Temporal Dispersion Of Repolarization Research Articles

Short-term variability of repolarization is equally modulated by atrial and (bi)ventricular high rate pacing in patients with an indication for an implantable cardioverter defibrillator

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background An increase in temporal dispersion of repolarization, quantified as short-term variability of the QT-interval (STV-QT), precedes ventricular arrhythmias and has therefore been proposed as a marker for monitoring of imminent arrhythmic risk. A reversal of an increased STV by high rate pacing at 100 bpm was anti-arrhythmic in the chronic atrioventricular block dog model susceptible to Torsade de Pointes arrhythmias upon challenge with an IKr-blocker. The objective of the current study was to investigate the physiological modulation of STV by pacing in patients with an indication for an implantable cardioverter defibrillator (ICD), and to compare atrial and ventricular pacing. Methods ECG recordings were obtained with a sampling frequency of 1200 Hz in 10 dual chamber ICD patients and 10 patients with cardiac resynchronization therapy with defibrillation function (CRT-D) during the implantation or replacement. One-minute recordings were made during sinus rhythm (SR), and during pacing at 80 and 100 beats per minute (bpm) from the atrium (AAI), atrium and right ventricle (DDD RVp), and during atrio-biventricular pacing (DDD BiVp). The QT-interval was determined offline with fiducial segment averaging at one minute of each pacing rate, and 31 consecutive beats were used to calculate STV-QT with the following formula: ∑|D(n + 1)-Dn |/(N×√2), where D represents the determinant of repolarization (in this case the QT interval), and N represents the number of beats taken into account minus 1. Results In the patients overall, STV-QT decreased from 1.27 ± 0.38 ms in SR (±58 bpm) to 0.86 ± 0.26 ms* during AAI80, and to 0.68 ± 0.22 ms*† during AAI100 (*p < 0.05 compared to SR, †p < 0.05 compared to 80 bpm). The same decrease was seen during DDD80 RVp (0.81 ± 0.28 ms*) and during DDD100 RVp (0.66 ± 0.22 ms*†) (fig. 1). Additionally, DDD BiVp decreased STV-QT to 0.78 ± 0.20 ms* at 80 bpm and to 0.62 ± 0.19 ms* at 100 bpm in CRT-D patients (fig. 2). Conclusion Pacing at 80 and 100 bpm decreases STV-QT compared to sinus rhythm both in dual chamber ICD patients and CRT-D patients. The modulation of STV-QT is similar during atrial, and atrio- right ventricular and atrio-biventricular pacing. Abstract Figure. Modulation of STV-QT by AAI and DDD RVp

Short-period temporal repolarization dispersion in subjects with atrial fibrillation and decompensated heart failure.

The association between chronic heart failure (CHF) and permanent atrial fibrillation is very frequent. The repolarization duration was already found predictive for atrial fibrillation. Aim of this study was to evaluate the influence of atrial fibrillation on short period repolarization variables in decompensated CHF patients. We used 5 min ECG recordings to assess the mean, standard deviation (SD), and normalized variance (NV) of the following variables: QT end (QTe), QT peak (QTp), and T peak to T end (Te) in 121 decompensated CHF, of whom 40 had permanent atrial fibrillation, too. We reported also the 30-day mortality. QTpSD (p<.01), TeSD (p<.01), QTpVN (p<.01), and TeVN (p<.01) were higher in the atrial fibrillation than among sinus rhythm CHF subjects. Multivariable logistic analysis selected only TeSD (odd ratio, o.r.: 1.32, 95% confidence interval, c.i.: 1.06-1.65, p: .015) associated with atrial fibrillation. A total of 27 patients died during the 30-days follow-up (overall mortality rate 22%), 7 (18%), and 20 (25%) respectively in the atrial fibrillation and sinus rhythm patients. Furthermore, the following variables were associated to the morality risk: NT-pro Brain Natriuretic Peptide (o.r.: 1.00, 95% c.i.: 1.00-1.00, p: .041), left ventricular end diastolic diameter (o.r.: 0.81, 95% c.i.: 0.67-0.96, p: .010), and Te mean (o.r.: 1.04, 95% c.i.: 1.02-1.09, p: .012). In decompensated CHF subjects, Te mean seems be associated to mortality and TeSD to the permanent atrial fibrillation. We could hypothesize that, during severe CHF, the multi-level ionic CHF channel derangement could be critical in influencing these non-invasive markers. (ClinicalTrials.gov number, NCT04127162).

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

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&amp;lt;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

High-rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias automatically by an implantable cardioverter-defibrillator in the chronic atrioventricular block dog model

The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades 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 before ventricular arrhythmias and has been proposed as a marker to guide HRP. The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias. Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STVICD) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STVRV,EGM/LV,MAPD). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STVICD threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STVICD threshold was reached. In experiment 1, 8 of 8 dogs had repetitive TdP, and STVICD increased from 0.96 ± 0.42 ms to 2.10 ± 1.26 ms (P <.05). In experiment 2, all dogs reached the STV threshold. HRP decreased STVRV,EGM/LV,MAPD from 2.02 ± 1.12 ms to 0.78 ± 0.28 ms, which was accompanied by prevention of TdP in 7 of 8 dogs. STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.

Antiarrhythmic effect of vernakalant in an experimental model of Long-QT-syndrome.

The antiarrhythmic drug vernakalant exerts antiarrhythmic effects in atrial fibrillation. Recent experimental data suggest interactions with the late sodium current and antiarrhythmic effects in ventricular arrhythmias. We aimed at investigating whether treatment with vernakalant reduces polymorphic ventricular tachycardia (VT) in an experimental model of Long-QT-syndrome (LQTS). Twenty-nine isolated rabbit hearts were assigned to two groups and treated with erythromycin (300 µM, n = 15) or veratridine (0.5 µM, n = 14) after obtaining baseline data. Thereafter, vernakalant (10 µM) was additionally infused. Infusion of erythromycin or veratridine significantly increased action potential duration (APD90) and QT interval. Erythromycin and veratridine also significantly augmented spatial dispersion of repolarization (erythromycin: +43 ms; veratridine: +55 ms, P < 0.01, respectively) and temporal dispersion of repolarization. After lowering extracellular [K+] in bradycardic hearts, 11 of 15 erythromycin-treated hearts and 4 of 14 veratridine-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with vernakalant resulted in a significant reduction of spatial dispersion of spatial dispersion in both groups (erythromycin: -32 ms; veratridine: -35 ms, P < 0.05 each) and a stabilization of temporal dispersion. After additional treatment with vernakalant, only 5 of 15 erythromycin-treated hearts (P = 0.07) and 1 of 14 veratridine-treated hearts (P = 0.32) presented polymorphic VT. Vernakalant has antiarrhythmic effects in this experimental model of acquired LQTS. A reduction of spatial dispersion of repolarization and a stabilization of temporal dispersion in hearts showing polymorphic VT represent the major underlying electrophysiological mechanisms.

Severe proarrhythmic potential of risperidone compared to quetiapine in an experimental whole-heart model of proarrhythmia

In several case reports, proarrhythmic effects of antipsychotic drugs have been reported. The aim of the present study was to investigate if application of risperidone or quetiapine has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In 24 isolated rabbit hearts, risperidone (5 and 10μM, n=12) or quetiapine (5 and 10μM, n=12) was infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of risperidone as compared with baseline (5μM: +29ms, 10μM: +35ms, p<0.01) accompanied by an increase of action potential duration. Administration of risperidone also significantly increased spatial dispersion of repolarization (5μM: +16ms, 4μM: +19ms; p<0.05) as well as temporal dispersion of repolarization. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 8 of 12 hearts and polymorphic ventricular tachycardia resembling torsade de pointes in 6 of 12 hearts (10μM, 49 episodes). The results were compared with hearts treated with quetiapine (5 and 10μM). Quetiapine led to an increase in QT interval (5μM: +10ms; 10μM: +28ms; p<0.05) and a similar increase of APD90. However, treatment with quetiapine did not result in significant alterations of spatial and temporal dispersion of repolarization. No ventricular arrhythmias were observed in this group. In the present study, quetiapine demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, risperidone led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization.

Abstract 18556: Renal Sympathetic Denervation Modulates Cardiac Repolarization in a Post Myocardial Infarction Pig Model

Introduction: Changes in cardiac repolarization parameters such as QT interval and QT dispersion have been implicated in cardiac arrhythmogenesis following acute myocardial infarction (AMI). These parameters are susceptible to sympathetic modulation. We therefore hypothesized that renal sympathetic denervation (RDN) may produce potential anti-arrhythmic actions through its effects on cardiac repolarization. Methods: Fifteen pigs randomized to AMI &amp; RDN (6 pigs), AMI &amp; sham RDN (6 pigs) and sham MI &amp; sham RDN (3 pigs) underwent percutaneous occlusion of the mid to distal LAD to achieve AMI. 2 weeks after infarction, the St. Jude EnligHTN® basket catheter was used to perform RDN bilaterally. Cardiac repolarization parameters were measured at 3 time points over the course of the 3 week study: baseline (immediately before MI), midpoint (2 weeks post MI; at time of RDN) and end (1 week post RDN). ECG data were acquired from limb leads. Results: In a ten beat span, the range in the durations of the QT interval was seen to increase from 18+/-7ms to 19+/-11ms in the real AMI &amp; sham RDN group while in the real AMI &amp; real RDN group it decreased from 17+/-5ms to 14+/-5ms (p=0.11). The mean QT interval which increased by 25% in the real AMI &amp; sham RDN group saw only an 11% increase in the real AMI &amp; real RDN group (p=0.048). The standard deviation of the average QT intervals post AMI, which quantifies the reduction in global dispersion of repolarization, saw a 41% decrease with RDN compared to an 8% decrease with sham RDN. The temporal dispersion of repolarization was also diminished by RDN. The dispersion of T wave peak to T wave end durations which increased in the real AMI &amp; sham RDN group (from 15+/-6ms to 22+/-10ms), was decreased in the real AMI &amp; real RDN group (from 19+/-7ms to 16+/-6ms) (p=0.05). T wave alternans values displayed no significant response to RDN (p=0.977). Conclusions: Adverse changes in cardiac repolarization parameters were attenuated via renal denervation in this post infarct pig model. These effects may mitigate post infarct arrhythmogenesis but require further study to evaluate the influence of local, reflex and circulating mediators.

Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms.

Drug-induced ventricular tachyarrhythmias can be caused by cardiovascular drugs, noncardiovascular drugs, and even nonprescription agents. They can result in arrhythmic emergencies and sudden cardiac death. If a new arrhythmia or aggravation of an existing arrhythmia develops during therapy with a drug at a concentration usually considered not to be toxic, the situation can be defined as proarrhythmia. Various cardiovascular and noncardiovascular drugs can increase the occurrence of polymorphic ventricular tachycardia of the 'torsade de pointes' type. Antiarrhythmic drugs, antimicrobial agents, and antipsychotic and antidepressant drugs are the most important groups. Age, female sex, and structural heart disease are important risk factors for the occurrence of torsade de pointes. Genetic predisposition and individual pharmacodynamic and pharmacokinetic sensitivity also have important roles in the generation of arrhythmias. An increase in spatial or temporal dispersion of repolarization and a triangular action-potential configuration have been identified as crucial predictors of proarrhythmia in experimental models. These studies emphasized that sole consideration of the QT interval is not sufficient to assess the proarrhythmic risk. In this Review, we focus on important triggers of proarrhythmia and the underlying electrophysiological mechanisms that can enhance or prevent the development of torsade de pointes.

Vernakalant in an Experimental Model of Pacing-Induced Heart Failure: Lack of Proarrhythmia Despite Prolongation of Repolarization

BackgroundThe present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible proarrhythmic effects of vernakalant in an experimental model of heart failure (HF). Methods and ResultsIn 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 μmol/L and 30 μmol/L) increase of action potential duration (APD90) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD90 was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 μmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K+ concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias. ConclusionIn the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts.

Improvement of QT analysis for Evaluating the Proarrhythmic Risk of Drug: The Importance of Spatial and Temporal Dispersion of Repolarization

Cardiac arrhythmias, in particular life-threatening Torsades de Pointes (TdP) are serious adverse effects associated with a number of pharmaceuticals belonging to different classes. It is therefore critical to have reliable biomarkers for assessing this risk during pre-clinical testing of new compounds. Prolongation of cardiac action potential and consequently of the QT interval of the ECG is generally considered as indicative of a risk of arrhythmia. Evaluation of drug effects on QT in preclinical studies is therefore requested by ICH (International Conference on Harmonization) guideline (S7B). However there is now growing evidence that the prolongation of mean QT interval is not an accurate indicator of the risk of arrhythmia and that other parameters of cardiac repolarization are more predictive. They include instability of action potential duration and increase in transmural heterogeneity of myocardial repolarization (spatial variability), which can be investigated in specific in vitro tests. We have conducted a number of experiments in dogs for evaluating the ECG correlates of both markers in studies testing the effects of isoproterenol, cisapride, astemizole and hypokaliemia, which are known to be associated with a proarrhythmic risk. Instability of action potential duration is associated with an increase in the beat-to-beat (temporal) variability of the QT interval that is evaluated by calculating the coefficient of variation of this parameter or by plotting QT from each beat versus QT of previous beat. Spatial variability of repolarization correlates with changes in the morphology of the T wave, in particular increase in the interval between the peak and the end of the T wave and notching of this wave. In these experiments, we have therefore established a simple method for in vivo assessment of spatial and temporal variability of cardiac repolarization, which may help in the evaluation the pro-arrhythmic risk of drugs.

New Insights into the Beneficial Electrophysiologic Profile of Ranolazine in Heart Failure: Prevention of Ventricular Fibrillation With Increased Postrepolarization Refractoriness and Without Drug-Induced Proarrhythmia

BackgroundRanolazine inhibits late Na+ and K+ currents. Earlier studies have reported an antiarrhythmic effect. The aim of the present study was to understand whether ranolazine could still preserve its antiarrhythmic properties in the settings of chronic heart failure (CHF). Methods and ResultsIn 12 female rabbits, CHF was induced by 4 weeks of rapid ventricular pacing leading to a decrease in ejection fraction. Twelve rabbits underwent sham operation. Isolated hearts were Langendorff perfused and demonstrated a significant QT prolongation after induction of heart failure. Ranolazine caused a concentration-dependent (10 and 30 μmol/L) increase of action potential duration (APD90) in sham-operated and failing hearts. Eight endo- and epicardial monophasic action potentials revealed a nonsignificant increase in spatial and temporal dispersion of repolarization. The increase in APD90 was accompanied by a greater increase in refractory period, resulting in a significant increase in postrepolarization refractoriness in sham-operated (+29 ms and +55 ms; P < .01) and failing (+22 ms and +30 ms; P < .05) hearts. In control conditions, programmed ventricular stimulation and a burst pacing protocol led to ventricular fibrillation (VF) in 5 of the 12 sham-operated (6 episodes) and in 7 of the 12 failing (18 episodes) hearts. In the presence of ranolazine, VF was inducible in only 2 of 12 failing hearts (5 episodes). In the presence of low [K+], only 1 ranolazine-treated sham-operated heart developed early afterdepolarizations and ventricular tachyarrhythmias despite significant QT prolongation. ConclusionsRanolazine decreases inducibility of VF in the presence of a significant increase in postrepolarization refractoriness. This antiarrhythmic effect in the intact heart is preserved in CHF and is not associated with drug-induced proarrhythmia.

Antiarrhythmic effects of free polyunsaturated fatty acids in an experimental model of LQT2 and LQT3 due to suppression of early afterdepolarizations and reduction of spatial and temporal dispersion of repolarization

Torsades de pointes (TdP) are induced by early afterdepolarizations (EADs) in the presence of an increased dispersion of repolarization. Free polyunsaturated fatty acids (PUFAs) have been suggested to influence cardiac repolarization. The purpose of this experimental study was to investigate the electrophysiologic effects of PUFAs in a model of LQT2 and LQT3. We investigated the acute antiarrhythmic potential of α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) in a whole-heart model of long QT2 (LQT2) and long QT3 (LQT3) syndrome. In 123 Langendorff-perfused rabbit hearts, the I(Kr)-blocking drug erythromycin (E; 300 μM) or veratridine (V; 0.5 μM), an inhibitor of sodium channel inactivation, significantly increased monophasic ventricular action potentials (MAPs), thereby mimicking LQT2 and LQT3 syndrome. In atrioventricular-blocked hearts, 8 epicardial and endocardial MAPs demonstrated a significant increase in spatial and temporal dispersion. After lowering potassium concentration, E led to EADs and TdP in 44 and 41 of 53 hearts, respectively. Pretreatment with V led to EAD (TdP) in 39 (32) of 43 hearts. Additional treatment with ALA, DHA, or EPA (10 to 20 μM) in the LQT2 model, randomly assigned to 3 groups, suppressed EAD in 72% of ALA-treated hearts and in all hearts that were treated with EPA or DHA. This led to a reduction of TdP of 67% (ALA) and to complete abolishment of TdP in all hearts that were treated with EPA or DHA. A comparable finding was seen in V-pretreated hearts. In addition, DHA and EPA significantly shortened MAP duration and reduced spatial and temporal dispersion of repolarization (P <.01). The present study showed for the first time that PUFAs are effective in preventing TdP in an experimental model of LQT2 and LQT3 syndrome due to a reversion of AP prolongation, a reduction of spatial and temporal dispersion of repolarization and a suppression of EAD. The PUFA effect is stronger in LQT2 than in LQT3 syndrome, and the antitorsadogenic effect is more remarkable with DHA and EPA as compared with ALA.

Oseltamivir Lacks Proarrhythmic Potential Leading to the Onset of Torsades de Pointes

Oseltamivir has been used for the treatment as well as prevention of influenza viral infection. Since sudden death after its administration has been reported, in this study we assessed the proarrhythmic potential of oseltamivir in comparison with a typical IKr channel blocker d-sotalol hydrochloride using the chronic atrioventricular conduction block (AVB) canine model. Moreover, in order to quantitatively assess their proarrhythmic potential, we used new marker of temporal dispersion of repolarization; namely, beat-to-beat variability of repolarization, which was calculated using 51 consecutive beats. Oseltamivir (3, 10 and 30 mg/kg/10 min, i.v., n=4) or d-sotalol hydrochloride (3 and 30 mg/kg, p.o., n=4) was administered to the AVB dogs with Holter ECG monitoring. Oseltamivir in any dose did not increase the beat-to-beat variability of repolarization or induced torsades de pointes, whereas its middle and high doses slightly prolonged the QT interval. On the other hand, d-sotalol prolonged the QT interval in both doses, increased beat-to-beat variability of repolarization in the high dose, and induced torsades de pointes in 1 out of 4 dogs in the low dose and in all animals in the high dose. These results indicated that intravenous administration of oseltamivir of up to 10 times of clinically recommended daily oral dose lacks proarrhythmic potential leading to the onset of torsades de pointes.

Effects of the Antiarrhythmic Drug Dofetilide on Transmural Dispersion of Repolarization in Ventriculum. A Computer Modeling Study

Dofetilide is a class-III drug that inhibits the rapid component of the delayed potassium current ( I(Kr)). Experimental studies have shown that the different layers of ventricular muscle present differences in action potential duration (APD) and different responses to class III agents. It has been suggested that it contributes to APD heterogeneity in the ventricles. However, in vivo studies suggest that the strong cellular coupling reduces APD dispersion in intact heart. The aim of this paper is to study the effect of dofetilide on the action potentials (APs) in isolated ventricular cells and on APD dispersion in a strand of ventricular tissue. A mathematical model of dofetilide effects on I(Kr) has been developed and incorporated into the Luo--Rudy dynamic model of ventricular AP. Our results show that dofetilide induces in midmyocardium cells a faster time-course inhibition of I(Kr) than in endocardial or epicardial cells, and periods of instability with beat-to-beat APs variability. This behavior could favor temporal dispersion of repolarization between the different cells. The results also indicate that although dofetilide increases, the transmural gradient of APD in the ventricular wall, early afterdepolarizations (EADs) did not appear even under strong uncoupling conditions. However, reduced repolarization reserve favors the induction of EADs, even under normal coupling conditions.

Cardiac repolarization analysis using the surface electrocardiogram

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.

Introduction. Editorial on ‘Signal processing in vital rhythms and signs’

Signal processing has become a core technology in medical devices today, as it is crucial in a wide range of applications. It is used to automate the measurement of various signal characteristics, which previously was done manually and, as a result, subjectivity is reduced and reliability is increased. Another purpose is to filter out undesired signal components of technical or physiological origin so that the signalto-noise ratio is improved and subsequent analysis facilitated. Signal processing is also of key importance when uncovering components with low amplitude and/or subtle variations in frequency, which are very difficult, if not impossible, to observe by the naked eye. For example, signal processing plays a crucial role for the detection of the alternans phenomenon occurring during cardiac repolarization. Information about alternans has turned out to be the most useful for risk stratification of certain cardiac patients. The analysis of heart rate variability represents another application where signal processing is essential for the characterization of tiny oscillations in rhythm; the resulting measurements convey unique information about the autonomic nervous system. Considering that today’s recording equipment and computers are quite powerful and available at affordable prices, limitations related to implementation are rather procedural than computational. The role of signal processing can therefore be expected to further increase in the future as novel techniques are developed and used to uncover and characterize hidden activity which may be present in a signal. Traditionally, biomedical signal processing has been largely synonymous to ‘unimodal’ analysis in which only one type of signal has been subjected to analysis at a time. Countless approaches have been developed to unimodal analysis of the most common bioelectrical signals, i.e. the electrocardiogram (ECG), the electroencephalogram (EEG) and the electromyogram (EMG). However, multimodal signal modelling and processing are currently receiving considerable attention as it is highly desirable to account for the interdependence that exists between different

Electrical remodeling and arrhythmias in long‐QT syndrome: lessons from genetic models in mice

Mutations in cardiac voltage‐gated K+channels cause long‐QT syndrome (LQTS) and sudden death. We have created a mouse with a long‐QT phenotype by overexpression of truncated K+channels in the heart and have investigated the phenotype of these mice. These mice have long‐QT phenotype, and spontaneous and inducible arrhythmias. Optical mapping of Kv1DN mice revealed spatial and temporal dispersion of repolarization that underlies the arrhythmias. Here I review our attempts to abolish arrhythmias in this model by crossbreeding with Kv4DN and Kv2DN mice or direct injection of adenoviral or adeno‐associated viral vectors expressing wild‐type Kv1.5 (AV‐Kv1.5) into the myocardium. Our published work suggests that the viral vectors rescue the phenotype at the cellular level, while crossbreeding with Kv4DN mice attenuates the spontaneous and inducible arrhythmias.

Proarrhythmia With Class III Antiarrhythmic Drugs: Types, Risks, and Management

The nature of the proarrhythmic reactions induced by antiarrhythmic drugs is linked to the electrophysiologic effects of these agents. Torsades de pointes is the classic form of proarrhythmia observed during therapy with any drug that prolongs repolarization, for example, the class III agents. Its precise electrophysiologic mechanism is not fully elucidated, although the arrhythmia is generally considered to be due either to early afterdepolarization in the context of prolonged cardiac repolarization or to an increase in spatial or temporal dispersion of repolarization. Among the class III drugs the proarrhythmic risk appears to be lowest for amiodarone, probably due to its complex electrophysiologic profile that may create significant myocardial electrical homogeneity. In the case of d,l-sotalol, the incidence of torsades de pointes increases with dose and the baseline values of the QT interval. Where d-sotalol and other pure class III agents might fall into the varying spectrum of proarrhythmic potential remains unclear. That d-sotalol has been found to increase mortality in postinfarction patients with ventricular dysfunction (the Survival With Oral d-Sotalol [SWORD] trial) is a matter of considerable concern. It raises the possibility that such a phenomenon may be a common property of most, if not all, pure class III compounds. Accordingly, care must be taken to minimize the likelihood of proarrhythmia; in particular, therapy with a class III agent should only be initiated in the presence of a defined indication established on the basis of clinical trials. When class III antiarrhythmic drug-induced proarrhythmia occurs, immediate cessation of therapy with the responsible agent and correction of predisposing factors, such as electrolyte disorders or bradycardia, is mandatory. Intravenous administration of high-dose magnesium sulfate has been demonstrated to be effective in terminating and preventing new episodes of torsades de pointes. Temporary pacing may be necessary.

Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications.

Antiarrhythmic drugs can and do induce unexpected and sometimes fatal reactions by either producing new symptomatic arrhythmias or by aggravating existing arrhythmias. The definition of proarrhythmia has changed since controlled clinical studies showed a dichotomy between arrhythmia suppression and mortality. The nature of proarrhythmic reactions is linked to the electrophysiologic effects of various antiarrhythmic drugs. Whereas Class I agents without accompanying effects on repolarization generally produce ventricular tachycardia (often incessant) or fibrillation, Class III agents typically produce torsades de pointes that may deteriorate into ventricular fibrillation. The precise mechanism of torsades de pointes is not fully elucidated, although early after-depolarization and increases in spatial or temporal dispersion of repolarization are likely possibilities. Proarrhythmic risk is lowest for amiodarone and is probably related to the drug's complex electrophysiologic profile. The incidence of torsades with sotalol increases with dose and the baseline values of the QT interval; the incidence with d-sotalol and other pure Class III agents remains unclear. Prospective, randomized, placebo-controlled studies to evaluate this are under way. The fact that d-sotalol increases mortality in postinfarction patients suggests that it may possibly be a common property of most, if not all, pure Class III compounds. The ongoing clinical trials with various Class III agents are likely to provide the critical information on this important therapeutic issue.

Effects of bepridil on ventricular depolarization and repolarization of rabbit isolated hearts with particular reference to its possible proarrhythmic properties.

1. Effects of bepridil on ventricular depolarization and repolarization sequences were examined in rabbit Langendorff-perfused hearts. 2. In distant bipolar electrograms (DBEs), bepridil, 10(-6) M, caused a significant prolongation of QT intervals. At 10(-5) M, the QT prolongation was further enhanced, and a significant prolongation of QRS duration was also observed. Polymorphous ventricular tachycardia was frequently induced by a single premature stimulus at the higher concentration. 3. In epicardial electrograms recorded through modified bipolar electrodes, bepridil, 10(-6) M, prolonged the interval from the peak negative deflection of the QRS complex to the apex of the T wave (Q-aT), which corresponded to the intracellular action potential duration at 90% repolarization (APD90). The Q-aT prolongation was larger in the base than in the apex, resulting in a marked distortion and dispersion of repolarization. The epicardial activation sequence was unaffected. 4. At 10(-5) M bepridil, the dispersion of repolarization was much more enhanced by activation delay in the epicardial surface. 5. These findings suggest that bepridil causes regionally different lengthening of APD in ventricular muscle leading to an increase in temporal dispersion of repolarization, and that this dispersion may be inducive for re-entrant arrhythmias when accompanied by slow conduction at toxic doses.