Gender-related differences in ion-channel and transporter subunit expression in non-diseased human hearts

Gaborit, Nathalie; Varró, András; Bouter, Sabrina Le; Szüts, Viktória; Escande, Denis; Nattel, Stanley; Demolombe, Sophie

doi:10.1016/j.yjmcc.2010.06.005

Cited by 157 publications

(137 citation statements)

References 43 publications

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“…2f) did not produce T-wave notching. In addition to these LQTS subtype-specific ECG phenotypes, our simulation system also reproduced clinically observed sex-specific differences in ECG parameters 8 based solely on knowledge of expression levels of ion channel genes 23 , thus further validating our in silico approach ( Supplementary Fig. 5).…”

Section: Resultssupporting

confidence: 63%

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

et al. 2014

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The heart rhythm disorder long QT syndrome (LQTS) can result in sudden death in the young or remain asymptomatic into adulthood. The features of the surface electrocardiogram (ECG), a measure of the electrical activity of the heart, can be equally variable in LQTS patients, posing well-described diagnostic dilemmas. Here we report a correlation between QT interval prolongation and T-wave notching in LQTS2 patients and use a novel computational framework to investigate how individual ionic currents, as well as cellular and tissue level factors, contribute to notched T waves. Furthermore, we show that variable expressivity of ECG features observed in LQTS2 patients can be explained by as little as 20% variation in the levels of ionic conductances that contribute to repolarization reserve. This has significant implications for interpretation of whole-genome sequencing data and underlies the importance of interpreting the entire molecular signature of disease in any given individual.

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Section: Resultssupporting

confidence: 63%

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

et al. 2014

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“…4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved.…”

mentioning

confidence: 61%

“…Recent studies (4,26,34) have shown that in other species, including rats, dogs, and humans, Irx5 is ex- Values are presented as means Ϯ SE. fast and slow, time constants for recovery of the fast and slow components, respectively; Afast and Aslow, contributions of the fast and slow components to recovery, respectively.…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes induces subendocardium-predominant reduction in transient outward K⁺ current with downregulation of Kv4.2 and KChIP2

Sato

Kobayashi

Kuno

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K ϩ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K ϩ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K ϩ current and L-type Ca 2ϩ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of (18). Diabetes is one of the diseases underlying heart failure with preserved left ventricular (LV) ejection fraction (2), and the prognosis of heart failure has been shown to be substantially worsened by diabetes. A number of studies in the past two decades have disclosed abnormalities in the microcirculation, mitochondria, and metabolism in diabetic hearts, as recently reviewed elsewhere (18). However, knowledge of electrical remodeling in the heart by type 2 DM (T2DM) is very limited. Most of the earlier studies used models of type 1 DM (T1DM; i.e., streptozotocin-induced and alloxan-induced diabetes) and showed that the action potential (AP) duration (APD) was prolonged and that the transient outward K ϩ current (I to ), L-type Ca 2ϩ current (I Ca,L ), and inward rectifier K ϩ current (I K1 ) were reduced in T1DM (31,38,45). However, it remains unclear whether T2DM induces the same electrical remodeling as that induced by T1DM. Hyperglycemia is a common feature in all animal models of diabetes, but plasma levels of insulin and lipids are different in T1DM and T2DM and also in models of T2DM (28,44). In addition, characteristics of LV pressurevolume relationship are different in T1DM and T2DM (25), indicating a possible difference in modifications of excitationcontraction coupling between the two types of DM.In the present study, we aimed to characterize the influence of T2DM on APD and ion currents in cardiomyocytes. We used Ots...

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“…A TaqMan low-density array was used to quantify the expression patterns of the genes encoding ion channels, membrane transporters, calciumhandling proteins, and regulatory proteins, as described previously (14,15,28). Briefly, transmural tissue segments for RNA extraction were harvested near the RV apex, immediately caudal to the functional tissue preparation.…”

Section: Methodsmentioning

confidence: 99%

Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling

Lou

Janks

Holzem

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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IR. Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling. Am J Physiol Heart Circ Physiol 303: H1426 -H1434, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00457.2012.-Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ϳ6.3 ϫ 6.3 cm 2 field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 Ϯ 44 vs. 448 Ϯ 39 ms, at BCL ϭ 2,000 ms, P Ͻ 0.05). Dispersion of APD was increased in three failing hearts (161 Ϯ 5 vs. 86 Ϯ 19 ms, at BCL ϭ 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 Ϯ 11 vs. 98 Ϯ 8 cm/s, at BCL ϭ 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF. action potential duration; conduction abnormality; human heart failure; dispersion of repolarization; right ventricle VENTRICULAR ARRHYTHMIA AND sudden cardiac death is common in patients with heart failure (HF) (12,29). However, the understanding of the origin and nature of arrhythmia in HF remains incomplete, particularly in humans. While clinical studies that demonstrate an increased QT dispersion and prolonged interval between T wave's peak and end (1, 13, 31) suggest a link between dispersion of repolarization and arrhythmia in HF patients, studies into the mechanism of repolarization dispersion in HF are limited and report inconsistent findings. In a tachypacing-induced HF dog model, increased dispersion of left ventricular (LV) repolarization was found to be present transmurally (between endocardium and epicardium) due to a disproportionate action potential duration (APD) prolongation of the M cells. However, this was not confirmed in the human heart with advanced HF. It was found that the dispersion of repolarization from endocardium to e...

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Gender-related differences in ion-channel and transporter subunit expression in non-diseased human hearts

Cited by 157 publications

References 43 publications

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Type 2 diabetes induces subendocardium-predominant reduction in transient outward K⁺ current with downregulation of Kv4.2 and KChIP2

Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling

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Gender-related differences in ion-channel and transporter subunit expression in non-diseased human hearts

Cited by 157 publications

References 43 publications

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2

Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling

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Type 2 diabetes induces subendocardium-predominant reduction in transient outward K⁺ current with downregulation of Kv4.2 and KChIP2