Increase of late sodium current contributes to enhanced susceptibility to atrial fibrillation in diabetic mice

Jin, Xuexin; Jiang, Yuan; Xue, Genlong; Yuan, Yin; Zhu, Hao; Zhan, Linfeng; Zhuang, Yuting; Huang, Qihe; Shi, Ling; Zhao, Yue; Li, Penghui; Sun, Yilin; Su, Wanzhen; Zhang, Yang; Yang, Baofeng; Lu, Yanjie; Wang, Zhiguo; Pan, Zhenwei

doi:10.1016/j.ejphar.2019.172444

Cited by 21 publications

(14 citation statements)

References 26 publications

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“…This might happen in diabetes; in fact, increased I Na,L has been found in type 1 and type 2 (db/db) mice with prolonged QTc ( Lu et al, 2013 ). Moreover, diabetic mice treated with the I Na,L inhibitor GS967 were more resistant to develop atrial fibrillation under an arrhythmia-inducing protocol than untreated diabetic animals ( Jin et al, 2019 ). In addition, cultured cells incubated in high glucose conditions showed an increase in the late sodium current ( Fouda et al, 2020 ).…”

Section: Ion Channels and Currents In The Diabetic Myocardiummentioning

confidence: 99%

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes

et al. 2021

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Diabetes is a chronic metabolic disease characterized by hyperglycemia in the absence of treatment. Among the diabetes-associated complications, cardiovascular disease is the major cause of mortality and morbidity in diabetic patients. Diabetes causes a complex myocardial dysfunction, referred as diabetic cardiomyopathy, which even in the absence of other cardiac risk factors results in abnormal diastolic and systolic function. Besides mechanical abnormalities, altered electrical function is another major feature of the diabetic myocardium. Both type 1 and type 2 diabetic patients often show cardiac electrical remodeling, mainly a prolonged ventricular repolarization visible in the electrocardiogram as a lengthening of the QT interval duration. The underlying mechanisms at the cellular level involve alterations on the expression and activity of several cardiac ion channels and their associated regulatory proteins. Consequent changes in sodium, calcium and potassium currents collectively lead to a delay in repolarization that can increase the risk of developing life-threatening ventricular arrhythmias and sudden death. QT duration correlates strongly with the risk of developing torsade de pointes, a form of ventricular tachycardia that can degenerate into ventricular fibrillation. Therefore, QT prolongation is a qualitative marker of proarrhythmic risk, and analysis of ventricular repolarization is therefore required for the approval of new drugs. To that end, the Thorough QT/QTc analysis evaluates QT interval prolongation to assess potential proarrhythmic effects. In addition, since diabetic patients have a higher risk to die from cardiovascular causes than individuals without diabetes, cardiovascular safety of the new antidiabetic drugs must be carefully evaluated in type 2 diabetic patients. These cardiovascular outcome trials reveal that some glucose-lowering drugs actually reduce cardiovascular risk. The mechanism of cardioprotection might involve a reduction of the risk of developing arrhythmia.

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Section: Ion Channels and Currents In The Diabetic Myocardiummentioning

confidence: 99%

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes

et al. 2021

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“…Intracardiac programmed electrical stimulus. As previously described, all groups were examined with electrophysiological characteristics via intracardiac programmed electrical stimulus (13). Each animal was anesthetized with 2% isoflurane (Beijing Hongxin Technology) inhalation and fixed on a heated pad at the prone position to maintain 37˚C body temperature.…”

Section: Intraperitoneal Glucose Tolerance Test (Ipgtt) and Intraperitoneal Insulin Tolerance Test (Ipitt)mentioning

confidence: 99%

Exogenous hydrogen sulfide reduces atrial remodeling and atrial fibrillation induced by diabetes mellitus via activation of the PI3K/Akt/eNOS pathway

et al. 2020

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Diabetes mellitus (DM) facilitates atrial fibrosis and increases the risk of atrial fibrillation (AF). The underlying mechanism of DM in causing AF remains mostly unknown and potential therapeutic targets for DM-induced AF are rarely reported. Hydrogen sulfide (H 2 S) has drawn considerable attention in recent years for its potential as a cardiovascular protector. Thus, the aim of the present study was to investigate the effect of H 2 S on DM-induced AF and the mechanism of action. Sprague-Dawley rats were divided into four groups, including the control group, the DM group, the H 2 S group and the DM+H 2 S group. The DM group and the DM+H 2 S group were administered streptozotocin to induce DM, whereas the other two groups were given citrate buffer as a control. The H 2 S group and the DM+H 2 S group were administered with an intraperitoneal injection of sodium hydrosulfide (precursor of H 2 S). AF inducibility, AF duration, atrial fibrosis and vital protein expression of oxidative stress were compared among the four groups. The DM group showed significantly higher AF incidence rates and duration (P<0.05). Histology results demonstrated severe atrial fibrosis in the DM group, and the PI3K/Akt/endothelial nitric oxide synthase (eNOS) pathway was significantly downregulated (P<0.05). However, when H 2 S was administered, the rats showed lower AF incidence and duration compared with the DM group. Additionally, H 2 S was able to mitigate the atrial fibrosis induced by DM, as well as the proliferation and migration of cardiac fibroblasts, as demonstrated by an MTT assay and real-time cell analyzer migration experiment. Western blotting showed that the expression levels of the PI3K/Akt/eNOS pathway in the DM+H 2 S group were significantly upregulated compared with those of the DM group (P<0.05). In summary, DM status can lead to the structural remodeling of atrial fibrosis, facilitating AF incidence and persistence. Administration of H 2 S does not affect the glucose level, but can significantly mitigate atrial fibrosis and reduce the incidence of AF induced by DM, probably via activation of the PI3K/Akt/eNOS pathway.

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“…Also at 6 weeks, electrophysiological characteristics of the animals’ hearts were determined using intracardiac programmed electrical stimulation. 12 Rats were anesthetized and a surface electrocardiogram (ECG) and intracardiac electrogram were recorded simultaneously for each animal. P wave duration and intra-atrial conduction time were measured.…”

Section: Methodsmentioning

confidence: 99%

Hydrogen-rich saline mitigates pressure overload-induced cardiac hypertrophy and atrial fibrillation in rats via the JAK-STAT signalling pathway

Wang

Pan

2020

J Int Med Res

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Objective To investigate if hydrogen-rich saline (HRS), which has been shown to have antioxidant and anti-inflammatory properties, could mitigate cardiac remodelling and reduce the incidence of atrial fibrillation (AF) in the rat model of cardiac hypertrophy. Methods Pressure overload was induced in rats by abdominal aortic constriction (AAC). The animals were separated into four groups: sham; AAC group; AAC plus low dose HRS (LHRS); AAC plus high dose HRS (HHRS). The sham and AAC groups received normal saline intraperitoneally and the LHRS and HHRS groups received 3 or 6 ml/kg HRS daily for six weeks, respectively. In vitro research was also performed using cardiotrophin-1 (CT-1)-induced hypertrophy of cultured neonatal rat cardiomyocytes. Results Cardiac hypertrophy was successfully induced by AAC and low and high dose HRS mitigated the pressure overload as shown by lower heart and atrial weights in these treatment groups. AF incidence and duration of the HRS groups were also significantly lower in the HRS groups compared with the AAC group. Atrial fibrosis was also reduced in the HRS groups and the JAK-STAT signalling pathway was down-regulated. In vitro experiments showed that hydrogen-rich medium mitigated the CT-1-induced cardiomyocyte hypertrophy with a similar effect as the JAK specific antagonists AG490. Conclusions HRS was found to mitigate cardiac hypertrophy induced by pressure overload in rats and reduce atrial fibrosis and AF which was possibly achieved via inhibition of the JAK-STAT signalling pathway.

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Increase of late sodium current contributes to enhanced susceptibility to atrial fibrillation in diabetic mice

Cited by 21 publications

References 26 publications

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes

Exogenous hydrogen sulfide reduces atrial remodeling and atrial fibrillation induced by diabetes mellitus via activation of the PI3K/Akt/eNOS pathway

Hydrogen-rich saline mitigates pressure overload-induced cardiac hypertrophy and atrial fibrillation in rats via the JAK-STAT signalling pathway

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