Empagliflozin Inhibits Cardiac Late Sodium Current by Ca/Calmodulin-Dependent Kinase II

Mustroph, Julian; Baier, Maria J.; Pabel, Steffen; Stehle, Thea; Trum, Maximilian; Provazník, Zdeněk; Mohler, Peter J.; Musa, Hassan; Hund, Thomas J.; Sossalla, Samuel; Maier, Lars S.; Wagner, Stefan

doi:10.1161/circulationaha.122.057364

Cited by 28 publications

(26 citation statements)

References 5 publications

(15 reference statements)

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“…As mentioned, a previous report demonstrated that acute application of 10 μM empa does not modify peak I Na at any stimulation frequency [ 10 ]. Moreover, acute application [ 10 ] or incubation (for 24 h or 30 min) [ 8 , 9 ] with 1 μM empa significantly decreased I NaL . Therefore, we decided to test effects produced by incubation with 1 μM dapa and empa in order to allow a comparison of our data with those reported previously for this concentration.…”

Section: Resultsmentioning

confidence: 99%

“…As mentioned, CaMKII is an important I Na regulator, since CaMKII-induced phosphorylation of Nav1.5 channels increases I NaL , slows fast I Na inactivation and reactivation, and shifts voltage-dependent inactivation to more negative potentials [ 26 ]. Empa decreased I NaL in mouse cardiomyocytes obtained from HF models with reduced [ 10 ] and preserved [ 9 ] ejection fraction, as well as in ventricular myocytes from patients with aortic stenosis [ 8 ]: effects that were attributed to an empa-induced CaMKII inhibition [ 8 , 9 ]. Our results suggest that the hyperpolarizing shift of the inactivation curve produced by empa could contribute, at least partially, to I NaL reduction via decrease of the window current.…”

Section: Discussionmentioning

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 ].…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

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“… 35 Pro-arrhythmic imbalances in calcium homeostasis may be mitigated by SGLT2i, which suppresses sodium–hydrogen exchange, promotes natriuresis, and decreases cardiac intra-cellular Na + and Ca 2+ . 36 , 37 For example, a prior study has shown that human atrial cardiomyocyte NHE1 expression is inhibited by empagliflozin in tissue derived from patients with HF and AF. 38 These effects have been linked to reduced adverse cardiac remodelling, hypertrophy, and decreased risk of arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Association between sodium–glucose cotransporter-2 inhibitors and arrhythmic outcomes in patients with diabetes and pre-existing atrial fibrillation

Fichadiya,

Quinn,

et al. 2024

Europace

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Aims Prior studies suggest that sodium–glucose cotransporter-2 inhibitors (SGLT2is) may decrease the incidence of atrial fibrillation (AF). However, it is unknown whether SGLT2i can attenuate the disease course of AF among patients with pre-existing AF and Type II diabetes mellitus (DM). In this study, our objective was to examine the association between SGLT2i prescription and arrhythmic outcomes among patients with DM and pre-existing AF. Methods and results We conducted a population-based cohort study of adults with DM and AF between 2014 and 2019. Using a prevalent new-user design, individuals prescribed SGLT2i were matched 1:1 to those prescribed dipeptidyl peptidase-4 inhibitors (DPP4is) based on time-conditional propensity scores. The primary endpoint was a composite of AF-related healthcare utilization (i.e. hospitalization, emergency department visits, electrical cardioversion, or catheter ablation). Secondary outcome measures included all-cause mortality, heart failure (HF) hospitalization, and ischaemic stroke or transient ischaemic attack (TIA). Cox proportional hazard models were used to examine the association of SGLT2i with the study endpoint. Among 2242 patients with DM and AF followed for an average of 3.0 years, the primary endpoint occurred in 8.7% (n = 97) of patients in the SGLT2i group vs. 10.0% (n = 112) of patients in the DPP4i group [adjusted hazard ratio 0.73 (95% confidence interval 0.55–0.96; P = 0.03)]. Sodium–glucose cotransporter-2 inhibitors were associated with significant reductions in all-cause mortality and HF hospitalization, but there was no difference in the risk of ischaemic stroke/TIA. Conclusion Among patients with DM and pre-existing AF, SGLT2is are associated with decreased AF-related health resource utilization and improved arrhythmic outcomes compared with DPP4is.

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“…171 Although SGLT2 is not expressed in cardiomyocytes, SGLT2 inhibition prevents CaMKII activation, spontaneous calcium sparks and impaired calcium transients in the hearts of mice with experimental type 2 diabetes. 172 These effects might be mediated by an indirect action of SGLT2 inhibitors to inhibit the late sodium current, potentially mediated by either interference with CaMKII or by an action to attenuate O-GlcNAcylation of Na v 1.5, 119,173 since these effects of SGLT2 inhibition were prevented by inhibition of OGA. 172 The investigators proposed that the reduction in O-GlcNAcylation was related to an observed reduction of glucose uptake by cardiomyocytes following SGLT2 inhibition, an action that is unrelated to the presence or absence SGLT2 protein 172,174,175 but possibly related to a direct or indirect effect of SGLT2 inhibitors to inhibit GLUT1.…”

Section: Therapeutic Suppression Of Excessive O-glcnacylation In Hear...mentioning

confidence: 99%

Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

Packer

2023

European J of Heart Fail

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The development of the foetal heart is driven by increased glucose uptake and activation of mammalian target of rapamycin (mTOR) and hypoxia‐inducible factor‐1α (HIF‐1α), which drives glycolysis. In contrast, the healthy adult heart is governed by sirtuin‐1 (SIRT1) and adenosine monophosphate‐activated protein kinase (AMPK), which promote fatty‐acid oxidation and the substantial mitochondrial ATP production required for survival in a high‐workload normoxic environment. During cardiac injury, the heart recapitulates the foetal signalling programme, which (although adaptive in the short term) is highly deleterious if sustained for long periods of time. Prolonged increases in glucose uptake in cardiomyocytes under stress leads to increased flux through the hexosamine biosynthesis pathway; its endproduct – uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) – functions as a critical nutrient surplus sensor. UDP‐GlcNAc drives the post‐translational protein modification known as O‐GlcNAcylation, which rapidly and reversibly modifies thousands of intracellular proteins. Both O‐GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O‐GlcNAcylation is regulated by only two enzymes, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), which adds or removes GlcNAc (N‐acetylglucosamine), respectively, from target proteins. Recapitulation of foetal programming in heart failure (regardless of diabetes) is accompanied by marked increases in O‐GlcNAcylation, both experimentally and clinically. Heightened O‐GlcNAcylation in the heart leads to impaired calcium kinetics and contractile derangements, arrhythmias related to activation of voltage‐gated sodium channels and Ca2+/calmodulin‐dependent protein kinase II, mitochondrial dysfunction, and maladaptive hypertrophy, microvascular dysfunction, fibrosis and cardiomyopathy. These deleterious effects can be prevented by suppression of O‐GlcNAcylation, which can be achieved experimentally by upregulation of AMPK and SIRT1 or by pharmacological inhibition of OGT or stimulation of OGA. The effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on the heart are accompanied by reduced O‐GlcNAcylation, and their cytoprotective effects are reportedly abrogated if their action to suppress O‐GlcNAcylation is blocked. Such an action may represent one of the many mechanisms by which enhanced AMPK and SIRT1 signalling following SGLT2 inhibition leads to cardiovascular benefits. These observations, taken collectively, suggest that UDP‐GlcNAc functions as a critical nutrient surplus sensor (which acting in concert with mTOR and HIF‐1α) can promote the development of cardiomyopathy.

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Empagliflozin Inhibits Cardiac Late Sodium Current by Ca/Calmodulin-Dependent Kinase II

Cited by 28 publications

References 5 publications

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

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

Association between sodium–glucose cotransporter-2 inhibitors and arrhythmic outcomes in patients with diabetes and pre-existing atrial fibrillation

Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

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