Calcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2

doi:10.1016/j.hrthm.2010.06.032

Heart Rhythm

Volume 7, Issue 11, November 2010, Pages 1686-1694

https://doi.org/10.1016/j.hrthm.2010.06.032 Get rights and content

Background

Alternans of intracellular Ca²⁺ (Ca_i) underlies T-wave alternans, a predictor of cardiac arrhythmias. A related phenomenon, T-wave lability (TWL), precedes torsades de pointes (TdP) in patients and animal models with impaired repolarization. However, the role of Ca_i in TWL remains unexplored.

Objective

This study investigated the role of Ca_i dynamics on TWL in a noncryoablated rabbit model of long QT syndrome type 2 (LQT2) using simultaneous measurements of Ca_i transient (CaT), action potentials (APs), and electrocardiogram (ECG) during paced rhythms and focused on events that precede ventricular ectopy.

Methods

APs and CaTs were mapped optically from paced Langendorff female rabbit hearts (n = 8) at 1.2-s cycle length, after atrioventricular node ablation. Hearts were perfused with normal Tyrode solution, then with dofetilide (0.5 μM), and reduced [K⁺] (2 mM) and [Mg²⁺] (0.5 mM) to elicit LQT2. Lability of ECG, voltage, and Ca_i signals were evaluated during regular paced rhythm, before and after dofetilide perfusion.

Results

In LQT2, lability of Ca_i, voltage, and ECG signals increased during paced rhythm, before the appearance of early afterdepolarizations (EADs). LQT2 resulted in AP prolongation and multiple (1 to 3) additional Ca_i upstrokes, whereas APs remained monophasic. When EADs appeared, Ca_i rose before voltage upstrokes at the origins of propagating EADs. Interventions (i.e., ryanodine and thapsigargin, n = 3 or low [Ca]_o and nifedipine, n = 4) that suppressed Ca_i oscillations also abolished EADs.

Conclusion

In LQT2, Ca_i oscillations (Ca_iO) precede EADs by minutes, indicating that they result from spontaneous sarcoplasmic reticulum Ca²⁺ release rather than spontaneous I_Ca,L reactivation. Ca_iO likely produce oscillations of Na/Ca exchange current, I_NCX. Depolarizing I_NCX during the AP plateau contributes to the generation of EADs by reactivating Ca²⁺ channels that have recovered from inactivation. TWL reflects CaTs and APs lability that occur before EADs and TdP.

Section snippets

Heart preparations

New Zealand White rabbits (female, 60 to 120 days old) were anesthetized with pentobarbital (35 mg/kg intravenously) and anticoagulated with heparin (200 U/kg intravenously). The heart was perfused with Tyrode solution (mM): 130 NaCl, 24 NaHCO₃, 1.0 MgCl₂, 4 KCl, 1.2 NaH₂PO₄, 50 dextrose, 1.25 CaCl₂, gassed with 95% O₂–5 % CO₂. The atrioventricular node was destroyed with electrocautery to control heart rate. To minimize motion artifact, blebbistatin (5 to 10 μM for approximately 15 minutes)

Results

TdP was induced by dofetilide perfusion in all hearts (n = 8) in <10 minutes and was preceded by short-coupled premature ventricular beats. Premature ventricular beats on the ECG corresponded to EADs on optical V_m tracings. In all cases, the onset of EADs was preceded by prolongation of APD (415 ± 118 vs. 678 ± 235 ms; P < .01) and of CaT duration (474 ± 144 vs. 702 ± 227 ms; P < .005) as compared with controls. The QT interval determined from epicardial ECG also prolonged markedly (481 ± 105

Discussion

The main finding of this report is that under LQT2 conditions, CaT oscillations occur in ventricular myocardium during regular rhythm. They are not caused by oscillations of membrane potential, which they precede by minutes. When EADs do appear, they usually follow CaT upstroke at the site of EAD origin.

Although Ca_i oscillations under LQT conditions have been reported before, they were always described in the presence of EADs and often understood as a consequence of I_Ca,L reactivation with

Limitations

Dofetilide was used at a relatively high dose to elicit drug-induced LQT2 because lower doses were less reliable at eliciting TdP. Our LQT2 model shows an extreme degree of impaired repolarization compared to most clinical situations and its clinical relevance must be validated. However, it has the advantage of reproducible TdP induction during an acute study.

Conclusion

In LQT2, APD prolongation promotes CaT oscillations, which precede the appearance of EADs. The data provide a mechanistic explanation for TWL and enhance our understanding of arrhythmogenesis in LQTS. This may lead to improved clinical management of patients with impaired repolarization.

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In long QT syndrome type 2, women are more prone than men to the lethal arrhythmia torsades de pointes. We previously reported that 17β-estradiol (E2) up-regulates L-type Ca²⁺ channels and current (I_Ca,L) (∼30%) in rabbit ventricular myocytes by a classic genomic mechanism mediated by estrogen receptor-α (ERα). In long QT syndrome type 2 (I_Kr blockade or bradycardia), the higher Ca²⁺ influx via I_Ca,L causes Ca²⁺ overload, spontaneous sarcoplasmic reticulum Ca²⁺ release, and reactivation of I_Ca,L that triggers early afterdepolarizations and torsades de pointes.
The purpose of this study was to investigate the molecular mechanisms whereby E2 up-regulates I_Ca,L, which are poorly understood.
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Incubation of H9C2 cells with E2 (10–100 nM) increased I_Ca,L density and Cav1.2α1C expression, which were suppressed by the ER antagonist ICI182,780 (1 μM). Enhanced I_Ca,L and Cav1.2α1C expression by E2 was suppressed by inhibitors of phosphoinositide-3-kinase (Pi3K) (30 μM LY294002; P <.05) and Akt (5 μM MK2206) but not of mitogen-activated protein kinase (5 μM U0126) or protein kinase A (1 μM KT5720). E2 incubation increased p-CREB via the Pi3K/Akt pathway, reached a peak in 20 minutes (3-fold), and leveled off to 1.5-fold 24 hours later. Furthermore, a CREB decoy oligonucleotide inhibited E2-induced Cav1.2α1C expression, whereas membrane-impermeable E2 (E2-bovine serum albumin) was equally effective at Cav1.2α1C up-regulation as E2.
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Acute myocardial ischemia is a common cause of ventricular arrhythmias, yet recent ECG methods predicting susceptibility to ventricular tachyarrhythmia have not been fully evaluated during spontaneous ischemia. We sought to evaluate the clinical utility of alternans and non-alternans components of repolarization variability from the standard 10-second 12-lead ECG signals to risk stratify patients with acute chest pain.
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After excluding patients with secondary repolarization changes (n = 123) and those with excessive noise (n = 90), our final sample included 537 patients (age 57 ± 16 years, 56% males). Patients with AMI (n = 47, 9%) had higher TWA and NARV values (p < 0.01). Mean RR correlated with TWA, and noise measures correlated with TWA and NARV, after adjusting for potential confounders. There was a high collinearity between TWA and NARV, and each was separately predictive of AMI after controlling for number of analyzed beats, noise measures, and other clinical variables.
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: Supported in part by a grant from Boston Scientific, Inc., to Dr. Němec; National Institutes of Health, National Heart, Lung, and Blood Institute grant HL-69097 to Dr. Salama; and a Three Rivers Affiliate of the American Heart Association Pre-Doctoral Fellowship to Jong J. Kim, MS. Jan Němec, MD and Jong J. Kim, MS, contributed equally to this work.

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Regular issueExperimental geneticCalcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2

Background

Objective

Methods

Results

Conclusion

Section snippets

Heart preparations

Results

Discussion

Limitations

Conclusion

J Am Coll Cardiol

Am J Cardiol

Lancet

J Am Coll Cardiol

Biophys J

Mayo Clin Proc

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Delayed afterdepolarizations in heart muscle: mechanisms and relevance

Pharm Rev

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

Cardiovasc Res

A dynamic model of the cardiac ventricular action potentialII. Afterdepolarizations, triggered activity, and potentiation

Circ Res

Upsurge in T-wave alternans and nonalternating repolarization instability precedes spontaneous initiation of ventricular tachyarrhythmias in humans

Circulation

Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy

Circulation

QT interval variability and adaptation to heart rate changes in patients with long QT syndrome

Pacing Clin Electrophysiol

Beat-to-beat repolarization lability identifies patients at risk for sudden cardiac death

J Cardiovasc Electrophysiol

Regular issue
Experimental genetic
Calcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2