Magnesium Deficiency Causes Transcriptional Downregulation of Kir2.1 and Kv4.2 Channels in Cardiomyocytes Resulting in QT Interval Prolongation

Shimaoka, Toru; Wang, Yan; Miyamoto, Masaki; Miyamoto, Shinj̀i; Ono, Katsushige

doi:10.1253/circj.cj-20-0310

Cited by 14 publications

(8 citation statements)

References 33 publications

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“…APD prolongation has been observed in many pathological conditions and has been shown to be proarrhythmic ( Antoniou et al, 2017 ; Dietrichs et al, 2019 ; Shimaoka et al, 2020 ). For example, APD prolongation and changes in electrophysiological characteristics caused by the downregulation of outward potassium currents, alterations of calcium channel kinetics and increases in late sodium currents create a substrate for ventricular arrhythmias in the case of heart failure ( Zhang et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study

Zhang²,

Jiang³

et al. 2022

Front. Physiol.

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Cardiovascular diseases are the primary cause of death of humans, and among these, ventricular arrhythmias are the most common cause of death. There is plausible evidence implicating inflammation in the etiology of ventricular fibrillation (VF). In the case of systemic inflammation caused by an overactive immune response, the induced inflammatory cytokines directly affect the function of ion channels in cardiomyocytes, leading to a prolonged action potential duration (APD). However, the mechanistic links between inflammatory cytokine-induced molecular and cellular influences and inflammation-associated ventricular arrhythmias need to be elucidated. The present study aimed to determine the potential impact of systemic inflammation on ventricular electrophysiology by means of multiscale virtual heart models. The experimental data on the ionic current of three major cytokines [i.e., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and interleukin-6 (IL-6)] were incorporated into the cell model, and the effects of each cytokine and their combined effect on the cell action potential (AP) were evaluated. Moreover, the integral effect of these cytokines on the conduction of excitation waves was also investigated in a tissue model. The simulation results suggested that inflammatory cytokines significantly prolonged APD, enhanced the transmural and regional repolarization heterogeneities that predispose to arrhythmias, and reduced the adaptability of ventricular tissue to fast heart rates. In addition, simulated pseudo-ECGs showed a prolonged QT interval—a manifestation consistent with clinical observations. In summary, the present study provides new insights into ventricular arrhythmias associated with inflammation.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study

Zhang²,

Jiang³

et al. 2022

Front. Physiol.

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“…In mice, hypomagnesemia has shown to downregulate the inward-rectifying K + current and transient-outward K + current, respectively, as Kir2.1 and Kv4.2. Intracellular Mg 2+ deficiency directly upregulates the transcription factor NFAT and downregulates CREB, which reduces Kir2.1 and Kv4.2 channel activity and results in QT interval prolongation ( 239 ), directly reflecting a greater propensity to AF ( 240 ). Thus, hypomagnesemia completely disturbs the cardiac action potential in people with and without T2D mainly by disturbances of ion channels.…”

Section: Potential Molecular Mechanisms Of Magnesium Involvement In C...mentioning

confidence: 99%

Hypomagnesemia and Cardiovascular Risk in Type 2 Diabetes

2022

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Hypomagnesemia is tenfold more common in individuals with type 2 diabetes (T2D), compared to the healthy population. Factors that are involved in this high prevalence are low Mg2+ intake, gut microbiome composition, medication use and presumably genetics. Hypomagnesemia is associated with insulin resistance, which subsequently increases the risk to develop T2D or deteriorates glycaemic control in existing diabetes. Mg2+ supplementation decreases T2D associated features like dyslipidaemia and inflammation; which are important risk factors for cardiovascular disease (CVD). Epidemiological studies have shown an inverse association between serum Mg2+ and the risk to develop heart failure (HF), atrial fibrillation (AF) and microvascular disease in T2D. The potential protective effect of Mg2+ on HF and AF may be explained by reduced oxidative stress, fibrosis and electrical remodeling in the heart. In microvascular disease, Mg2+ reduces the detrimental effects of hyperglycemia and improves endothelial dysfunction. Though, clinical studies assessing the effect of long-term Mg2+ supplementation on CVD incidents are lacking and gaps remain on how Mg2+ may reduce CVD risk in T2D. Despite the high prevalence of hypomagnesemia in people with T2D, routine screening of Mg2+ deficiency to provide Mg2+ supplementation when needed is not implemented in clinical care as sufficient clinical evidence is lacking. In conclusion, hypomagnesemia is common in people with T2D and is both involved as cause, probably through molecular mechanisms leading to insulin resistance, and consequence and is prospectively associated with development of HF, AF and microvascular complications. Whether long-term supplementation of Mg2+ is beneficial, however, remains to be determined.

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“…Antipsychotic dosage (CP equivalent) has been reported to be significantly associated with QT prolongation 6 . Hypomagnesemia aggravates QT prolongation 7 …”

Section: Discussionmentioning

confidence: 99%