Empagliflozin Ameliorates Diastolic Dysfunction and Left Ventricular Fibrosis/Stiffness in Nondiabetic Heart Failure

Santos‐Gallego, Carlos G.; Requena-Ibáñez, Juan Antonio; Antonio, Rodolfo San; García‐Ropero, Álvaro; Ishikawa, Kiyotake; Watanabe, Shin; Picatoste, Belén; Vargas-Delgado, Ariana P.; Flores‐Umanzor, Eduardo; Sanz, Javier; Fuster, Valentín; Badimón, Juan J.

doi:10.1016/j.jcmg.2020.07.042

Cited by 154 publications

(114 citation statements)

References 31 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…These effects may ultimately lead to lowered stroke work, cardiac stretch and attenuated remodeling [ 15 ]. Kang et al have shown some of the direct effects of empagliflozin on cardiomyocytes, and others exhibited even its long term (10–12 weeks) cardiac efficacy in vivo, yet little is known about the mechanism by which empagliflozin exerts its effect in diabetes and non-diabetes after MI [ 14 , 16 , 17 ]. It was suggested that empagliflozin affected cellular hypertrophy by attenuated ANP mRNA expression in a hypertension-induced heart failure model [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

The impact of empagliflozin on cardiac physiology and fibrosis early after myocardial infarction in non-diabetic rats

Daud

Ertracht

Bandel

et al. 2021

Cardiovasc Diabetol

View full text Add to dashboard Cite

Background Myocardial fibrosis is a multistep process, which results in collagen deposition in the injured muscle. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), decreases cardiovascular events risk. Little is known on the effects of empagliflozin in non-diabetic patients early post myocardial infarction. Methods Fourteen non-diabetic rats underwent myocardial infarction induction, and treated or not (control)immediately after myocardial infarction by daily empagliflozin (30 mg/kg/day). We evaluated cardiac function at baseline, 2 and 4 weeks after myocardial infarction by echocardiography, and prior to sacrifice by Millar pressure–volume system. We performed histological and biochemical evaluation of fibrosis and humoral factors promoting fibrosis. Results Baseline ejection fractions were 69.9 ± 5.3% and 76.4 ± 5.4%, and dropped to final values of 40.1 ± 5.8% and 39.4 ± 5.4% in the control and empagliflozin groups, respectively (P < 0.001 vs. baseline, P > 0.05 between groups). Collagen deposition, measured as collagen volume fraction, was higher in both the scar and the remote cardiac areas of the control group 79.1 ± 6.2% and 4.6 ± 2.5% for control, and 53.8 ± 5.4% and 2.5 ± 1.3% for empagliflozin group, respectively (P < 0.05 for each). Remote cardiac muscle collagen, measured by hydroxyproline, was 4.1 ± 0.4 μg/μl and 3.6 ± 0.2 μg/μl (P = 0.07). TGF-β1 and Smad3 expression decreased by empagliflozin—18.73 ± 16.32%, 9.16 ± 5.69% and 16.32 ± 5.4%, 7.00 ± 5.28% in the control and empagliflozin groups, respectively (P < 0.05). Conclusion/interpretation Empagliflozin administered early after myocardial infarction reduce myocardial fibrosis and inhibit the TGF-β1/Smad3 fibrotic pathway, probably prior to exerting any hemodynamic or physiological effect.

show abstract

Section: Discussionmentioning

confidence: 99%

The impact of empagliflozin on cardiac physiology and fibrosis early after myocardial infarction in non-diabetic rats

Daud

Ertracht

Bandel

et al. 2021

Cardiovasc Diabetol

View full text Add to dashboard Cite

show abstract

“…An in vivo experiment suggested that canagliflozin (CANA) restored endothelium-dependent relaxation of pulmonary arteries in hyperglycemic mice [ 6 ]. Recently, another study showed that empagliflozin (EMPA) attenuated diastolic function in non-diabetic HF pigs via restoration of NO availability and PKG activity [ 7 ]. The improved diastolic function might explain the beneficial effect of EMPA on patients with HF [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Sodium Glucose Co-Transporter 2 Inhibitors Ameliorate Endothelium Barrier Dysfunction Induced by Cyclic Stretch through Inhibition of Reactive Oxygen Species

Römer

Kerindongo

et al. 2021

IJMS

View full text Add to dashboard Cite

SGLT-2i’s exert direct anti-inflammatory and anti-oxidative effects on resting endothelial cells. However, endothelial cells are constantly exposed to mechanical forces such as cyclic stretch. Enhanced stretch increases the production of reactive oxygen species (ROS) and thereby impairs endothelial barrier function. We hypothesized that the SGLT-2i’s empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) exert an anti-oxidative effect and alleviate cyclic stretch-induced endothelial permeability in human coronary artery endothelial cells (HCAECs). HCAECs were pre-incubated with one of the SGLT-2i’s (1 µM EMPA, 1 µM DAPA and 3 µM CANA) for 2 h, followed by 10% stretch for 24 h. HCAECs exposed to 5% stretch were considered as control. Involvement of ROS was measured using N-acetyl-l-cysteine (NAC). The sodium-hydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) were inhibited by cariporide, or GKT136901, respectively. Cell permeability and ROS were investigated by fluorescence intensity imaging. Cell permeability and ROS production were increased by 10% stretch; EMPA, DAPA and CANA decreased this effect significantly. Cariporide and GKT136901 inhibited stretch-induced ROS production but neither of them further reduced ROS production when combined with EMPA. SGLT-2i’s improve the barrier dysfunction of HCAECs under enhanced stretch and this effect might be mediated through scavenging of ROS. Anti-oxidative effect of SGLT-2i’s might be partially mediated by inhibition of NHE1 and NOXs.

show abstract

“…In this model empagliflozin treatment for 5 weeks improved diastolic function and reduced myocardial hypertrophy without affecting fibrosis [ 134 ]. Recently, in a porcine model of MI-induced HFrEF, treatment with empagliflozin for 2 months was shown to improve diastolic function as assessed by transthoracic echocardiography, cardiac magnetic resonance imaging as well as invasive hemodynamics [ 135 ]. This was associated with reduced myocardial fibrosis, reduced oxidative stress as well as improved eNOS-NO-cGMP-PKG signaling with consequent increase in titin phosphorylation, which contributes—when hypophosphorylated—to cardiomyocyte stiffness and diastolic dysfunction [ 135 , 136 ].…”

Section: Potential Role Of Reduced [Na + ] I For Cardioprotection By Sglt2imentioning

confidence: 99%

“…Recently, in a porcine model of MI-induced HFrEF, treatment with empagliflozin for 2 months was shown to improve diastolic function as assessed by transthoracic echocardiography, cardiac magnetic resonance imaging as well as invasive hemodynamics [ 135 ]. This was associated with reduced myocardial fibrosis, reduced oxidative stress as well as improved eNOS-NO-cGMP-PKG signaling with consequent increase in titin phosphorylation, which contributes—when hypophosphorylated—to cardiomyocyte stiffness and diastolic dysfunction [ 135 , 136 ]. In line with this, recent studies in rodent as well as human HFrEF and HFpEF demonstrated improved diastolic function upon empagliflozin treatment due to reduced passive myofilament stiffness, which was also explained by enhanced titin phosphorylation [ 101 , 113 ].…”

Section: Potential Role Of Reduced [Na + ] I For Cardioprotection By Sglt2imentioning

confidence: 99%

Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na+?

Trum

Riechel

Wagner

2021

IJMS

View full text Add to dashboard Cite

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are emerging as a new treatment strategy for heart failure with reduced ejection fraction (HFrEF) and—depending on the wistfully awaited results of two clinical trials (DELIVER and EMPEROR-Preserved)—may be the first drug class to improve cardiovascular outcomes in patients suffering from heart failure with preserved ejection fraction (HFpEF). Proposed mechanisms of action of this class of drugs are diverse and include metabolic and hemodynamic effects as well as effects on inflammation, neurohumoral activation, and intracellular ion homeostasis. In this review we focus on the growing body of evidence for SGLT2i-mediated effects on cardiac intracellular Na+ as an upstream mechanism. Therefore, we will first give a short overview of physiological cardiomyocyte Na+ handling and its deterioration in heart failure. On this basis we discuss the salutary effects of SGLT2i on Na+ homeostasis by influencing NHE1 activity, late INa as well as CaMKII activity. Finally, we highlight the potential relevance of these effects for systolic and diastolic dysfunction as well as arrhythmogenesis.

show abstract

Empagliflozin Ameliorates Diastolic Dysfunction and Left Ventricular Fibrosis/Stiffness in Nondiabetic Heart Failure

Cited by 154 publications

References 31 publications

The impact of empagliflozin on cardiac physiology and fibrosis early after myocardial infarction in non-diabetic rats

The impact of empagliflozin on cardiac physiology and fibrosis early after myocardial infarction in non-diabetic rats

Sodium Glucose Co-Transporter 2 Inhibitors Ameliorate Endothelium Barrier Dysfunction Induced by Cyclic Stretch through Inhibition of Reactive Oxygen Species

Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na+?

Contact Info

Product

Resources

About