Empagliflozin prevents doxorubicin-induced myocardial dysfunction

Sabatino, Jolanda; Rosa, Salvatore De; Tammè, Laura; Iaconetti, Claudio; Sorrentino, Sabato; Polimeni, Alberto; Mignogna, Chiara; Amorosi, Andrea; Spaccarotella, Carmen; Yasuda, Masakazu; Indolfi, Ciro

doi:10.1186/s12933-020-01040-5

Cited by 95 publications

(69 citation statements)

References 53 publications

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Section: Discussionsupporting

confidence: 88%

“…Different mechanisms of [Na + ] lowering seem plausible: SGLT-2 inhibitors have been demonstrated to inhibit the Na + /H + exchanger in murine cardiomyocytes [32]. Indeed, our results confirm not only the debated presence of SGLT-2 in the LA [11] but also support the notion of altered cytosolic [Na + ] and [Ca 2+ ] by its inhibition. Work by Lambert et al indicates a contribution of the SGLT-1 transporter to cytosolic [Na + ] in failing hearts, in particular in the presence of metabolic dysfunction (T2DM, obesity), making it another plausible site-of-action [14].…”

Section: Discussionsupporting

confidence: 79%

“…Gliflozins show varying SGLT type 2 over type 1 selectivity (empagliflozin: 2680-fold, dapagliflozin: 1242-fold, canagliflozin: 155-fold) [ 7 ]. Sotagliflozin (Sota) was designed to exert a 20-fold lower affinity for SGLT type 2 over type 1, while the presence of SGLT-2 in the heart, particular across species, remains a question of debate [ 10 , 11 ]. SGLT-1 inhibition reduces glucose uptake in the proximal intestine, which significantly blunts and delays postprandial hyperglycemia [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

Bode

Semmler

Wakula

et al. 2021

Cardiovasc Diabetol

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Background Sodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. Methods 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student’s t-test, as applicable. Results Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium–calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition. Conclusion The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

Bode

Semmler

Wakula

et al. 2021

Cardiovasc Diabetol

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“…Same studies indicated that human and murine cardiomyocytes express SGLT-2 [30]. To con rm this data, we analysed SGLT-2 expression in cardiomyocytes and heart tissue of mice.…”

Section: Sglt-2 Expression Through Western Blot Analysismentioning

confidence: 76%

The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

Quagliariello

Laurentiis

Rea

et al. 2021

Preprint

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BackgroundEmpagliflozin, a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA‐REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of empagliflozin in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analyzed . We aimed to evaluate the effects of empagliflozin on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and Myd88-related pathways resulting in anti-apoptotic and anti-fibrotic effects.Methods Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to empagliflozin. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed: expression of NLRP3 inflammasome, MyD88 myddosome and p65/NF-κB associated to secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin (DOXO, n=6), empagliflozin (EMPA, n=6) or doxorubicin combined to empagliflozin (DOXO-EMPA, n=6). DOXO was injected intraperitoneally. Radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac fibrosis and apoptosis were histologically studied through Picrosirius red and TdT-mediated dUTP nick-end labelling (TUNEL) assay, respectively. Tissue NLRP3, Myd88 and cytokines were quantified after treatments.ResultsCardiomyocytes exposed to doxorubicin increased the intracellular Ca2+ content and expression of several pro-inflammatory markers associated to cell death; co-incubation with empagliflozin reduced significantly the magnitude of the effects. In preclinical study, empagliflozin prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin (radial strain (RS) 30.3 % in EMPA-DOXO vs 15.7% in DOXO mice ; longitudinal strain (LS) -17% in EMPA-DOXO vs -11,7% in DOXO mice (p<0.001 for both). A significant reduction of cardiac fibrosis and apoptosis were also seen. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart, liver and kidneys was also seen in DOXO-EMPA group compared to DOXO mice (p<0.001)ConclusionEmpagliflozin reduced fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in a significant improvement of myocardial strain. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.

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“…Our data con rm that empagli ozin treatment reduces HOMA-IR, as described previously [23], which would improve insulin resistance. In line with a bene cial effect of empagli ozin, the drug has recently been reported to protect the heart from in ammation and energy depletion via AMPK activation [24], as well as preventing doxorubicin-induced myocardial dysfunction [25].…”

Section: Discussionmentioning

confidence: 91%

Empagliflozin Ameliorates Leukocyte – Endothelium Cell Interactions and Inflammation in Type 2 Diabetic Patients

Iannantuoni¹,

Canet²,

López‐Domènech³

et al. 2020

Preprint

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Abstract Background: SGLT2 inhibitors (iSGLT2) such as empagliflozin can reduce cardiovascular risk in patients with type 2 diabetes, but the underlying molecular mechanisms are yet to be determined. In the present study we evaluate the effects of empagliflozin on anthropometric and endocrine parameters, leukocyte-endothelium interactions, adhesion molecules and NFkB-p65 transcription factor expression. Methods: Eighteen patients with type 2 diabetes were recruited for the study. Patients received 10 mg/day of empagliflozin according to standard clinical protocols and were followed-up during a 24-week period. Anthropometric and analytical measurements were performed at baseline, 12-weeks and 24-weeks. Interactions between polymorphonuclear leukocytes and human umbilical vein endothelial cells (HUVECs), serum levels of adhesion molecules (P-selectin, VCAM-1 and ICAM-1) and NFkB-p65 protein levels were measured. Results: We observed a decrease in body weight, BMI and HbA1C levels from 12 weeks of treatment, which had become more pronounced at 24 weeks and was accompanied by a significant reduction in waist circumference, glucose, and hs-CRP levels. Leukocyte-endothelium interactions were reduced due to an enhancement of leukocyte rolling velocity from 12 weeks onwards, together with a significant decrease in leukocyte rolling flux and adhesion at 24 weeks. Accordingly, a significant decrease in ICAM-1 levels and NFkB-p65 expression were observed. Conclusions: Empagliflozin reduced leukocyte-endothelium interactions, adhesion molecules and NFkB-p65 expression in type 2 diabetic patients after 24 weeks of treatment.

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Empagliflozin prevents doxorubicin-induced myocardial dysfunction

Cited by 95 publications

References 53 publications

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

Empagliflozin Ameliorates Leukocyte – Endothelium Cell Interactions and Inflammation in Type 2 Diabetic Patients

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