Usefulness of Short-Term Variability of QT Intervals as a Predictor for Electrical Remodeling and Proarrhythmia in Patients With Nonischemic Heart Failure

Hinterseer, Martin; Beckmann, Britt-Maria; Thomsen, Morten B.; Pfeufer, Arne; Ulbrich, Michael; Sinner, Moritz F.; Perz, Siegfried; Wichmann, H‐Erich; Lengyel, Csaba; Schimpf, Rainer; Maier, Sebastian; Varró, András; Vos, Marc A.; Steinbeck, Gerhard; Kääb, Stefan

doi:10.1016/j.amjcard.2010.02.033

Cited by 96 publications

(103 citation statements)

References 28 publications

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“…Prolongation of the QT interval and increased dispersion of repolarization have been observed in the diabetic population,4, 5, 6, 7, 8, 9, 10 and these variables, together with intervening comorbidities,11 represent critical substrates for the occurrence of electrical disturbances 4, 12, 13, 14, 15, 16, 17. But whether alterations at the cellular level contribute to protracted electrical recovery and repolarization variability with diabetes remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the protracted AP predisposes myocytes to the occurrence of early afterdepolarizations, which may trigger extrasystoles and tachyarrhythmias and/or aggravate the dispersion of repolarization of the myocardium in the presence of local nonpropagating responses 21. Similarly, beat‐to‐beat variability of repolarization, which is observed at the single‐cell level and in the whole heart,22, 23 has detrimental consequences on myocardial electrical stability by facilitating the development of reentrant arrhythmias 15, 16, 21, 24. Importantly, these defects may be equally operative in the diabetic heart, representing important variables in the propensity to develop ventricular arrhythmias and sudden death in the presence of this disease.…”

Section: Introductionmentioning

confidence: 99%

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Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Meo

Meste

Signore

et al. 2016

JAHA

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BackgroundDiabetes is associated with prolongation of the QT interval of the electrocardiogram and enhanced dispersion of ventricular repolarization, factors that, together with atherosclerosis and myocardial ischemia, may promote the occurrence of electrical disorders. Thus, we tested the possibility that alterations in transmembrane ionic currents reduce the repolarization reserve of myocytes, leading to action potential (AP) prolongation and enhanced beat‐to‐beat variability of repolarization.Methods and ResultsDiabetes was induced in mice with streptozotocin (STZ), and effects of hyperglycemia on electrical properties of whole heart and myocytes were studied with respect to an untreated control group (Ctrl) using electrocardiographic recordings in vivo, ex vivo perfused hearts, and single‐cell patch‐clamp analysis. Additionally, a newly developed algorithm was introduced to obtain detailed information of the impact of high glucose on AP profile. Compared to Ctrl, hyperglycemia in STZ‐treated animals was coupled with prolongation of the QT interval, enhanced temporal dispersion of electrical recovery, and susceptibility to ventricular arrhythmias, defects observed, in part, in the Akita mutant mouse model of type I diabetes. AP was prolonged and beat‐to‐beat variability of repolarization was enhanced in diabetic myocytes, with respect to Ctrl cells. Density of Kv K+ and L‐type Ca2+ currents were decreased in STZ myocytes, in comparison to cells from normoglycemic mice. Pharmacological reduction of Kv currents in Ctrl cells lengthened AP duration and increased temporal dispersion of repolarization, reiterating features identified in diabetic myocytes.ConclusionsReductions in the repolarizing K+ currents may contribute to electrical disturbances of the diabetic heart.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Meo

Meste

Signore

et al. 2016

JAHA

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“…The SBVR or the beat-to-beat variability of the QT interval occurs as random variations of the ventricular repolarization duration or QT intervals in consecutive heart beats at stable rates [9][10][11]. The exact mechanism underlying SBVR is not completely understood.…”

Section: The Short Term Beat-to-beat Variability Of Cardiac Action Pomentioning

confidence: 99%

“…These results question the association between QT prolongation and the arrhythmia development. Thus, quantitative assessment of SBVR could be a reliable parameter to predict proarrhythmic conditions [3, 9,11].…”

Section: The Short Term Beat-to-beat Variability Of Cardiac Action Pomentioning

confidence: 99%

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

Magyar

Bányász

Szentandrássy

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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“…Beat-to-beat APD variability, compared with APD itself, is a more accurate predictor of arrhythmogenic potential in cardiac disease models (20,21) as well as individuals with heart disease (22) and LQTS (23). We recorded 50 sequential APs paced at 1 Hz and report APD variability as the 50-beat APD 90 variance (Fig.…”

Section: Significancementioning

confidence: 99%

hERG 1b is critical for human cardiac repolarization

Jones¹,

Liu²,

Vaidyanathan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The human ether-à-go-go-related gene (hERG; or KCNH2) encodes the voltage-gated potassium channel underlying I Kr , a repolarizing current in the heart. Mutations in KCNH2 or pharmacological agents that reduce I Kr slow action potential (AP) repolarization and can trigger cardiac arrhythmias associated with long QT syndrome. Two channel-forming subunits encoded by KCNH2 (hERG 1a and 1b) are expressed in cardiac tissue. In heterologous expression systems, these subunits avidly coassemble and exhibit biophysical and pharmacological properties distinct from those of homomeric hERG 1a channels. Despite these findings, adoption of hERG 1a/1b heteromeric channels as a model for cardiac I Kr has been hampered by the lack of evidence for a direct functional role for the 1b subunit in native tissue. In this study, we measured I Kr and APs at physiological temperature in cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs). We found that specific knockdown of the 1b subunit using shRNA caused reductions in 1b mRNA, 1b protein levels, and I Kr magnitude by roughly one-half. AP duration was increased and AP variability was enhanced relative to controls. Early afterdepolarizations, considered cellular substrates for arrhythmia, were also observed in cells with reduced 1b expression. Similar behavior was elicited when channels were effectively converted from heteromers to 1a homomers by expressing a fragment corresponding to the 1a-specific N-terminal Per-Arnt-Sim domain, which is omitted from hERG 1b by alternate transcription. These findings establish that hERG 1b is critical for normal repolarization and that loss of 1b is proarrhythmic in human cardiac cells.T he human ether-à-go-go-related gene (hERG; or KCNH2) encodes the voltage-gated potassium channel underlying a native cardiac current known as I Kr (1, 2). Mutations in the gene or drugs that block the channel can diminish I Kr and slow ventricular repolarization, thus prolonging the QT interval on the surface electrocardiogram and causing long QT syndrome (LQTS) (1-3). Individuals with LQTS have an increased risk for torsades de pointes arrhythmia, syncope, and sudden cardiac death. Since 2005, a cell-based assay expressing the hERG 1a isoform as a proxy for I Kr has been the cornerstone of drug safety screening for new drug development (4). Thus, whether current drug safety assays accurately represent the native channel is of paramount importance.The first studies of heterologously expressed hERG channels described biophysical (1, 2) and pharmacological (2, 5) properties uniquely characteristic of cardiac I Kr . Subsequently, alternate transcripts of KCNH2 in mouse and human heart were shown to encode two subunits: 1a (the original isolate) and 1b (6, 7). In the hERG 1b transcript, an alternate 5′ exon replaces 1a exons 1-5, resulting in a shorter, unique N terminus that lacks a Per-Arnt-Sim (PAS) domain (also known as the ether-à-go-go domain) (8, 9). In heterologous systems, hERG 1b subunits avidly associate with hERG 1a but fail as homomer...

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Usefulness of Short-Term Variability of QT Intervals as a Predictor for Electrical Remodeling and Proarrhythmia in Patients With Nonischemic Heart Failure

Cited by 96 publications

References 28 publications

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

hERG 1b is critical for human cardiac repolarization

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