Cytosolic calcium accumulation and delayed repolarization associated with ventricular arrhythmias in a guinea pig model of Andersen-Tawil syndrome

doi:10.1016/j.hrthm.2010.03.044

Heart Rhythm

Volume 7, Issue 10, October 2010, Pages 1428-1435.e1

https://doi.org/10.1016/j.hrthm.2010.03.044 Get rights and content

Background

Andersen-Tawil syndrome (ATS1)–associated ventricular arrhythmias are initiated by frequent, hypokalemia-exacerbated, triggered activity. Previous ex vivo studies in drug-induced Andersen-Tawil syndrome (DI-ATS1) models have proposed that arrhythmia propensity in DI-ATS1 derives from cytosolic Ca²⁺ ([Ca²⁺]_i) accumulation leading to increased triggered activity.

Objective

The purpose of this study was to test the hypothesis that elevated [Ca²⁺]_i with concomitant APD prolongation, rather than APD dispersion, underlies arrhythmia propensity during DI-ATS1.

Methods

DI-ATS1 was induced in isolated guinea pig ventricles by perfusion of 2 mM KCl Tyrode solution containing 10 μM BaCl₂. APD and [Ca²⁺]_i from the anterior epicardium were quantified by ratiometric optical voltage (di-4-ANEPPS) or Ca²⁺ (Indo-1) mapping during right ventricular pacing with or without the ATP-sensitive potassium channel opener pinacidil (15 μM).

Results

APD gradients under all conditions were insufficient for arrhythmia induction by programmed stimulation. However, 38% of DI-ATS1 preparations experienced ventricular tachycardias (VTs), and all preparations experienced a high incidence of premature ventricular complexes (PVCs). Pinacidil decreased APD and APD dispersion and reduced VTs (to 6%), and PVC frequency (by 79.5%). However, PVC frequency remained significantly greater relative to control (0.5% ± 0.3% of DI-ATS1). Importantly, increased arrhythmia propensity during DI-ATS1 was associated with diastolic [Ca²⁺]_i accumulation and increased [Ca²⁺]_i transient amplitudes. Pinacidil partially attenuated the former but did not alter the latter.

Conclusion

The study data suggest that arrhythmias during DI-ATS1 may be a result of triggered activity secondary to prolonged APD and altered [Ca²⁺]_i cycling and less likely dependent on large epicardial APD gradients forming the substrate for reentry. Therefore, therapies aimed at reducing [Ca²⁺]_i rather than APD gradients may prove effective in treatment of ATS1.

Introduction

Anderson-Tawil syndrome (ATS1) is an inherited channelopathy that results from loss of function of the inward-rectifier K⁺ current (I_K1) secondary to mutations in KCNJ2, the gene that encodes the Kir2.1 channel.1, 2 ATS1 is characterized electrocardiographically by a prolonged QT interval (hence its classification as long QT syndrome type 7) and nonsustained ventricular tachycardias (VTs) that often are foreshadowed by frequent triggered activity and occur more frequently during hypokalemia.2, 3 Therefore, it has been proposed that arrhythmias in ATS1 may be caused by electrical substrate remodeling4, 5 giving rise to the prolonged QT interval and increased triggered activity frequency. Although heterogeneous action potential duration (APD) prolongation and increased dispersion, both transmural and interventricular, have been reported in experimental models of ATS1,5, 6, 7 whether these gradients of repolarization are sufficient for reentry to occur remains unknown.

The high frequency and focal nature of bidirectional VTs in ATS1 suggest that triggered activity underlies, at least in part, the observed arrhythmias in ATS1.⁶ In general, focal arrhythmias have been linked to cytosolic Ca²⁺ ([Ca²⁺]_i) accumulation.8, 9, 10 Indeed, in silico models of ATS1 support the hypothesis that [Ca²⁺]_i accumulation underlies increased triggered activity during partial I_K1 blockade.11, 12 Based on ex vivo studies in drug-induced Anderson-Tawil syndrome (DI-ATS1) models, Morita et al⁶ and Poelzing and Veeraraghavan⁷ proposed that arrhythmia propensity in ATS1 derives from [Ca²⁺]_i accumulation leading to increased triggered activity. However, [Ca²⁺]_i accumulation has yet to be demonstrated in an experimental model of ATS1, in part due to limitations in whole-heart [Ca²⁺]_i measurement techniques.

Although the development of ratiometric (i.e., dual wavelength) fluorescent Ca²⁺ probes has helped minimize artifacts due to inhomogeneities in fluorescence and motion, whole-heart Ca²⁺ optical mapping has lacked a calibration procedure that would satisfactorily account for multiple excitation light exposures.13, 14 Therefore, we designed and validated a ratiometric Ca²⁺ optical mapping system capable of simultaneous, quantitative, multisite measurements and use the system here to test the hypothesis that elevated [Ca²⁺]_i concomitant with APD prolongation, rather than APD dispersion, underlies arrhythmia propensity during DI-ATS1.

We demonstrate in guinea pig Langendorff-perfused ventricles that gradients of epicardial APD dispersion in DI-ATS1 were insufficient for arrhythmia induction by premature stimuli. However, APD prolongation was associated with increased incidence and severity of spontaneous and rapid pacing induced arrhythmias. Importantly, we demonstrate that this increased arrhythmia incidence is associated with significant diastolic [Ca²⁺]_i accumulation. Furthermore, APD abbreviation with the ATP-sensitive potassium channel opener pinacidil alleviated both diastolic [Ca²⁺]_i accumulation and the consequent increased arrhythmia burden.

Section snippets

Methods

This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was approved by the Institutional Animal Care and Use Committee of the University of Utah (Protocol No. 05-07002).

Guinea pig Langendorff preparation

Guinea pig ventricles were perfused as Langendorff preparations as previously described.⁷ In brief, adult male guinea pig breeders (weight 800–1,000 g) were anesthetized with sodium pentobarbital (30 mg/kg intraperitoneally). Their hearts were rapidly excised and the atria removed and perfused as Langendorff preparations (perfusion pressure 55 mmHg) with oxygenated (100% O₂) Tyrode solution at 36.5°C of the following composition (in mmol/L): CaCl₂ 2, NaCl 140, KCl 4.5, dextrose 10, MgCl₂ 1, and

Statistical analysis

Statistical analysis was performed with two-tailed Student's t-test for paired and unpaired data. Multiple regression analyses were used to characterize fluorescence Ca²⁺ signal drift both in vitro and in ex vivo preparations. Fisher exact test was used to test differences in nominal data. P <.05 was considered significant. All values are reported as mean ± SE unless otherwise noted.

Drug induced-ATS1

A representative volume-conducted ECG shown in Figure 1A demonstrates QT-interval prolongation by approximately 60 ms during DI-ATS1 relative to control. Additionally, the T wave, which was monophasic under control conditions, was biphasic during DI-ATS1. Over all experiments, QTc during DI-ATS1 (286.7 ± 15.2 ms) was significantly longer relative to control (210.7 ± 5.2 ms, Figure 1B). Underlying the observed QTc prolongation during DI-ATS1 was APD prolongation illustrated by representative

Discussion

Several studies hypothesized that [Ca²⁺]_i accumulation concomitant with APD prolongation underlies arrhythmias in ATS111, 17 and DI-ATS1.6, 7 However, [Ca²⁺]_i accumulation had not been demonstrated in whole-heart preparations in part because of methodologic difficulties in quantitative [Ca²⁺]_i measurement using ratiometric Ca²⁺ optical mapping. In this study, we demonstrate that DI-ATS1 was associated with [Ca²⁺]_i accumulation concomitant with APD prolongation. Attenuating [Ca²⁺]_i accumulation

Study limitations

Although APD gradients in guinea pig (present study) or canine⁵ were not associated with increased arrhythmia propensity, APD distribution and heterogeneity are know to vary among animal models.33, 34 The nature of electrophysiologic remodeling induced by chronic functional I_K1 down-regulation, as occurs in patients with ATS1, remains unclear.5, 6, 7, 11, 17 Furthermore, it is well appreciated that pharmacologic models of cardiac disease should be interpreted cautiously due to the acute nature

Conclusion

This study suggests that arrhythmias during DI-ATS1 may be the result of triggered activity secondary to prolonged APD and altered [Ca²⁺]_i cycling and less likely dependent on large gradients of repolarization acting as a substrate for reentrant arrhythmias. Therefore, ameliorating myocyte [Ca²⁺]_i load may prove a more effective therapeutic goal in ATS1 compared to decreasing APD gradients.

References (35)

N.M. Plaster et al.
Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome
Cell
(2001)
M. Tsuboi et al.
Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7)
Heart Rhythm
(2006)
R. Coronel et al.
Dispersion of repolarization and arrhythmogenesis
Heart Rhythm
(2009)
R. Brandes et al.
Quantitation of cytosolic [Ca²⁺] in whole perfused rat hearts using Indo-1 fluorometry
Biophys J
(1993)
M. Wahl et al.
Intracellular Ca²⁺ measurement with Indo-1 in substrate-attached cells: advantages and special considerations
Cell Calcium
(1990)
W.J. Scheenen et al.
Photodegradation of indo-1 and its effect on apparent Ca²⁺ concentrations
Chem Biol
(1996)
A. Luckhoff
Measuring cytosolic free calcium concentration in endothelial cells with indo-1: the pitfall of using the ratio of two fluorescence intensities recorded at different wavelengths
Cell Calcium
(1986)
M. Tristani-Firouzi et al.
Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)
J Clin Invest
(2002)
R. Tawil et al.
Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features
Ann Neurol
(1994)
L. Zhang et al.
Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype
Circulation
(2005)

H. Morita et al.

Mechanism of U wave and polymorphic ventricular tachycardia in a canine tissue model of Andersen-Tawil syndrome

Cardiovasc Res

(2007)

S. Poelzing et al.

Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig

Am J Physiol Heart Circ Physiol

(2007)

E. Marban et al.

Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle

J Clin Invest

(1986)

H.B. Nuss et al.

Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure

Am J Physiol

(1999)

P.G. Volders et al.

Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts

Cardiovasc Res

(2000)

R.J. Sung et al.

Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced I_K1: a simulation study

Am J Physiol Heart Circ Physiol

(2006)

J. Silva et al.

Mechanism of pacemaking in I(K1)-downregulated myocytes

Circ Res

(2003)

Cited by (17)

Intercellular Sodium Regulates Repolarization in Cardiac Tissue with Sodium Channel Gain of Function
2020, Biophysical Journal
Citation Excerpt :
All animal study protocols were approved by the Institutional Animal Care and Use Committee at the Virginia Polytechnic Institute and State University. Optical mapping of Langendorff-perfused guinea pig hearts has been extensively described by the Poelzing group (10,36). Briefly, male retired breeder guinea pigs were anesthetized with isoflurane inhalation, and hearts were rapidly excised and retrogradely perfused through the aorta.
In cardiac myocytes, action potentials are initiated by an influx of sodium (Na⁺) ions via voltage-gated Na⁺ channels. Na⁺ channel gain of function (GOF), arising in both inherited conditions associated with mutation in the gene encoding the Na⁺ channel and acquired conditions associated with heart failure, ischemia, and atrial fibrillation, enhance Na⁺ influx, generating a late Na⁺ current that prolongs action potential duration (APD) and triggering proarrhythmic early afterdepolarizations (EADs). Recent studies have shown that Na⁺ channels are highly clustered at the myocyte intercalated disk, facilitating formation of Na⁺ nanodomains in the intercellular cleft between cells. Simulations from our group have recently predicted that narrowing the width of the intercellular cleft can suppress APD prolongation and EADs in the presence of Na⁺ channel mutations because of increased intercellular cleft Na⁺ ion depletion. In this study, we investigate the effects of modulating multiple extracellular spaces, specifically the intercellular cleft and bulk interstitial space, in a novel computational model and experimentally via osmotic agents albumin, dextran 70, and mannitol. We perform optical mapping and transmission electron microscopy in a drug-induced (sea anemone toxin, ATXII) Na⁺ channel GOF isolated heart model and modulate extracellular spaces via osmotic agents. Single-cell patch-clamp experiments confirmed that the osmotic agents individually do not enhance late Na⁺ current. Both experiments and simulations are consistent with the conclusion that intercellular cleft narrowing or expansion regulates APD prolongation; in contrast, modulating the bulk interstitial space has negligible effects on repolarization. Thus, we predict that intercellular cleft Na⁺ nanodomain formation and collapse critically regulates cardiac repolarization in the setting of Na⁺ channel GOF.
Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1
2020, Journal of the American College of Cardiology
Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported.
This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1.
Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis.
We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00).
Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.
Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations
2015, Heart Rhythm
Citation Excerpt :
APD prolongation also elicits an increase in calcium influx, leading to intracellular calcium overload. In addition, subsequent spontaneous calcium release may depolarize the membrane potential to the threshold of L-type calcium channel via transient inward currents carried by the Na+-Ca2+exchanger.4,25,26 APD prolongation, instability of the resting membrane potential, and calcium overload result in the onset of delayed afterdepolarization.4,24
Andersen-Tawil syndrome (ATS) is an autosomal dominant genetic or sporadic disorder characterized by ventricular arrhythmias (VAs), periodic paralyses, and dysmorphic features. The optimal pharmacological treatment of VAs in patients with ATS remains unknown.
We evaluated the efficacy and safety of flecainide for VAs in patients with ATS with KCNJ2 mutations.
Ten ATS probands (7 females; mean age 27 ± 11 years) were enrolled from 6 institutions. All of them had bidirectional VAs in spite of treatment with β-blockers (n = 6), but none of them had either aborted cardiac arrest or family history of sudden cardiac death. Twenty-four-hour Holter recording and treadmill exercise test (TMT) were performed before (baseline) and after oral flecainide therapy (150 ± 46 mg/d).
Twenty-four-hour Holter recordings demonstrated that oral flecainide treatment significantly reduced the total number of VAs (from 38,407 ± 19,956 to 11,196 ± 14,773 per day; P = .003) and the number of the longest ventricular salvos (23 ± 19 to 5 ± 5; P = .01). At baseline, TMT induced nonsustained ventricular tachycardia (n = 7) or couplets of premature ventricular complex (n = 2); treatment with flecainide completely (n = 7) or partially (n = 2) suppressed these exercise-induced VAs (P = .008). In contrast, the QRS duration, QT interval, and U-wave amplitude of the electrocardiogram were not altered by flecainide therapy. During a mean follow-up of 23 ± 11 months, no patients developed syncope or cardiac arrest after oral flecainide treatment.
This multicenter study suggests that oral flecainide therapy is an effective and safe means of suppressing VAs in patients with ATS with KCNJ2 mutations, though the U-wave amplitude remained unchanged by flecainide.
Andersen-Tawil syndrome: Clinical and molecular aspects
2013, International Journal of Cardiology
Andersen–Tawil syndrome (ATS) is a rare hereditary multisystem disorder. Ventricular arrhythmias, periodic paralysis and dysmorphic features constitute the classic triad of ATS symptoms. The expressivity of these symptoms is, however, extremely variable, even within single ATS affected families, and not all ATS patients present with the full triad of symptoms. ATS patients may show a prolongation of the QT interval, which explains the classification as long QT syndrome type 7 (LQT7), and specific neurological or neurocognitive defects. In ATS type 1 (ATS1), the syndrome is associated with a loss-of-function mutation in the KCNJ2 gene, which encodes the Kir2.1 inward rectifier potassium channel. In ATS type 2 (ATS2), which does not differ from ATS1 in its clinical symptoms, the genetic defect is unknown. Consequently, ATS2 comprises all cases of ATS in which genetic testing did not reveal a mutation in KCNJ2. The loss-of-function mutations in KCNJ2 in ATS1 affect the excitability of both skeletal and cardiac muscle, which underlies the cardiac arrhythmias and periodic paralysis associated with ATS. Thus far, the molecular mechanism of the dysmorphic features is only poorly understood. In this review, we summarize the clinical symptoms, the underlying genetic and molecular defects, and the management and treatment of ATS.
Store-dependent deactivation: Cooling the chain-reaction of myocardial calcium signaling
2013, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
CPVT has been attributed to “leaky” RyR2s resulting in spontaneous Ca2 + release during diastole [51,69,68]. Whereas the link between spontaneous Ca2 + release and the consequent membrane depolarization (delayed after depolarization, DAD) is well established and involves NCX stimulated by elevated cytosolic Ca2 + [62,70–72], the mechanism responsible for spontaneous Ca2 + release in CPVT has been an area of intense investigation. Based on studies using recombinant RyR2, Chen and colleagues suggested that spontaneous release associated with CPVT is due to direct activation of SR Ca2 + release by luminal Ca2 + [28,51].
In heart cells, Ca^2 + released from the internal storage unit, the sarcoplasmic reticulum (SR) through ryanodine receptor (RyR2) channels is the predominant determinant of cardiac contractility. Evidence obtained in recent years suggests that SR Ca^2 + release is tightly regulated not only by cytosolic Ca^2 + but also by intra-store Ca^2 + concentration. Specifically, Ca^2 +-induced Ca^2 + release (CICR) that relies on auto-catalytic action of Ca^2 + at the cytosolic side of RyR2s is precisely balanced and counteracted by RyR2 deactivation dependent on a reciprocal decrease of Ca^2 + at the luminal side of RyR2s. Dysregulation of this inherently unstable Ca^2 + signaling is considered to be an underlying cause of triggered arrhythmias, and is associated with genetic and acquired forms of sudden cardiac death. In this article, we present an overview of recent advances in our understanding of the regulatory role luminal Ca^2 + plays in Ca^2 + handling, with a particular emphasis on the role of Ca^2 +release refractoriness in aberrant Ca^2 + release. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.
Inhibition of Na<sup>+</sup> channels ameliorates arrhythmias in a drug-induced model of Andersen-Tawil syndrome
2013, Heart Rhythm
Citation Excerpt :
ATS1 is characterized electrocardiographically by a mildly prolonged QT interval and ventricular arrhythmias that are initiated by frequent PVA that occur more frequently during hypokalemia.1 Previously, our group2 as well as others3 have linked PVA to abnormal Ca2+ regulation, where the regional Na+/Ca2+-exchange (NCX) dominance coupled to slower sarcoplasmic reticulum (SR) Ca2+ loading was associated with a greater arrhythmia incidence.4 Specifically, increasing global NCX dominance by SR Ca2+ ATPase inhibition increased arrhythmia propensity, while NCX blockade significantly reduced these events.4
Andersen-Tawil syndrome (ATS1)-associated ventricular tachycardias (VTs) are initiated by frequent, hypokalemia-exacerbated, premature ventricular activity (PVA). We previously demonstrated that a guinea pig model of drug-induced ATS1 (DI-ATS1) evidenced increased arrhythmias from regions with high Na⁺/Ca²⁺-exchange expression.
Therefore, we hypothesize that reduced cytosolic Na⁺ entry through either cardiac isoform of or tetrodotoxin (TTX)-sensitive Na⁺ channels during DI-ATS1 can ameliorate arrhythmia burden.
DI-ATS1 was induced with 10 μM BaCl₂ and 2 mM extracellular K⁺. Ca²⁺ transients and conduction velocity (CV) were optically mapped with indo-1 and di-4-ANEPPS, respectively, from Langendorff-perfused guinea pig ventricles.
Nonselective Na⁺ channel blockade with 1 μM flecainide reduced amplitude (Ca_A), slowed left ventricular CV, reduced tissue excitability, and abolished the incidence of VT while decreasing the incidence of PVA relative to DI-ATS1. Selective, TTX-sensitive Na⁺ channel blockade with TTX (100 nM) during DI-ATS1 decreased Ca_A and decreased the inducibility of VTs and PVA relative to DI-ATS1 without slowing CV. Ranolazine altered Ca_A, left ventricular CV, tissue excitability, and reduced inducibility of VT and PVA in a concentration-dependent manner. None of the aforementioned interventions altered diastolic Ca²⁺ levels or Ca²⁺ transient decay time constant.
These data suggest that cytosolic Na⁺ entry and its modulation of Ca²⁺ handling are necessary for arrhythmogenesis. During the loss of inward-rectifier K⁺ current function, not only Na⁺/Ca²⁺-exchange dominance but Na⁺ flux may determine arrhythmia burden. Therefore, selective inhibition of TTX-sensitive Na⁺ channels may offer a potential therapeutic target to alleviate arrhythmias during states of Ca²⁺ overload secondary to loss of inward-rectifier K⁺ current function without compromising the excitability reserve.

View all citing articles on Scopus

: Dr. Poelzing was supported by the Nora Eccles Treadwell Foundation and National Institutes of Health Grant R21 HL094828-01A1.

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Focus issue: Sudden cardiac arrestExperimentalCytosolic calcium accumulation and delayed repolarization associated with ventricular arrhythmias in a guinea pig model of Andersen-Tawil syndrome

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Guinea pig Langendorff preparation

Statistical analysis

Drug induced-ATS1

Discussion

Study limitations

Conclusion

Cell

Heart Rhythm

Heart Rhythm

Biophys J

Cell Calcium

Chem Biol

Cell Calcium

Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)

J Clin Invest

Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features

Ann Neurol

Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype

Circulation

Mechanism of U wave and polymorphic ventricular tachycardia in a canine tissue model of Andersen-Tawil syndrome

Cardiovasc Res

Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig

Am J Physiol Heart Circ Physiol

Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle

J Clin Invest

Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure

Am J Physiol

Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts

Cardiovasc Res

Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study

Am J Physiol Heart Circ Physiol

Mechanism of pacemaking in I(K1)-downregulated myocytes

Circ Res

Focus issue: Sudden cardiac arrest
Experimental
Cytosolic calcium accumulation and delayed repolarization associated with ventricular arrhythmias in a guinea pig model of Andersen-Tawil syndrome

Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced I_K1: a simulation study