scholarly journals Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Valerie Y. H. van Weperen ◽  
Albert Dunnink ◽  
Alexandre Bossu ◽  
Jet D. M. Beekman ◽  
Veronique M. F. Meijborg ◽  
...  
Keyword(s):  
Spatial Dispersion ◽  
Torsade De Pointes ◽  
Left Ventricular ◽  
Dispersion Of Repolarization ◽  
Dog Model ◽  
Severe Bradycardia ◽  
Idioventricular Rhythm ◽  
Surface Electrocardiogram ◽  
Temporal Dispersion ◽  
Unipolar Electrograms

IntroductionTorsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.MethodsDofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.ResultsIVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate).ConclusionIn CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

scholarly journals High rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias autonomically by an ICD

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Smoczynska ◽  
V Loen ◽  
A.A Hernandez ◽  
H.D.M Beekman ◽  
M Meine ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Torsade De Pointes ◽  
Left Ventricular ◽  
High Rate ◽  
Monophasic Action Potential ◽  
Funding Source ◽  
Short Term ◽  
Dispersion Of Repolarization ◽  
Temporal Dispersion ◽  
Short Term Variability

Abstract Background The anesthetized, chronic complete atrioventricular block (CAVB) dog model allows reproducible inducibility of Torsade de Pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr-blocker. High rate pacing (HRP) prevents ventricular arrhythmias, but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases prior to ventricular arrhythmias and has been proposed as a marker to guide HRP. Purpose A proof-of-principle study to show STV determined automatically and in real-time by an ICD can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an ICD (Medtronic, lead in the right ventricular (RV) apex), with software to automatically determine STV online (STV-ICD). STV was determined from the activation recovery interval (ARI) of 31 consecutive beats with the formula: STV = Σ|ARI(n+1) − ARI(n)|/(N*√2). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg i.v. in 5 minutes or until the first TdP). In the first experiment, the individual STV-ICD threshold was determined prior to the first arrhythmic event and programmed into the ICD. In a serial experiment, HRP was initiated automatically once the STV-ICD threshold was reached, by gradually increasing the heart rate to 100 bpm. Occurrence of TdPs was monitored for 10 minutes from the start of dofetilide infusion in both experiments. During HRP, STV was measured offline from RV electrograms (EGM) and left ventricular (LV) monophasic action potential durations (MAPD) (STV-offline). Results During the inducibility experiment, 8/8 dogs had repetitive TdPs and STV-ICD increased from 0.96±0.42 to 2.10±1.26 ms* (*p<0.05). During the prevention experiment, all dogs reached the STV threshold. HRP decreased STV-offline from 2.02±1.12 to 0.78±0.28 ms*, which was accompanied by prevention of TdPs in 7/8 dogs* (Figure 1). Conclusion Temporal dispersion of repolarization, quantified as STV, can guide HRP automatically by an ICD to prevent ventricular arrhythmias. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Public Private Partnership

Modeling of IK1 mutations in human left ventricular myocytes and tissue

2007 ◽  
Vol 292 (1) ◽  
pp. H549-H559 ◽  
Author(s):  
Gunnar Seemann ◽  
Frank B. Sachse ◽  
Daniel L. Weiss ◽  
Louis J. Ptáček ◽  
Martin Tristani-Firouzi
Keyword(s):  
Action Potential ◽  
Cardiac Tissue ◽  
Ventricular Myocytes ◽  
Torsade De Pointes ◽  
Low Frequency ◽  
Mechanistic Explanation ◽  
Left Ventricular ◽  
Autosomal Dominant Disorder ◽  
Modeling Approach ◽  
Dispersion Of Repolarization

Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in inward rectifier potassium channel (Kir)2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V Kir2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V Kir2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T-wave flattening, and QRS widening. Thus our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for the low frequency of torsade de pointes arrhythmia in ATS.

Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of Torsades de Pointes in the chronic AV-block dog

2021 ◽  
Author(s):  
Agnieszka Smoczynska ◽  
Errol W. Aarnink ◽  
Albert Dunnink ◽  
Alexandre Bossu ◽  
Valerie Y.H. van Weperen ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Spatial Dispersion ◽  
Three Dimensional ◽  
Torsades De Pointes ◽  
Av Block ◽  
Dispersion Of Repolarization ◽  
Ectopic Beats ◽  
The Mean ◽  
Temporal And Spatial ◽  
Temporal Dispersion

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and Torsades de Pointes (TdP, defined as >5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic AV-block (CAVB) dog by dofetilide (IKr-blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (>3 TdPs/10') CAVB dogs were observed for 10' from the start of dofetilide infusion (0.025mg/kg, 5'). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARI) on the intracardiac EGM, using the formula: . The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion prior to first 1) sEB (occurrence at 100±35"), 2) mEB (224±96"), and 3) non self-terminating TdP (454±298"). STVARI increased from 2.15±0.32ms at BL to 3.73±0.99ms* prior to the first sEB and remained increased without further significant progression to mEB (4.41±0.45ms*) and TdP (5.07±0.84ms*) (*p<0.05 compared to BL). SDR3D did not change from 31±11ms at BL to 43±13ms prior to sEB, but increased significantly prior to mEB (68±7ms*) and to TdP (86±9ms*+) (+p<0.05 compared to sEB). An increase in STV contributes to the initiation of sEB whereas an increase in SDR is important for the perpetuation of non self-terminating TdPs.

Cardiac repolarization analysis using the surface electrocardiogram

2008 ◽  
Vol 367 (1887) ◽  
pp. 213-233 ◽  
Author(s):  
Esther Pueyo ◽  
Juan Pablo Martínez ◽  
Pablo Laguna
Keyword(s):  
Qt Interval ◽  
Western World ◽  
Cardiac Repolarization ◽  
T Wave ◽  
Dispersion Of Repolarization ◽  
Pathological Conditions ◽  
T Wave Alternans ◽  
Electrocardiogram Ecg ◽  
Surface Electrocardiogram ◽  
Temporal Dispersion

Sudden cardiac death (SCD) is a challenging health problem in the western world. Analysis of cardiac repolarization from the electrocardiogram (ECG) provides valuable information for stratifying patients according to their risk of suffering from arrhythmic events that could end in SCD, as well as for assessing efficacy of antiarrhythmic therapies. In this paper, we start by exploring the cellular basis of ECG repolarization waveforms under both normal and pathological conditions. We then describe basic preprocessing steps that need to be accomplished on the ECG signal before extracting repolarization indices. A comprehensive review of techniques aimed to characterize spatial or temporal repolarization dispersion is provided, together with a summary of their usefulness for clinical risk stratification. Techniques that describe spatial dispersion of repolarization are based on either differences in repolarization duration or T-wave loop morphology. Techniques that evaluate temporal dispersion of repolarization include the analysis of QT interval adaptation to heart rate changes, QT interval and T-wave variability, and T-wave alternans.

scholarly journals Dexmedetomidine reduces ventricular arrhythmias in a model of drug-induced QT-prolongation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
G Frommeyer ◽  
J Brandt ◽  
C Ellermann ◽  
J Wolfes ◽  
L Eckardt
Keyword(s):  
Qt Interval ◽  
Ventricular Arrhythmias ◽  
Spatial Dispersion ◽  
Torsade De Pointes ◽  
Qt Prolongation ◽  
Recent Experimental Data ◽  
Moderate Increase ◽  
Drug Induced ◽  
Dispersion Of Repolarization ◽  
Significant Prolongation

Abstract Background Dexmedetomidine is increasingly employed for conscious sedation during electrophysiological procedures. Recent experimental data have suggested direct effects of dexmedetomidine on cardiac electrophysiology. The aim of the present study was to assess the effects of dexmedetomidin on drug-induced QT-prolongation. Methods and results In 12 isolated rabbit hearts the macrolide antibiotic erythromycin (300μM) was infused as a potent Ikr blocker after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant prolongation of QT-interval (+25ms, p&lt;0.05) accompanied by a moderate increase of action potential duration (APD, +5ms, p=ns) after infusion of erythromycin as compared with baseline. Effective refractory period (ERP) was also elevated (+33ms, p&lt;0.05). Erythromycin (+26ms, p&lt;0.05) also significantly increased spatial dispersion of repolarisation. Additional infusion of dexmedetomidine (3μM) resulted in a rather stable QT-interval (+7ms, p=ns) and APD (+7ms, p=ns) as compared with sole erythromycin treatment. Of note, a significant decrease of spatial dispersion (−24ms, p&lt;0.05) was observed while ERP was moderately increased (+13ms, p=ns). Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) and drug induced proarrhythmia with torsade de pointes in 6 of 12 erythromycin-treated hearts (40 episodes). Additional infusion of dexmedetomidine reduced the occurrence of torsade de pointes (4 of 12 hearts, 9 episodes). Conclusion Infusion of dexmedetomidine resulted in a reduction of spatial dispersion of repolarization in the presence of a prolonged repolarization period. This resulted in a reduction of torsade de pointes with dexmedetomidine. Furthermore, an increase of ventricular refractory periods reduced inducibility of ventricular arrhythmias. Thus, in an experimental setting dexmedetomidine shows significant antiarrhythmic effects, which may influence electrophysiologic findings during clinical electrophysiologic studies. This needs to be studied in the clinical setting. Funding Acknowledgement Type of funding source: None

Abstract 13875: Torsade de Pointes Arrhythmias Arise at the Site of Maximal Heterogeneity of Repolarization in the Chronic Complete AV-block Dog

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
A Dunnink ◽  
TRG Stams ◽  
HDM Beekman ◽  
A Bossu ◽  
SC Wijers ◽  
...  
Keyword(s):  
Torsade De Pointes ◽  
Complete Atrioventricular Block ◽  
Drug Induced ◽  
Dispersion Of Repolarization ◽  
Highly Sensitive ◽  
Before And After ◽  
Complete Atrioventricular ◽  
Complete Av Block ◽  
Unipolar Electrograms ◽  
Anterior Posterior

Introduction: The chronic complete atrioventricular block (CAVB) dog model is highly sensitive for drug-induced Torsade de Pointes (TdP) arrhythmias. Focal mechanisms have been considered as trigger for the onset of TdP, however, its exact mechanism remains unclear. In this study, detailed mapping of the heart was performed to assess intraventricular heterogeneity of repolarization in relation to the initation of TdP. Methods: In 6 animals, 48 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500ms) local unipolar electrograms were recorded before and after administration of dofetilide. Activation- and repolarization times (RT) were measured at baseline and before occurrence of the first TdP or at 5 minutes after start of dofetilide infusion in inducible and non-inducible dogs. Maximal RT differences were calculated in the left ventricle 1) within adjacent electrodes in different planes (transmural, apex-base, anterior-posterior) and 2) within a square of 4 needles (3D dispersion). Results: TdP could be induced in 3 out of 6 animals. No difference in mean RT was observed between inducible and non-inducible dogs both at baseline (343±30 vs. 345±17ms) and after dofetilide administration (582±73 vs. 508±15ms). Maximal dispersion of RT was not different between both groups at baseline: 36±32 vs. 32±7ms (transmural), 50±20 vs. 42±9ms (apex-base), 71±28 vs. 47±13ms (anterior-posterior), 83±19 vs. 70±6ms (3D dispersion). After dofetilide infusion anterior-posterior (203±28 vs. 142±34ms, p=0.04) and 3D dispersion (268±41 vs. 176±48ms, p=0.03) showed a higher RT difference in the inducible animals. No differences were observed for transmural (124±14 vs. 116±18ms, p=0.557) and apex-base dispersion (142±12 vs. 121±23ms, p=0.229). The initiating beat of the TdP arose consistently from the region with the largest local spatial dispersion of repolarization moments. Conclusion: TdP arises from a region with maximal heterogeneity of repolarization and animals susceptible for TdP demonstrate higher RT differences. These results suggest that a certain gradient of repolarization moments is required in order to initiate TdP in CAVB dogs.

scholarly journals Safe electrophysiologic profile of dexmedetomidine in different experimental arrhythmia models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christian Ellermann ◽  
Jonas Brandt ◽  
Julian Wolfes ◽  
Kevin Willy ◽  
Felix K. Wegner ◽  
...  
Keyword(s):  
Action Potentials ◽  
Cardiac Electrophysiology ◽  
Spatial Dispersion ◽  
Torsade De Pointes ◽  
Experimental Models ◽  
Additional Treatment ◽  
Cardiac Repolarization ◽  
Dispersion Of Repolarization ◽  
Repolarization Reserve ◽  
Experimental Arrhythmia

AbstractPrevious studies suggest an impact of dexmedetomidine on cardiac electrophysiology. However, experimental data is sparse. Therefore, purpose of this study was to investigate the influence of dexmedetomidine on different experimental models of proarrhythmia. 50 rabbit hearts were explanted and retrogradely perfused. The first group (n = 12) was treated with dexmedetomidine in ascending concentrations (3, 5 and 10 µM). Dexmedetomidine did not substantially alter action potential duration (APD) but reduced spatial dispersion of repolarization (SDR) and rendered the action potentials rectangular, resulting in no proarrhythmia. In further 12 hearts, erythromycin (300 µM) was administered to simulate long-QT-syndrome-2 (LQT2). Additional treatment with dexmedetomidine reduced SDR, thereby suppressing torsade de pointes. In the third group (n = 14), 0.5 µM veratridine was added to reduce the repolarization reserve. Further administration of dexmedetomidine did not influence APD, SDR or the occurrence of arrhythmias. In the last group (n = 12), a combination of acetylcholine (1 µM) and isoproterenol (1 µM) was used to facilitate atrial fibrillation. Additional treatment with dexmedetomidine prolonged the atrial APD but did not reduce AF episodes. In this study, dexmedetomidine did not significantly alter cardiac repolarization duration and was not proarrhythmic in different models of ventricular and atrial arrhythmias. Of note, dexmedetomidine might be antiarrhythmic in acquired LQT2 by reducing SDR.

scholarly journals Changes in left ventricular electromechanical relations during targeted hypothermia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Kristin Wisløff-Aase ◽  
Viesturs Kerans ◽  
Kristina Haugaa ◽  
Per Steinar Halvorsen ◽  
Helge Skulstad ◽  
...  
Keyword(s):  
Heart Rate ◽  
Qt Interval ◽  
Clinical Importance ◽  
Left Ventricular ◽  
Peak Strain ◽  
Time To Peak ◽  
Mechanical Dispersion ◽  
Dispersion Of Repolarization ◽  
Aortic Valve Closure ◽  
Prolonged Qt Interval

Abstract Background Targeted hypothermia, as used after cardiac arrest, increases electrical and mechanical systolic duration. Differences in duration of electrical and mechanical systole are correlated to ventricular arrhythmias. The electromechanical window (EMW) becomes negative when the electrical systole outlasts the mechanical systole. Prolonged electrical systole corresponds to prolonged QT interval, and is associated with increased dispersion of repolarization and mechanical dispersion. These three factors predispose for arrhythmias. The electromechanical relations during targeted hypothermia are unknown. We wanted to explore the electromechanical relations during hypothermia at 33 °C. We hypothesized that targeted hypothermia would increase electrical and mechanical systolic duration without more profound EMW negativity, nor an increase in dispersion of repolarization and mechanical dispersion. Methods In a porcine model (n = 14), we registered electrocardiogram (ECG) and echocardiographic recordings during 38 °C and 33 °C, at spontaneous and atrial paced heart rate 100 beats/min. EMW was calculated by subtracting electrical systole; QT interval, from the corresponding mechanical systole; QRS onset to aortic valve closure. Dispersion of repolarization was measured as time from peak to end of the ECG T wave. Mechanical dispersion was calculated by strain echocardiography as standard deviation of time to peak strain. Results Electrical systole increased during hypothermia at spontaneous heart rate (p < 0.001) and heart rate 100 beats/min (p = 0.005). Mechanical systolic duration was prolonged and outlasted electrical systole independently of heart rate (p < 0.001). EMW changed from negative to positive value (− 20 ± 19 to 27 ± 34 ms, p = 0.001). The positivity was even more pronounced at heart rate 100 beats/min (− 25 ± 26 to 41 ± 18 ms, p < 0.001). Dispersion of repolarization decreased (p = 0.027 and p = 0.003), while mechanical dispersion did not differ (p = 0.078 and p = 0.297). Conclusion Targeted hypothermia increased electrical and mechanical systolic duration, the electromechanical window became positive, dispersion of repolarization was slightly reduced and mechanical dispersion was unchanged. These alterations may have clinical importance. Further clinical studies are required to clarify whether corresponding electromechanical alterations are accommodating in humans.

Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na+ current in the heart

2009 ◽  
Vol 297 (3) ◽  
pp. H1048-H1057 ◽  
Author(s):  
Lin Wu ◽  
Sridharan Rajamani ◽  
Hong Li ◽  
Craig T. January ◽  
John C. Shryock ◽  
...  
Keyword(s):  
Torsade De Pointes ◽  
Polymorphic Ventricular Tachycardia ◽  
Isolated Hearts ◽  
T Wave ◽  
Dispersion Of Repolarization ◽  
Transmural Dispersion Of Repolarization ◽  
Repolarization Reserve ◽  
Monophasic Action Potentials ◽  
Transmural Dispersion

Reduction of repolarization reserve increases the risk of arrhythmia. We hypothesized that inhibition of K+ current ( IK) to decrease repolarization reserve would unmask the proarrhythmic role of endogenous, physiological late Na+ current (late INa). Monophasic action potentials (MAP) and 12-lead electrocardiogram were recorded from female rabbit isolated hearts. To block IK and reduce repolarization reserve, E-4031, 4-aminopyridine, and BaCl2 were used; to block endogenous late INa, tetrodotoxin (TTX) and ranolazine were used. E-4031 (1–60 nM) concentration-dependently prolonged MAP duration (MAPD90) and increased duration of the T wave from Tpeak to Tend (Tpeak-Tend), transmural dispersion of repolarization (TDR), and beat-to-beat variability (BVR) of MAPD90. E-4031 caused spontaneous and pause-triggered polymorphic ventricular tachycardia [ torsade de pointes (TdP)]. In the presence of 60 nM E-4031, TTX (0.6–3 μM) and ranolazine (5–10 μM) shortened MAPD90, decreased TDR, BVR, and Tpeak-Tend ( n = 9–20, P < 0.01), and abolished episodes of TdP. In hearts treated with BaCl2 or 4-aminopyridine plus E-4031, TTX (0.6–3 μM) shortened MAPD90 and decreased Tpeak-Tend. Ranolazine could not reverse the effect of E-4031 to inhibit human ether-a-go-go-related gene (HERG) K+ current; thus, the reversal by ranolazine of effects of E-4031 was likely due to inhibition of late INa and not to antagonism of the HERG-blocking action of E-4031. We conclude that endogenous, physiological late INa contributes to arrhythmogenesis in hearts with reduced repolarization reserve. Inhibition of this current partially reverses MAPD prolongation and abolishes arrhythmic activity caused by IK inhibitors.

Sign in / Sign up

Export Citation Format

Share Document