Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1

Balasubramaniam, Richard; Grace, Andrew A.; Saumarez, Richard C.; Vandenberg, Jamie I.; Huang, Christopher

doi:10.1111/j.1469-7793.2003.00535.x

Cited by 28 publications

(48 citation statements)

References 51 publications

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“…We also reproduced the arrhythmogenic effects of isoprenaline by increasing extracellular [Ca 2+ ]. These findings thus complemented earlier studies of arrhythmogenesis following genetic (SCN5a, KCNE1) as opposed to pharmacological manipulation in mouse hearts [1,15]. The experiments went further to investigate the effects of both β-adrenergic stimulation and Ca 2+ channel blockade upon fluo-3 fluorescence signals reflecting SR Ca 2+ release in enzymatically-isolated myocytes subject to repetitive stimulation and imaged using confocal microscopy.…”

Section: Introductionmentioning

confidence: 72%

“…Paired platinum stimulating and recording electrodes of 1 mm inter-pole spacing were positioned on the basal epicardial surfaces of the right and left ventricles respectively and the hearts paced initially for 20 min at 10 Hz before beginning PES using an adaptation of corresponding clinical techniques [1,15,22,23]. The stimulation protocols initially applied standard pacing stimuli at frequencies of 8 or 10 Hz for 20 s and, following this initial short pacing period, a drive train of eight paced beats (S1), again at 8 or 10 Hz, was followed by an extra stimulus (S2) every ninth beat, initially at an S1S2 interval equal to the pacing interval and reduced by 1 ms with each nine-beat cycle until ventricular refractoriness was reached whereupon the S2 stimulus elicited no electrogram.…”

Section: Methodsmentioning

confidence: 99%

“…The whole-heart experiments were carried out using a Langendorff perfusion system adapted for the murine heart as described in detail elsewhere [1]. Briefly, mice were given heparin (100 IU i. p.) to prevent thrombosis and 10 min later, killed by cervical dislocation in accordance with Schedule 1 of the U.K.…”

Section: Methodsmentioning

confidence: 99%

“…Both these conditions may present with potentially fatal, triggered ventricular arrhythmogenesis accentuated by β-adrenergic stimulation [2,8,20,24]. Previous reports have introduced mouse systems with altered Na + [15] and K + channel expression [1]. We further adapted clinical protocols using programmed electrical stimulation (PES) that has been introduced recently to assess arrhythmogenesis in patients [23].…”

Section: Introductionmentioning

confidence: 99%

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Nifedipine and diltiazem suppress ventricular arrhythmogenesis and calcium release in mouse hearts

Balasubramaniam

Chawla

Mackenzie

et al. 2004

Pflugers Arch - Eur J Physiol

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Ventricular arrhythmogenesis leading to sudden cardiac death remains responsible for significant mortality in conditions such as cardiac failure and the long-QT syndrome (LQTS). Arrhythmias may be accentuated by beta-adrenergic stimulation and, accordingly, the present study explored the possible effects of beta-adrenergic stimulation and L-type Ca(2+) channel blockade on ventricular arrhythmogenesis and Ca(2+) handling using the mouse heart as an experimental system. Studies in whole, Langendorff-perfused hearts using programmed electrical stimulation protocols adapted from clinical practice demonstrated sustained ventricular tachycardia following addition of 0.1 microM isoprenaline (n=15), whilst no arrhythmias were observed in the absence of the drug (n=15). Arrhythmias were suppressed by nifedipine or diltiazem pre-treatment (both 1 microM) (n=8 and 4 respectively) and were also induced by elevating external [Ca(2+)] (n=3). At the cellular level, 0.1 microM isoprenaline significantly increased normalized fluorescence (F/F(0)) in field-stimulated fluo-3-loaded mouse ventricular myocytes imaged using confocal microscopy, reflecting increases in sarcoplasmic reticulum Ca(2+) release (n=8). Elevated external [Ca(2+)] also increased F/F(0) (n=4) whilst 0.1 microM nifedipine or 0.1 microM diltiazem significantly decreased F/F(0) (n=13 and 6 respectively). Pre-treatment with 0.1 microM nifedipine or 0.1 microM diltiazem suppressed the increases in F/F(0) induced by 0.1 microM isoprenaline alone (n=14 and 6 respectively). The findings thus paralleled suppression of isoprenaline-induced arrhythmias seen with nifedipine or diltiazem at the whole-heart level. Taken together, the findings may have implications for the use of L-type Ca(2+) channel blockade in conditions associated with beta-adrenergically driven ventricular arrhythmias such as cardiac failure and LQTS.

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Section: Introductionmentioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nifedipine and diltiazem suppress ventricular arrhythmogenesis and calcium release in mouse hearts

Balasubramaniam

Chawla

Mackenzie

et al. 2004

Pflugers Arch - Eur J Physiol

Self Cite

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“…KCNQ1 A340E/+ mice showed a prolonged QT-interval, which resembled the LQT1 syndrome in humans [88]. KCNE-/-mice displayed inner ear defects [90] and ventricular tachycardia, which could be induced by the addition of an extra stimulus [91]. Treatment with the L-type calcium channel blocker nifedipine suppressed ventricular arrhythmias in KCNE -/-mice and ECG showed that the electrogram duration was increased.…”

Section: Models For Cardiac Diseasesmentioning

confidence: 99%

Human stem cells as a model for cardiac differentiation and disease

Beqqali

Eldik

Mummery

et al. 2009

Cell. Mol. Life Sci.

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Studies on identification, derivation and characterization of human stem cells in the last decade have led to high expectations in the field of regenerative medicine. Although it is clear that for successful stem cell-based therapy several obstacles have to be overcome, other opportunities lay ahead for the use of human stem cells. A more immediate application would be the development of human models for cell-type specific differentiation and disease in vitro. Cardiomyocytes can be generated from stem cells, which have been shown to follow similar molecular events of cardiac development in vivo. Furthermore, several monogenic cardiovascular diseases have been described, for which in vitro models in stem cells could be generated. Here, we will discuss the potential of human embryonic stem cells, cardiac stem cells and the recently described induced pluripotent stem cells as models for cardiac differentiation and disease.

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Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange‐Nielsen Syndrome and Romano‐Ward Syndrome

et al. 2018

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KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel‐complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange‐Nielson syndrome (JLNS1 and JLNS2), a cardio‐auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal‐hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano‐Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild‐type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss‐of‐function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype‐phenotype spectrum for KCNE1 variants.

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Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1

Cited by 28 publications

References 51 publications

Nifedipine and diltiazem suppress ventricular arrhythmogenesis and calcium release in mouse hearts

Nifedipine and diltiazem suppress ventricular arrhythmogenesis and calcium release in mouse hearts

Human stem cells as a model for cardiac differentiation and disease

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange‐Nielsen Syndrome and Romano‐Ward Syndrome

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