Juliana Mira; Shen, Erin Y.; Habibi, Nima R.; Bossuyt, Julie; Bers, Donald M.

doi:10.1161/circulationaha.121.057237

Cited by 35 publications

(32 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of studies have already shown the restorative effects of empagliflozin on the increased by some impacts late Na + current [ 25 , 26 ], on the disturbed L-type Ca 2+ and Na + /Ca 2+ exchanger (NCX) currents in the ventricular myocytes of diabetes mellitus rats [ 27 ]. There are controversial data regarding the inhibition of Na + /H + exchanger activity by empagliflozin [ 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SGLT2 Inhibitor Empagliflozin Modulates Ion Channels in Adult Zebrafish Heart

Karpushev

Михайлова

Klimenko

et al. 2022

IJMS

View full text Add to dashboard Cite

Empagliflozin, an inhibitor of sodium-glucose co-transporter 2 (iSGLT2), improves cardiovascular outcomes in patients with and without diabetes and possesses an antiarrhythmic activity. However, the mechanisms of these protective effects have not been fully elucidated. This study aimed to explore the impact of empagliflozin on ion channel activity and electrophysiological characteristics in the ventricular myocardium. The main cardiac ionic currents (INa, ICaL, ICaT, IKr, IKs) and action potentials (APs) were studied in zebrafish. Whole-cell currents were measured using the patch clamp method in the isolated ventricular cardiomyocytes. The conventional sharp glass microelectrode technique was applied for the recording of APs from the ventricular myocardium of the excised heart. Empagliflozin pretreatment compared to the control group enhanced potassium IKr step current density in the range of testing potentials from 0 to +30 mV, IKr tail current density in the range of testing potentials from +10 to +70 mV, and IKs current density in the range of testing potentials from −10 to +20 mV. Moreover, in the ventricular myocardium, empagliflozin pretreatment shortened AP duration APD as shown by reduced APD50 and APD90. Empagliflozin had no influence on sodium (INa) and L- and T-type calcium currents (ICaL and ICaT) in zebrafish ventricular cardiomyocytes. Thus, we conclude that empagliflozin increases the rapid and slow components of delayed rectifier K+ current (IKr and IKs). This mechanism could be favorable for cardiac protection.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Importantly, the effects of empagliflozin on the late Na + current [ 25 , 26 ], L-type Ca 2+ and Na + /Ca 2+ exchanger (NCX) currents [ 27 ] have been recently shown. Moreover, empagliflozin reduced calcium-calmodulin kinase II (CaMKII) activity and CaMKII-dependent SR Ca 2+ leak [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

SGLT2 Inhibitor Empagliflozin Modulates Ion Channels in Adult Zebrafish Heart

Karpushev

Михайлова

Klimenko

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…SGLT2i has a regulating and stabilizing effect on cardiac electrophysiological changes, which may be a potential mechanism by which SGLT2i exerts its antiarrhythmic effect. Research has shown that empagliflozin reduced late sodium channel current (late-INa) in cardiomyocytes in mice with heart failure or a sodium channel mutation, but not in healthy murine cardiac myocytes ( 74 ). A reduction in late-INa contributes to less prolongation of the cardiac action potential duration (APD) and may protect against arrhythmias associated with prolonged action potentials ( 64 ).…”

Section: Direct Mechanisms By Which Sglt2i Mediates Anti-arrhythmic E...mentioning

confidence: 99%

Antiarrhythmic effects and mechanisms of sodium-glucose cotransporter 2 inhibitors: A mini review

Liu

Wei

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new type of oral hypoglycaemic agent with good cardiovascular protective effects. There are several lines of clinical evidence suggest that SGLT2i can significantly reduce the risks of heart failure, cardiovascular death, and delay the progression of chronic kidney disease. In addition, recent basic and clinical studies have also reported that SGLT2i also has good anti-arrhythmic effects. However, the exact mechanism is poorly understood. The aim of this review is to summarize recent clinical findings, studies of laboratory animals, and related study about this aspect of the antiarrhythmic effects of SGLT2i, to further explore its underlying mechanisms, safety, and prospects for clinical applications of it.

show abstract

Section: Introductionmentioning

confidence: 99%

“…At the cellular level, empa (1–10 µM) inhibits the late component of the Na + current (I NaL ) recorded in ventricular myocytes from patients with aortic stenosis [ 8 ] as well as in transfected cells and cardiomyocytes dissociated from mouse models of HF with preserved and reduced ejection fraction [ 9 , 10 ]. Conversely, acute application of empa does not modify peak Na + current (I Na ) at any stimulation frequency [ 9 , 10 ]. In a rat model of metabolic syndrome, in which I Na and K + currents were increased and decreased, respectively, administration of dapa ameliorated electrical remodeling produced by the metabolic syndrome [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin and Dapagliflozin Increase Na+ and Inward Rectifier K+ Current Densities in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells (hiPSC-CMs)

Dago

Crespo-García

Cámara-Checa

et al. 2022

Cells

View full text Add to dashboard Cite

Dapagliflozin (dapa) and empagliflozin (empa) are sodium-glucose cotransporter-2 inhibitors (SGLT2is) that reduce morbidity and mortality in heart failure (HF) patients. Sodium and inward rectifier K+ currents (INa and IK1), carried by Nav1.5 and Kir2.1 channels, respectively, are responsible for cardiac excitability, conduction velocity, and refractoriness. In HF patients, Nav1.5 and Kir2.1 expression are reduced, enhancing risk of arrhythmia. Incubation with dapa or empa (24-h,1 µM) significantly increased INa and IK1 densities recorded in human-induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs) using patch-clamp techniques. Dapa and empa, respectively, shifted to more hyperpolarized potentials the INa activation and inactivation curves. Identical effects were observed in Chinese hamster ovary (CHO) cells that were incubated with dapa or empa and transiently expressed human Nav1.5 channels. Conversely, empa but not dapa significantly increased human Kir2.1 currents in CHO cells. Dapa and empa effects on INa and IK1 were also apparent in Ca-calmodulin kinase II-silenced CHO cells. Cariporide, a Na+/H+ exchanger type 1 (NHE1) inhibitor, did not increase INa or IK1 in hiPSC-CMs. Dapa and empa at therapeutic concentrations increased INa and IK1 in healthy human cardiomyocytes. These SGLT2is could represent a new class of drugs with a novel and long-pursued antiarrhythmic mechanism of action.

show abstract

Empagliflozin Reverses Late Na ⁺ Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murine Model of Heart Failure With Preserved Ejection Fraction

Cited by 35 publications

References 5 publications

SGLT2 Inhibitor Empagliflozin Modulates Ion Channels in Adult Zebrafish Heart

SGLT2 Inhibitor Empagliflozin Modulates Ion Channels in Adult Zebrafish Heart

Antiarrhythmic effects and mechanisms of sodium-glucose cotransporter 2 inhibitors: A mini review

Empagliflozin and Dapagliflozin Increase Na+ and Inward Rectifier K+ Current Densities in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells (hiPSC-CMs)

Contact Info

Product

Resources

About

Empagliflozin Reverses Late Na + Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murine Model of Heart Failure With Preserved Ejection Fraction

Cited by 35 publications

References 5 publications

SGLT2 Inhibitor Empagliflozin Modulates Ion Channels in Adult Zebrafish Heart

SGLT2 Inhibitor Empagliflozin Modulates Ion Channels in Adult Zebrafish Heart

Antiarrhythmic effects and mechanisms of sodium-glucose cotransporter 2 inhibitors: A mini review

Empagliflozin and Dapagliflozin Increase Na+ and Inward Rectifier K+ Current Densities in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells (hiPSC-CMs)

Contact Info

Product

Resources

About

Empagliflozin Reverses Late Na ⁺ Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murine Model of Heart Failure With Preserved Ejection Fraction