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The role of a border zone in arrhythmogenesis is not fully understood. In this study we evaluated independent contributions of action potential duration (APD) and dispersion of repolarization (DOR) across the normal/ischemic border to the development of ventricular tachycardia and/or fibrillation (VT/VF). Ischemia-reperfusion episodes were induced in anesthetized rats by transient coronary occlusion. Unipolar electrograms were recorded from ischemic and perfused areas using a 64-lead array to obtain activation times (ATs), repolarization times (RTs), activationrepolarization intervals (ARIs, a surrogate for APD) and dispersion of repolarization (DOR, as a difference between the earliest and latest RTs). Pinacidil (0.3 mg/kg) and glibenclamide (2 mg/kg) were applied to reduce DOR and to clamp APD at a lower and upper levels, respectively. In the control animals, APD shortened in the ischemic zone, DOR increased to 9 ± 3 ms, and VT/VF developed at reperfusion (6 out of 10). Pre-occlusion application of glibenclamide prolonged APD in the ischemic and perfused zones, decreased DOR to 5 ± 2 ms and did not affect VT/VF development (4 out of 11). Post-occlusion infusion of pinacidil shortened APD in the perfused zone, decreased DOR to 6 ± 3 ms and VT/VF incidence (2 out of 11). Extrasystolic burden at reperfusion was associated with VT/VF incidence in logistic regression analysis (β = 1.182, 95%CI 1.008 - 1.386, p = 0.04) and was lesser (p < 0.01) in the pinacidil group as compared to the control and glibenclamide groups. In conclusion, the results of this study suggest that the APDs in the perfused zone were a superior arrhythmogenic factor in respect to DOR in the present ischemia-reperfusion model. [ABSTRACT FROM AUTHOR]

Background: Acquired QT interval prolongation has been linked with malignant ventricular arrhythmias, such as torsade de pointes , in turn predisposing to sudden cardiac death. Increased dispersion of repolarization has been identified as a pro-arrhythmic factor and can be observed as longer Tpeak – Tend interval and higher Tpeak – Tend/QT ratio on the electrocardiogram. However, the values of these repolarization indices for predicting adverse outcomes in this context have not been systematically evaluated. Method: PubMed, Embase and Cochrane Library databases were searched until 14th February 2018, identifying 232 studies. Results: Five studies on acquired QT prolongation met the inclusion criteria and 308 subjects with drug-induced LQTS patients (mean age: 66 ± 18 years old; 46% male) were included in this meta-analysis. Tpeak – Tend intervals were longer [mean difference [MD]: 76 ms, standard error [SE]: 26 ms, P = 0.003; I2 = 98%] and Tpeak – Tend/QT ratios were higher (MD: 0.14, SE: 0.03, P = 0.000; I2 = 29%) in patients with torsade de pointes compared to those without these events. Conclusion: Tpeak – Tend interval and Tpeak – Tend/QT ratio were higher in patients with acquired QT prolongation suffering from torsade de pointes compared to those who did not. These repolarization indices may provide additional predictive value for identifying high-risk individuals. [ABSTRACT FROM AUTHOR]

Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF). This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF. The Ten Tusscher-Panfilov (TP06) human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D) fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR) curves, dispersion of repolarization (DOR), QT interval and spiral wave dynamics. R858H "mutant" L-type calcium current (ICaL) augmented sarcoplasmic reticulum calcium content, leading to the development of afterdepolarizations at the single cell level and focal activities at the tissue level. It also produced inhomogeneous APD prolongation, causing QT prolongation and repolarization dispersion amplification, rendering R858H "mutant" tissue more vulnerable to the induction of reentry compared with other conditions. In conclusion, altered ICaL due to the CACNA1C R858H mutation increases arrhythmia risk due to afterdepolarizations and increased tissue vulnerability to unidirectional conduction block. However, the observed reentry is not due to afterdepolarizations (not present in our model), but rather to a novel blocking mechanism. [ABSTRACT FROM AUTHOR]

Background: Striking temporal associations exist between ventricular arrhythmia and acute mental stress, for example, during natural disasters, or defibrillator shocks associated with stressful events. We hypothesized that electrophysiological changes in response to mental stress may be exaggerated at short coupling intervals and hence relevant to arrhythmia initiation.Objective: The aim of this study was to determine the dynamic response in human electrophysiology during mental stress.Methods: Patients with normal hearts and supraventricular tachycardia underwent electrophysiological studies avoiding sedation. Conditions of relaxation and stress were induced with standardized psychometric protocols (mental arithmetic and anger recall) during decremental S1S2 right ventricular (RV) pacing. Unipolar electrograms were acquired simultaneously from the RV endocardium, left ventricular (LV) endocardium (LV endo), and epicardium (LV epi), and activation-recovery intervals (ARIs) computed.Results: Twelve patients ( 9 women; median age 34 years) were studied. During stress, effective refractory period (ERP) reduced from 228 ± 23 to 221 ± 21 ms (P < .001). ARIs reduced during mental stress (P < .001), with greater reductions in LV endocardium than in the epicardium or RV endocardium (LV endo -8 ms; LV epi -5 ms; RV endo -4 ms; P < .001). Mental stress depressed the entire electrical restitution curve, with minimal effect on slope. A substantial reduction in minimal ARIs on the restitution curve in LV endo occurred, commensurate with the reduction in ERP (LV endo ARI 195 ± 31 ms at rest to 182 ± 32 ms during mental stress; P < .001). Dispersion of repolarization increased sharply at coupling intervals approaching ERP during stress but not at rest.Conclusion: Mental stress induces significant electrophysiological changes. The increase in dispersion of repolarization at short coupling intervals may be relevant to observed phenomena of arousal-associated arrhythmia. [ABSTRACT FROM AUTHOR]

Background Sudden cardiac death is prevalent in chronic hemodialysis (HD) patients while the dialysis process may have arrhythmogenic potential. We sought to examine the effect of HD on conventional electrocardiographic parameters as well as on novel indexes of repolarization, given that increased spatial dispersion of repolarization is related to ventricular arrhythmias. Methods We recorded clinical, echocardiographic, and laboratory parameters as well as electrocardiographic indexes before and after a single HD session. Specifically, we calculated the QTc interval, the QRS duration, the T peak-to-end (Tpe) interval, and the Tpe/QT ratio. Results The study population consisted of 66 chronic HD patients (mean age: 68.9 ± 11.8 years, 40 males). Heart rate, blood pressure, QRS duration, QTc interval, and QT dispersion did not change significantly after the HD session. However, the Tpe interval and the Tpe/QT ratio increased significantly (80 [65-90] ms vs 85 [77.5-100] ms; P = 0.04, and 0.21 [0.18-0.24] vs 0.25 [0.21-0.28]; P = 0.05, respectively). Correlation analysis and multiple regression analysis failed to show significant associations between the baseline parameters and the baseline values of Tpe and Tpe/QT or between the change of the laboratory parameters during HD and the corresponding change of the Tpe and the Tpe/QT values. No significant arrhythmias were observed during the HD sessions. Conclusions HD induces an increase in novel markers of spatial dispersion of ventricular repolarization. Whether the assessment of these indexes of heterogeneity of repolarization at baseline or their change during HD has a prognostic value with regard to future untoward events, remains to be elucidated. [ABSTRACT FROM AUTHOR]

Abstract: Increased dispersion of action potential duration across cardiac tissue has long been considered an important substrate for the development of most electrical arrhythmias. Although this dispersion has been studied previously by characterizing the static intrinsic gradients in cellular electrophysiology and dynamical gradients generated by fast pacing, few studies have concentrated on dispersions generated solely by structural effects. Here we show how boundaries and geometry can produce spatially dependent changes in action potential duration (APD) in homogeneous and isotropic tissue, where all the cells have the same APD in the absence of diffusion. Electrotonic currents due to coupling within the tissue and at the tissue boundaries can generate dispersion, and the profile of this dispersion can change dramatically depending on tissue size and shape, action potential morphology, tissue dimensionality, and stimulus frequency and location. The dispersion generated by pure geometrical effects can be on the order of tens of milliseconds, enough under certain conditions to produce conduction blocks and initiate reentrant waves. [Copyright &y& Elsevier]

Objectives: We tested the hypothesis that exposure to concentrated ambient particles (CAP) and/or ozone (O3) would increase dispersion of ventricular repolarization. Background: Elevated levels of air pollution are associated with cardiac arrhythmias through mechanisms yet to be elucidated. Methods: Each of 25 volunteers (18 to 50 years of age) had four 2-h exposures to 150 μg/m3 CAP; 120 parts per billion O3; CAP + O3; and filtered air (FA). Exposure-induced changes (Δ = 5-min epochs at end-start) in spatial dispersion of repolarization were determined from continuous 12-lead electrocardiographic recording. Results: Spatial dispersion of repolarization assessed by corrected ΔT-wave peak to T-wave end interval increased significantly for CAP + O3 (0.17 ± 0.03, p < 0.0001) exposure only, remaining significant when factoring FA (CAP + O3 − FA) as control (0.11 ± 0.04, p = 0.013). The influence on repolarization was further verified by a significant increase in ΔQT dispersion (for CAP + O3 compared with FA (5.7 ± 1.4, p = 0.0002). When the low-frequency to high-frequency ratio of heart rate variability (a conventional representation of sympathetic-parasympathetic balances) was included as a covariate, the effect estimate was positive for both corrected ΔT-wave peak to T-wave end interval (p = 0.002) and ΔQT dispersion (p = 0.038). When the high-frequency component (parasympathetic heart rate modulation) was included as a covariate with corrected ΔT-wave peak to T-wave end interval, the effect estimate for high frequency was inverse (p = 0.02). Conclusions: CAP + O3 exposure alters dispersion of ventricular repolarization in part by increasing sympathetic and decreasing parasympathetic heart rate modulation. Detection of changes in repolarization parameters, even in this small cohort of healthy individuals, suggests an underappreciated role for air pollutants in urban arrhythmogenesis. [Copyright &y& Elsevier]

Transseptal Dispersion and TdP. Objective: This study was designed to quantitate transseptal dispersion of repolarization (DR) and delineate its role in arrhythmogenesis using the calcium agonist BayK 8644 to mimic the gain of function of calcium channel current responsible for Timothy syndrome. Background: Amplification of transmural dispersion of repolarization (TDR) has been shown to contribute to development of Torsade de Pointes (TdP) arrhythmias under long-QT conditions. Methods: An arterially perfused septal wedge preparation was developed via cannulation of the septal artery. Action potentials (APs) were recorded using floating microelectrodes together with a transseptal electrocardiogram (ECG). These data were compared to those recorded from arterially perfused canine left ventricular (LV) wedge preparations. Results: Under control conditions, the shortest AP duration measured at 90% repolarization (APD90) was observed in right ventricular (RV) endocardium (181.8 ± 15 ms), APD90 peaked close to midseptum (278.0 ± 32 ms), and abbreviated again as LV endocardium was approached (207.3 ± 9 ms). Transseptal DR averaged 106 ± 24 ms and Tpeak–Tend 84 ± 7 ms (n = 6). TDR and Tpeak–Tend recorded from LV wedge were 36 ± 9 ms and 34 ± 19 ms, respectively (n = 30). BayK 8644 increased transseptal DR to 123.2 ± 35 ms (n = 5) and induced early and delayed afterdepolarizations (3/5), rate-dependent ST-T-wave alternans (5/5), and TdP arrhythmias (3/5). Conclusions: Our data indicate that dispersion of repolarization across the interventricular septum is twice that of the LV free wall, predisposing to development of TdP under long-QT conditions. Our findings suggest that the coronary-perfused ventricular septal preparation may be a sensitive model in which to assess the potential arrhythmogenic effects of drugs and pathophysiological conditions. (J Cardiovasc Electrophysiol, Vol. 21, pp. 441–447, April 2010) [ABSTRACT FROM AUTHOR]

Background: The impact of altered ventricular activation, including biventricular (BV) pacing, on T-wave alternans (TWA) and arrhythmic substrates is unclear. We studied how differing ventricular activation sequence alters TWA; the interval from peak-to-end of the T-wave (TpTe) and T-wave amplitude during right (RV), left (LV), and biventricular (BV) pacing; and right atrial (RA) pacing in patients with preexisting conduction delay. Methods and Results: We measured TWA during RA, RV, LV, and BV pacing in 33 patients receiving cardiac-resynchronization-therapy-defibrillators. TWA magnitude (Valt) was lower during BV than RV (P < 0.01), RA (P < 0.01), or LV pacing. As a result, BV-TWA was more often negative than RV-TWA (P < 0.01), LV-TWA, and RA-TWA, particularly when discordant between pacing modes (P < 0.01). Overall, 83% of TWA recordings were abnormal (25% indeterminate), and 17% negative. BV pacing reduced T-wave amplitude (P < 0.05) and TpTe (P < 0.005) compared to RV pacing and LV pacing (P < 0.05; P < 0.005 respectively). Notably, TWA magnitude varied linearly with T-wave amplitude for all pacing modes (P < 0.001). Over 410 ± 252 days' follow-up, RV-TWA predicted the combined endpoint of death and ICD therapy with 86% negative predictive value (P < 0.05). BV-TWA, RA-TWA, and other repolarization indices were not predictive. Conclusions: BV pacing attenuates TWA in tandem with reduced T-wave magnitude. In these patients with baseline QRS prolongation, RV-TWA predicted events more effectively than BV-TWA and RA-TWA. Further studies are required to understand how altered ventricular activation influences repolarization dynamics and arrhythmic tendency. [ABSTRACT FROM AUTHOR]

Background: QT dispersion (QTd) has evoked a lot of interest in recent years as regards the basic concept of dispersion of repolarization, which it is supposed to reflect on a surface ECG, as being a marker or substrate for arrhythmogenesis. QTd has been shown to be high in patients with ventricular fibrillation and tachycardia. But there is still some debate about its possible role as a marker or substrate for arrhythmogenesis. We studied whether it has any correlation with simple benign ventricular ectopic beats (VEB) after acute myocardial infarction. Study: We studied four different dispersion parameters (QTd, QTcd, JTcd, AQTd) on 2 different days after AMI and also obtained a 24-h ambulatory ECG on the 2nd day after admission in 64 out of a total of 90 patients. Patients were divided into five groups based on VEB frequency/h on a 24-h ambulatory ECG. Results: We found a gradual increase in dispersion parameters across the five groups with increasing frequency of VEB. A significant difference was noticed between group 1 (VEB 0.0–0.9/h) and group V (>30/h) on the day of admission: QTd 88.8±28.5 versus 123.3±23.4, P<0.02; QTcd 100.5±27.6 versus 160.3±30.7, P<0.01; JTcd 95.5±31.0 versus 160.4±30.9, P<0.01; AQTd 29.6±8.2 versus 48.6±13.7, P<0.01. We also noticed a significant positive correlation between VEB frequency and dispersion parameters on both days. Conclusion: We hypothesize that with increasing dispersion of repolarization the chances or the frequency of ventricular arrhythmias increase. Our findings also point to a definite role of QTd as an arrhythmogenic marker or substrate. [Copyright &y& Elsevier]

Introduction: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current IKr is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. Methods and results: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10-5M and 2 × 10-5M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 ± 1 to 48 ± 2 ms at 100 ms basic cycle length (BCL), from 38 ± 2 to 54 ± 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 ± 1 vs. 4 ± 1 ms, APD90max-min: 12 ± 1 vs. 5 ± 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K+ =3.0 mM and in 10 of 12 hearts at K+ = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 ± 3 ms; APD90max-min: 25 ± 3 ms; p < 0.05). Conclusions: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions. [ABSTRACT FROM AUTHOR]

A patient with long QT syndrome and a history of palpitations underwent electrophysiologic study. Runs of polymorphic self-terminating atrial tachyarrhythmias were easily induced and occurred spontaneously several times. Atrial monophasic action potential (MAP) durations were prolonged at shod pacing cycle lengths. Premature high right atrial extra- stimuli prolonged MAP durations in the low right atrium, resulting in an inverse electrical restitution curve, and increased dispersion of repolarization. MAP morphology showed gradually increasing early afterdepolarizations. When the arrhythmia was initiated, a new action potential reproducibly emerged from these afterdepolarizations. To the knowledge of the authors, this is the first reported case of "atrial torsades de pointes" in a patient. [ABSTRACT FROM AUTHOR]

Summary. Several in vitro and in vivo investigations have provided data supporting the existence of M cells in the deep subepicardial layers of the ventricles in a number of species. Characterized by unique electrophysiological and pharmacological features, this population of cells is regarded to have a significant role in creating dispersion of repolarization in the ventricular wall and thus contribute importantly to arrhythmogenesis, in particular to intramural reentry and triggered activity. Focusing on M cells, the authors summarize recent findings and concepts concerning the pharmacological heterogeneity of different cell and tissue types found within the ventricles and explore how these differences may contribute to electrocardiographic manifestations. On the basis of literarary data and of their own results they conclude that studying the electrical and pharmacological inhomogeneity within the ventricular wall may provide a better understanding of the pathophysiological processes that give rise to cardiac rhythm disturbances and the mechanisms by which antiarrhythmic agents act to suppress and in some cases aggravate arrhythmias. [ABSTRACT FROM AUTHOR]

The LQTS is a prime example of bow molecular biology, ion channel, cellular, and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and acquired LQTS are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying cardiac repolarization. In this review, the continually unraveling molecular biology of congenital LQTS is discussed. The various pharmacological agents associated with the acquired LQTS are listed. Although it is difficult to predict which patients are at risk for TdP, careful assessment of the risk-benefit ratio is important before prescribing drugs known to be able to cause QT prolongation. The in vivo electrophysiological mechanism of TdP in the LQTS is described using, as a paradigm, the anthopleurin-A canine model, a surrogate for LQT3. In the LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization. Prolongation of repolarization also acts as a primary step for the generation of EADs. The focal EAD induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant VT, sometimes having the characteristic twisting QHS configuration known as TdP. The review concludes by discussion of the clinical manifestations and current management of both the congenital and acquired LQTS. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug. This therapy seems to be effective in LQT1 and LQT2 patients, but may not be as effective in LQT3 patients. Other therapeutic options include pacemakers, cervicothoracic sympathectomy, and the implantable cardioverter defibrillator. Recent molecular genetic studies have suggested several genotype specific therapies; however, long-term efficacy data are not available. [ABSTRACT FROM AUTHOR]

BACKGROUND: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 µM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. METHODS AND RESULTS: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) from 227.8 +/- 6.3 ms (n = 20) to 262.3 +/- 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 +/- 9.2 (n = 21) to 308.3 +/- 7.1 (n = 19; P <.05). Acute superfusion of 5 µM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 +/- 13.6 ms to 281.9 +/- 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 µM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 µM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 µM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 µM dofetilide + 20 µM BaCl(2) + 2 mM CsCl) in 5 of 6 experiments and caused strong use-dependent V(max) block with relatively fast onset kinetics (rate constant = 1.23 +/- 0.13 AP(-1), n = 5) and offset (time constant = 364 +/- 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 µM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. CONCLUSIONS: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings. [ABSTRACT FROM AUTHOR]

QT dispersion has been adopted as a new index for the noninvasive assessment of the inhomogeneity of repolarization and has been evaluated in several clinical studies as an index of arrhythmia propensity. In most of these studies, indices of dispersion of repolarization were rate corrected by the Bazett formula calculating QT dispersion as QTcmax-QTcmin or JT dispersion as JTcmax-JTcmin, implying that dispersion of repolarization also changes with heart rate. This study aimed to determine in the electrically paced isolated heart whether dispersion of ventricular repolarization is rate dependent. Multiple (5–7) monophasic action potentials (MAPs) were recorded simultaneously from the epicardium and endocardium of both ventricles in 18 isolated Langendorff-perfused rabbit hearts. Hearts were paced from a right ventricular site at basic cycle lengths (CL) between 1,200 and 300 ms in 100-ms decrements. Action potential duration was measured at 90% repolarization (APD90), and recovery time (RT) was defined as the sum of APD90 and activation time in each of the simultaneous MAP recordings. The dispersion of APD90 and RT, respectively, were calculated as the maximal difference among all recordings. APD90 and RT shortened continuously throughout the range of paced steady-state CLs from 1,200 to 300 ms. APD90 was 197.6 ± 6.1 ms at a CL of 1,200 ms and decreased to 148.5 ± 2.5 ms at a CL of 300 ms (P < 0.0001). RT was 228.2 ± 6.2 ms at a CL of 1,000 ms and decreased to 175.9 ± 2.9 at a CL of 300 ms (P < 0.0001). In contrast, dispersion of APD90 and RT did not change significantly. Dispersion of APD90 was 24.8 ± 2.3 ms at a CL of 1,200 ms, 26.1 ± 1.9 msec at a CL of 1,000 ms, and 21.6 ± 2.1 at a CL of 300 ms (NS). Dispersion of RT was 29.7 ± 3.4 ms at a CL of 1,200 ms, 29.0 ± 3.0 ms at a CL of 1,000 ms, and 32.7 ± 3.2 ms at a CL of 300 ms (NS). In contrast to the duration of the QT interval, dispersion of ventricular repolarization does not change significantly with pacing induced changes in CL. Assuming that the rate-dependent behavior of action potential duration is similar between the rabbit and human heart, a rate correction of parameters of dispersion of repolarization is probably unnecessary. [ABSTRACT FROM AUTHOR]

Introduction: The exact electro-physiologic mechanism of torsades de pointes (TdP) is under intense investigation. No isolated animal heart model of this particular arrhythmia exists. Methods and Results: In isolated rabbit hearts. TdP was induced by means of bradycardia in the presence of a high concentration of d-sotalol (1-4 M) and shortly after lowering the concentration of potassium and magnesium in the perfusate. Multiple simultaneous epicardial and endocardial monophasic action potentials (MAPs) and volume-conducted 12-lead ECGs were recorded. d-Sotalol prolonged repolarization and increased dispersion of ventricular repolarization compared to baseline recordings. With the onset of low potassium and magnesium concentrations, repolarization was further prolonged and dispersion of repolarization was further increased followed by the occurrence of early afterdepolarizations (EADs) in the majority of MAP recordings, i.e., at both endocardial and epicardial locations of both ventricles. Upon increase of EAD amplitude, triggered arrhythmias with TdP of up to 42 beats ensued in 10 of 11 hearts studied. MAP duration at 90% repolarization (APD90), dispersion of APD90, and the incidence of EADs as well as dispersion of the QT interval and T wave area were significantly higher in beats triggering bigemini, couplets, or runs of TdP. Conclusion: TdP observed in this new isolated heart model was associated with markedly increased dispersion of ventricular repolarization and the occurrence of EADs in multiple locations of the heart. TdP is initiated when the amplitude of an EAD reaches threshold for initiation of the first beat of an episode. [ABSTRACT FROM AUTHOR]

Introduction: Treatment with Class III antiarrhythmic agents may lead to increased dispersion of repolarization and early afterdepolarizations (EADs), which are both likely substrates for torsades de pointes. Recent studies in vivo have shown that the prevalence of proarrhythmias induced by Class III agents may be reduced by Na+- or Ca2+-blocking agents. In the present study, tentative mechanisms for this protective effect were investigated in vitro. Methods and Results: Transmembrane action potentials were recorded simultaneously from rabbit isolated ventricular muscle (VM) and Purkinje fibers (PF). At a basic cycle length (BCL) of 500 msec, the Class III agent almokalant (0.1 µM) increased the dispersion by prolonging the action potential duration (APDl significantly more in the PF (33% ± 4.2%, n = 18) than in the VM (17% ± 5.9%, n = 18. P < 0.05). In six of the preparations, addition of 1. 5. and 25 µM lidocaine reduced the almokalant-induced prolongation in a concentration-dependent manner mainly in the PF, thereby decreasing the dispersion. At 5 µM lidocaine. the remaining prolongation was 7% ± 12.2% (P < 0.05 vs time controls) in the PF and 14% ± 6.4% in the VM, respectively. In six other preparations, the addition of 0.01, 0.05, and 0.25 µM nisoldipine did not reduce the almokalant-induced prolongation in the PF and VM, but attenuated the spike-and-dome appearance of the action potential in the PF. In separate experiments performed at a BCL of 1000 msec, EADs developed in 2 of 6 and 5 of 6 PF during superfusion with almokalant (0.3 and 1 µM, respectively) at an APD of 828 ± 41.4 msec. In six separate preparations pretreated with lidocaine (5 µM), the almokalant-induced prolongation in the PF was less pronounced and EADs were not observed. Pretreatment with nisoldipine (0.05 µM) did not influence the response to almokalant, and in 4 of 6 preparations the APD exceeded 1000 msec. Despite this extensive prolongation, EADs did not appear. Conclusion: At concentrations that did not affect the APD in the VM but reduced the APD in the PF, lidocaine suppressed almokalant-induced dispersion and the development of EADs. Nisoldipine, on the other hand, inhibited almokalant-induced EADs directly. Hence, the primary APD-prolonging effect of a Class III agent may be preserved, but the risk of proarrhythmias reduced, during concomitant treatment with low concentrations of a Na+- or Ca2+-blocking agent. [ABSTRACT FROM AUTHOR]

Background: Coronary-perfused ventricular wedge preparations have proven valuable in the elucidation of the mechanisms of arrhythmias. This study was undertaken to develop an arterially perfused model of the interventricular (IV) septum.Methods: A canine septal preparation was developed via cannulation of the septal artery. Action potentials were recorded from ventricular endocardial surfaces and locations within the septum using floating microelectrodes; a transseptal electrocardiogram was simultaneously recorded. In some experiments, the calcium agonist BayK 8644 was used to enhance transseptal heterogeneity of action potential (AP) duration.Results: Distinctive electrocardiographic waveforms and dissimilar AP morphologies and durations were observed across the IV septum. The range of AP durations observed exceeded that found in the left ventricular wedge. BayK 8644 further accentuated these differences and induced torsades de pointes arrhythmias.Conclusions: The arterially perfused septal preparation is a sensitive model for the study of arrhythmias that may arise from the IV septum. [ABSTRACT FROM AUTHOR]

Experimental studies have shown that transmural dispersion of repolarization (DoR), defined as the difference in action potential duration between mid-myocardial M-cells, epicardial, and endocardial cells is reflected in the duration of the terminal portion of the T wave (TpTe) on the surface ECG. Since DoR is an important factor associated with the propensity for reentrant arrhythmias, this study examined if TpTe may serve as a marker of risk of ventricular arrhythmias. Data from 18 patients with coronary artery disease and inducible sustained ventricular tachycardia (VT group) were compared with those of 16 survivors of myocardial infarction with out inducible VT (control group). TpTe was automatically measured in each beat of 24-hour ECG recordings, and programmed ventricular stimulation was performed in the antiarrhythmic drug-free state. TpTe was expressed as the absolute interval in milliseconds, and relative to the duration of QTe (TpTe/QTe X 100%). TpTe duration was 74 ± 14 ms in the VT group versus 63 ± 16 ms in the control group (P < 0.004). The TpTe interval expressed as a percent of the QT interval was 21 ± 4% in the VT group versus 17 ± 3% in the control group (P = 0.02). In patients with coronary artery disease, TpTe was longer in patients with, versus without, inducible VT. The results of this study support the hypothesis that TpTe reflects transmural dispersion of repolarization. [ABSTRACT FROM AUTHOR]

Abstract: Unlike other variants of long QT syndrome, LQT3 patients are particularly susceptible to cardiac events during sleep. Changes in heart rate alone fail to fully account for this phenomenon. We hypothesize that the parasympathetic nervous system may play a role in increasing arrhythmic risk in the mammalian ventricular myocardium via acetylcholine (ACh)-mediated effects on repolarisation gradients and, furthermore, that the effects of ACh exhibit rate dependency. Here, we investigate this hypothesis in a mathematical model of action potential generation and excitation-contraction coupling in a canine left ventricular epicardial myocyte, using a previously developed formulation for the muscarinic K+ current I K,ACh. Our model was able to reproduce an experimentally observed dose-dependent reduction in canine epicardial action potential duration90 at 90% repolarization in response to application of ACh. Moreover, our model also predicts a rate-dependent reduction of epicardial APD90 with the greatest effects occurring at slower rates. This is likely to be due to decreased repolarisation reserve at these rates. Our results suggest that ACh-mediated effects on epicardial myocytes may amplify already steep repolarisation gradients in the mammalian left ventricular wall of LQT3 patients and consequently increase the risk of arrhythmia formation. [Copyright &y& Elsevier]