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A noninvasive tool for cardiovascular risk stratification has not yet been established in the clinical routine analysis. Previous studies suggest a prolonged Tpeak-Tend interval (the interval from the peak to the end of the T-wave) to be predictive of death. This meta-analysis was designed to systematically evaluate the association of the Tpeak-Tend interval with mortality outcomes. Medline (via PubMed), Embase and the Cochrane Library were searched from 1 January 2008 to 21 July 2020 for articles reporting the ascertainment of the Tpeak-Tend interval and observation of all-cause-mortality. The search yielded 1920 citations, of which 133 full-texts were retrieved and 29 observational studies involving 23,114 patients met the final criteria. All-cause deaths had longer Tpeak-Tend intervals compared to survivors by a standardized mean difference of 0.41 (95% CI 0.23–0.58) and patients with a long Tpeak-Tend interval had a higher risk of all-cause death compared to patients with a short Tpeak-Tend interval by an overall odds ratio of 2.33 (95% CI 1.57–3.45). Heart rate correction, electrocardiographic (ECG) measurement methods and the selection of ECG leads were major sources of heterogeneity. Subgroup analyses revealed that heart rate correction did not affect the association of the Tpeak-Tend interval with mortality outcomes, whereas this finding was not evident in all measurement methods. The Tpeak-Tend interval was found to be significantly associated with all-cause mortality. Further studies are warranted to confirm the prognostic value of the Tpeak-Tend interval. [ABSTRACT FROM AUTHOR]

Moderate hypothermia has been used to improve outcomes in comatose out‐of‐hospital cardiac arrest survivors during the past two decades, although the effects remain controversial. We have recently shown in an experimental study that myocardial electrophysiological and mechanical relationships were altered during moderate hypothermia. Electromechanical window positivity increased, and electrical dispersion of repolarization decreased, both of which are changes associated with decreased arrhythmogenicity in clinical conditions. Mechanical dispersion, a parameter also linked to arrhythmic risk, remained unaltered. Whether corresponding electrophysiological and mechanical changes occur in humans during moderate hypothermia, has not been previously explored. Twenty patients with normal left ventricular function were included. Measurements were obtained at 36 and 32°C prior to ascending aortic repair while on partial cardiopulmonary bypass and at 36°C after repair. Registrations were performed in the presence of both spontaneous and comparable paced heart rate during standardized loading conditions. The following electrical and mechanical parameters were explored: (1) Electromechanical window, measured as time difference between mechanical and electrical systole, (2) dispersion of repolarization from ECG T‐wave, and (3) mechanical dispersion, measured as segmental variation in time to peak echocardiographic strain. At moderate hypothermia, mechanical systolic prolongation (425 ± 43–588 ± 67 ms, p < 0.001) exceeded electrical systolic prolongation (397 ± 49–497 ± 79 ms, p < 0.001), whereby, electromechanical window positivity increased (29 ± 30–86 ± 50 ms, p < 0.001). Dispersion of repolarization and mechanical dispersion remained unchanged. Corresponding electrophysiological and mechanical relationships were present at comparable paced heart rates. After rewarming, the increased electromechanical window was reversed in the presence of both spontaneous and paced heart rates. Moderate hypothermia increased electromechanical window positivity, while dispersion of repolarization and mechanical dispersion remained unchanged. This impact of hypothermia may be clinically relevant for selected groups of patients after cardiac arrest. [ABSTRACT FROM AUTHOR]

The effect of preventive administration of melatonin on the arrhythmogenic substrate in the myocardium was studied in the rabbit model of acute ischemia/reperfusion in vivo. The animals treated with melatonin 60 min before ischemia induction had shorter median activation time compared to the control group (p=0.039), less pronounced shortening of repolarization durations in the ischemic zone during coronary occlusion (p=0.008), and more complete recovery of repolarization during reperfusion (p=0.027). In the melatonin group, the dispersion of repolarization was less than in the control group during both ischemic period (p=0.043) and reperfusion (p=0.038). Thus, preventive administration of melatonin mitigated the arrhythmogenic substrate in the heart under conditions of ischemia/reperfusion. [ABSTRACT FROM AUTHOR]

Key points: T‐wave alternans (TWA) and T‐wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre‐existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re‐entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. Abstract: T‐wave alternans (TWA) and irregular beat‐to‐beat T‐wave variability or T‐wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization‐mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre‐existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L, resulted in a tissue‐scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re‐entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate‐induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions. [ABSTRACT FROM AUTHOR]

Abstract: Aims: A significant antiarrhythmic potential of ryanodine receptor inhibition was reported in experimental studies. The aim of the present study was to assess potential antiarrhythmic effects of dantrolene in an experimental whole‐heart model of drug‐induced long‐QT syndrome (LQTS). Methods: In 12 isolated rabbit hearts, long‐QT‐2‐syndrome was simulated by infusion of erythromycin (300 μM). Twelve rabbit hearts were treated with veratridine (0.5 μM) to mimic long‐QT‐3‐syndrome. Results: Monophasic action potentials and ECG showed a significant prolongation of QT‐interval (+71 ms, P < 0.01) and action potential duration (APD, +43 ms, P < 0.01) after infusion of erythromycin as compared with baseline. Similar results were obtained in veratridine‐treated hearts (QT‐interval: +43 ms, P < 0.01; APD: +36 ms, P < 0.01). Both erythromycin (+36 ms, P < 0.05) and veratridine (+38 ms) significantly increased dispersion of repolarization. Additional infusion of dantrolene (20 μM) did not significantly alter QT‐interval and APD but resulted in a significant reduction of dispersion of repolarization (erythromycin group: –33 ms, P < 0.05; veratridine group: –29 ms, P < 0.05). Lowering of potassium concentration resulted in the occurrence of early afterdepolarizations (EAD) and polymorphic ventricular tachycardia (VT) in 9 of 12 erythromycin‐treated hearts (175 episodes) and 8 of 12 veratridine‐treated hearts (66 episodes). Additional infusion of dantrolene significantly reduced occurrence of polymorphic VT and resulted in occurrence of EAD and polymorphic VT in 1 of 12 erythromycin‐treated hearts (18 episodes) and 1 of 12 veratridine‐treated hearts (3 episodes). Conclusion: Inhibition of the ryanodine receptor by dantrolene significantly reduced occurrence of polymorphic VT in drug‐induced LQTS. A significant reduction of spatial dispersion of repolarization represents a major antiarrhythmic mechanism. These results imply that dantrolene may represent a promising antiarrhythmic option in drug‐induced LQTS. [ABSTRACT FROM AUTHOR]

Background The polyphenol resveratrol and its metabolite piceatannol have beneficial health effects including antiarrhythmic properties in ischemia/reperfusion. The objective of this study was to determine potential antiarrhythmic effects in acquired long-QT-syndrome (LQTS). Methods and results 26 rabbit hearts were isolated and Langendorff-perfused. The I Kr -blocker sotalol (100 μM) was infused to mimic LQTS-2. Hearts were assigned to two groups. Sotalol significantly prolonged action potential duration (APD 90 ) and QT-interval in both groups (group 1:APD 90 : + 18 ms, p < 0.01;QT: + 59 ms, p < 0.01; group 2: APD 90 : + 22 ms, p < 0.01; QT: + 30 ms, p < 0.01) and also significantly increased dispersion of repolarization (group 1: + 21 ms, p < 0.01; group 2: + 23 ms, p < 0.01). Thereafter, hearts were additionally perfused either with resveratrol (50 μM, group 1, n = 14) or with piceatannol (10 μM, group 2, n = 12). Administration of resveratrol significantly reduced APD 90 (− 29 ms, p < 0.01), QT-interval(− 60 ms, p < 0.01) and dispersion of repolarization (− 26 ms, p < 0.01). In contrast, piceatannol did not significantly alter APD 90 (± 0 ms) but shortened QT-interval (− 19 ms, p < 0.01) and increased dispersion of repolarization (+ 15 ms, p < 0.01). With sotalol, 7 of 14 bradycardic, AV-blocked hearts in group 1 and 8 of 12 in group 2 showed early afterdepolarizations (EAD) after lowering potassium concentration (p < 0.01each). Polymorphic ventricular tachycardia (PVT) occurred in 5 of 14 (p < 0.05) and 4 of 12 hearts (p = 0.09) with a total number of 42 (p < 0.05) and 44 episodes (p = 0.07), respectively. Additional infusion of resveratrol reduced EAD (2 of 14, p = 0.11) and PVT (1 of 14 hearts, p = 0.16, 3 episodes, p < 0.05). Piceatannol did not suppress EAD or TdP (EAD in 9 of 12 and TdP in 7 of 12 hearts,50 episodes). Conclusion Resveratrol showed beneficial antiarrhythmic properties in acquired LQTS. Underlying mechanism is a substantial decrease dispersion of repolarization leading to a suppression of triggered activity. [ABSTRACT FROM AUTHOR]

In several case reports proarrhythmic effects of citalopram and escitalopram have been reported. Systematic analyses on prorarrhythmic effects of these drugs are not yet available. The aim of the present study was to investigate if application of citalopram, escitalopram or haloperidol provokes polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In isolated rabbit hearts monophasic action potentials and ECG showed a significant QT-prolongation after application of citalopram (2 µM: +47 ms, 4 µM: +56ms, P<0.05) accompanied by an increase of action potential duration (APD) but not dispersion of repolarization. Reduced potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EAD) in 2 of 12 hearts but no polymorphic ventricular tachycardia (pVT). Application of escitalopram also increased QT-interval (2 µM: +3 ms, 4 µM: +30 ms, P<0.05) and APD without effects on dispersion. 3 of 10 hearts showed EAD and pVT in 2 of 10 hearts (32 episodes). The results were compared to 12 rabbits treated with haloperidol which led to an increase in QT-interval (1 µM:+62 ms; 2 µM:+96ms; P<0.01), APD and dispersion (1 µM:+15 ms, 2 µM:+40 ms; P<0.01) and induced EAD in all 12 and pVT in 10 of 12 hearts (152 episodes). Citalopram and escitalopram demonstrated a rather safe electrophysiologic profile despite significant QT prolongation. In contrast, haloperidol led to significant increase of dispersion of repolarization while this parameter remained stable under the influence of citalopram or escitalopram. These results imply that application of citalopram or escitalopram is not as proarrhythmic as some case reports might suggest while haloperidol is torsadogenic. [ABSTRACT FROM AUTHOR]

The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RVendo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1-S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site (30-ms difference during RVendo pacing, 25-ms during LVendo, and 48-ms during LVepi; 50th quantile, P < 0.01). Basal LVepi pacing resulted in a significant transmural gradient of RT (77 ms, 50th quantile: P < 0.01), due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling (mean slope -1.36 ± 1.9 and -0.71 ± 0.4, respectively). Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic. [ABSTRACT FROM AUTHOR]

In several case reports a prolongation of the QT-interval and even proarrhythmic effects of fluconazole and voriconazole were reported. The aim of the present study was to investigate if application of fluconazole or voriconazole has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In female rabbits, fluconazole (10, 30 and 50 µM, n=6) and voriconazole (10, 30 and 50 µM, n=6) were 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 fluconazole as compared with baseline (10 µM:+12 ms, 30 µM:+22 ms, 50 µM:+37 ms; P<0.05) accompanied by an increase of action potential duration (APD 90 ). Administration of voriconazole also induced QT prolongation (30 µM:+10 ms, 50 µM:+20 ms, P<0.05). Spatial dispersion of repolarization remained stable in voriconazole-treated hearts while fluconazole induced a significant increase (30 µM:+15 ms, 50 µM:+16 ms; P<0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts did not provoke any early afterdepolarizations (EADs) or polymorphic ventricular tachycardia in voriconazole-treated hearts. Application of fluconazole led to the reproducible induction of EADs in 4 of 6 hearts and polymorphic ventricular tachycardia in 3 of 6 hearts (36 episodes). In the present study, voriconazole demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, fluconazole led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization. These results imply that application of fluconazole might be torsadogenic and the QT-interval should be closely monitored. [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]

Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ~6.3 × 6.3 cm2 field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 ± 44 vs. 448 ± 39 ms, at BCL = 2,000 ms, P < 0.05). Dispersion of APD was increased in three failing hearts (161 ± 5 vs. 86 ± 19 ms, at BCL < 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 ± 11 vs. 98 ± 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF. [ABSTRACT FROM AUTHOR]

The article presents a study to test the hypothesis that mild hypothermia induced prior to myocardial ischemia and reperfusion will have a beneficial effect on ischemia-related arrhythmia substrates. A canine model of global myocardial ischemia and reperfusion was developed in order to investigate the transmural electrophysiologic effects of ischemia at different temperatures. Findings suggest that therapeutic hypothermia may decrease arrhythmogenesis during myocardial ischemia.

G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10 μg/kg G-CSF s.c. over 17 ± 4 days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33 ± 12 ms; p < 0.01). Moreover, a significant increase in dispersion of repolarization contributed to a significantly higher rate of ventricular tachyarrhythmias in CHF. G-CSF-pre-treated hearts showed a further increase in prolongation of repolarization as compared with S and CHF. The further increase in dispersion of repolarization [S-G-CSF: +23 ± 9 ms (spatial), +13 ± 7 ms (temporal); CHF-G-CSF: +38 ± 14 ms (spatial), +10 ± 4 ms (temporal); p < 0.05 as compared with S and CHF], increased the incidence of ventricular tachyarrhythmias. In summary, chronic G-CSF treatment has moderate beneficial effects on parameters potentially related to hemodynamic function in the non-ischemic rabbit CHF model. However, a significant reduction of repolarization reserve might seriously challenge its suitability as a therapeutic agent for chronic CHF therapy. [ABSTRACT FROM AUTHOR]

Aims Life-threatening arrhythmias are a major problem in chronic heart failure (CHF). The aim of the present study was to investigate the mechanism underlying the low proarrhythmic potential of amiodarone in a model of pacing-induced heart failure. Methods and results Heart failure was induced in 35 female rabbits by rapid ventricular pacing, resulting in a significant decrease of ejection fraction. Thirty-four rabbits were sham-operated. In 17 of 35 CHF-rabbits and 20 of 34 ‘sham’-rabbits, amiodarone (50 mg/kg/day) was fed for 6 weeks. Eight monophasic action potentials and a simultaneously recorded 12-lead electrocardiogram showed prolongation of QT-interval and action potential duration (APD90) in all failing hearts (P< 0.05). Amiodarone pre-treatment led to a prolongation of APD90 (+19 ms) as compared with sham-controlled hearts but showed only a marginal effect on APD90 in failing hearts. Infusion of sotalol (50–100 µM) led to a significant prolongation of APD90 in sham and a further prolongation of APD90 in failing hearts [+55 ms (50 µM); +70 ms (100 µM); P< 0.01 as compared with sham hearts]. Sotalol led to a triangular action potential configuration in sham and failing hearts, whereas amiodarone did not cause triangularization but caused a rapid phase-III repolarization. Moreover, amiodarone did not increase dispersion of repolarization either in sham or in failing hearts. Infusion of sotalol led to a significant increase in dispersion of repolarization in sham (+29 ms) and a further increase in failing hearts (+67 ms; P< 0.05). Conclusion Chronic amiodarone results in a rapid phase-III-repolarization and does not increase dispersion of repolarization. These electrophysiological findings are present in healthy hearts and are preserved in heart failure. This contributes to the low proarrhythmic potential of amiodarone in heart failure. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronization therapy (CRT) may be proarrhythmic in some patients. This may be due to the effect of left ventricular (LV) epicardial pacing on ventricular repolarization. The purpose of this study was to evaluate the effect of endocardial versus epicardial LV biventricular pacing on surface electrocardiogram (ECG) parameters that are known markers of arrhythmogenic repolarization. Methods: ECG markers of repolarization (QT dispersion, QTD; T peak to end, Tpeak-end; Tpeak-end dispersion, Tpeak-endD; QTc) were retrospectively measured before and after CRT in seven patients with transseptal LV endocardial leads (TS group), 28 matched patients with coronary sinus (CS) LV leads (CS group), and eight patients with surgical LV epicardial leads (SUR group). All ECGs were scanned and analyzed using digital callipers. Results: Compared to the CS group, the TS group CRT was associated with a significant postpacing reduction in QTD (−45.2 ± 35.6 vs −4.3 ± 43.6 ms, P = 0.03) and Tpeak-end (−24.2 ± 22.1 vs 3.4 ± 26.7 ms, P = 0.02). There was a nonsignificant post-CRT reduction in both Tpeak-endD (−11.3 ± 31.0 vs 2.4 ± 28.9 ms, P = 0.27) and QTc (−50.0 ± 46.4 vs 4.4 ± 70.2 ms, P = 0.06) in the TS versus the CS group. In contrast, there were no differences between the SUR and CS groups in terms of the effect of CRT on these repolarization parameters. Conclusions: CRT with (atrial transseptal) endocardial LV lead placement is associated with repolarization characteristics that are considered to be less arrhythmogenic than those generated by CS (epicardial) LV lead placement. Further work is needed to determine whether these changes translate to a reduction in proarrhythmia. (PACE 2011; 34:1258-1266) [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]

Aim: Hypokalaemia is an independent risk factor contributing to arrhythmic death in cardiac patients. In the present study, we explored the mechanisms of hypokalaemia-induced tachyarrhythmias by measuring ventricular refractoriness, spatial repolarization gradients, and ventricular conduction time in isolated, perfused guinea-pig heart preparations. Methods: Epicardial and endocardial monophasic action potentials from distinct left ventricular (LV) and right ventricular (RV) recording sites were monitored simultaneously with volume-conducted electrocardiogram (ECG) during steady-state pacing and following a premature extrastimulus application at progressively reducing coupling stimulation intervals in normokalaemic and hypokalaemic conditions. Results: Hypokalaemic perfusion (2.5 mm K+ for 30 min) markedly increased the inducibility of tachyarrhythmias by programmed ventricular stimulation and rapid pacing, prolonged ventricular repolarization and shortened LV epicardial and endocardial effective refractory periods, thereby increasing the critical interval for LV re-excitation. Hypokalaemia increased the RV-to-LV transepicardial repolarization gradients but had no effect on transmural dispersion of APD90 and refractoriness across the LV wall. As determined by local activation time recordings, the LV-to-RV transepicardial conduction and the LV transmural (epicardial-to-endocardial) conduction were slowed in hypokalaemic heart preparations. This change was attributed to depressed diastolic excitability as evidenced by increased ventricular pacing thresholds. Conclusion: These findings suggest that hypokalaemia-induced arrhythmogenicity is attributed to shortened LV refractoriness, increased critical intervals for LV re-excitation, amplified RV-to-LV transepicardial repolarization gradients and slowed ventricular conduction in the guinea-pig heart. [ABSTRACT FROM AUTHOR]

Background and purpose:The slow delayed rectifier K+ current (IKs) contributes to ventricular repolarization when the action potential (AP) is prolonged. IKs block during drug-induced AP prolongation may promote Torsades de Pointes (TdP), but whether this is due to additional AP prolongation is uncertain.Experimental approach:In bradycardic perfused rabbit ventricles, the incidence of spontaneous TdP, monophasic AP duration at 90% repolarization (MAPD90) and ECG interval between the peak and the end of T wave (Tpeak−end) (index of dispersion of repolarization) were measured after the administration of veratridine (125 nM, slows Na+ channel inactivation), dofetilide (7.5 or 10 nM, a rapid delayed rectifier blocker) and HMR 1556 (HMR, 100 nM, an IKs blocker), alone or in combinations (n=6 each).Key results:HMR did not prolong MAPD90, whereas veratridine or 7.5 nM dofetilide prolonged MAPD90 (P<0.01) without inducing TdP. Veratridine+7.5 nM dofetilide additively prolonged MAPD90 (P<0.05), induced 4±6 TdP per heart and prolonged Tpeak−end by 12±10 ms. Subsequent addition of HMR did not further prolonged MAPD90, but increased the number of TdP to 22±18 per heart and increased Tpeak−end by 39±21 ms (P<0.05). Increasing dofetilide concentration from 7.5 to 10 nM (added to veratridine) produced a longer MAPD90, but fewer TdP (5±5 per heart) and less Tpeak−end prolongation (17±8 ms) compared to the veratridine+7.5 nM dofetilide+HMR group (P<0.05).Conclusions and implications:Adding IKs block markedly increases TdP incidence in hearts predisposed to TdP development by increasing the dispersion of repolarization, but without additional AP prolongation.British Journal of Pharmacology (2008) 155, 1185–1194; doi:10.1038/bjp.2008.354; published online 6 October 2008 [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: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. Methods and Results: Pinacidil, an IK-ATP channel opener, was administered in increasing concentrations (50–100 μM) in 48 Langendorff-perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the IKr blocker sotalol (100 μM) and the class I antiarrhythmic drugs flecainide (2 μM) and quinidine (0.5 μM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. Conclusion: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization. [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]

Effects of cardiac mechanical heterogeneity on the electrical function of the heart are difficult to assess experimentally, yet they pose a serious (patho-)physiological challenge. Here, we present an in silico study of the effects of mechanical heterogeneity on action potential duration (APD) in mechanically interacting muscle regions and consequent effects on the dispersion of repolarization, a well-established determinant of cardiac arrhythmogenesis. Using a novel mathematical description of ventricular electromechanical activity (virtual muscle), we first assessed how differences in intrinsic contractile properties affect the electrical behavior of cardiac muscle representations. In spite of identical electrophysiological model descriptions in virtual muscle samples, faster muscle models show shorter APD than their slower counterparts. This is a consequence of Ca[sup 2+]-mediated feedback from mechanical to electrical activity in the individual muscle models. This mechano-electric feedback (MEF) is, of course, significantly more complex in native cardiac tissue, as the heterogeneous muscle elements interact both mechanically and electrically. Cardiac mechanical heterogeneity, in its most reduced form, can be represented by a duplex consisting of two mechanically interacting muscle segments. Our in silico model of heterogeneous myocardium therefore consists of two individual virtual muscles that are mechanically interconnected in-series to form a virtual heterogeneous duplex. During isometric contraction of the duplex (i.e. at constant external length), internal mechanical interactions affect Ca[sup 2+] handling and APD of muscle elements, resulting in an increased dispersion of repolarization beyond the intrinsic APD differences. Duplex electromechanical activity is strongly affected by the activation sequence of its elements. Late activation of the faster (subepicardial type) duplex element, postponed by time-lags that correspond to normal transmural activation delays, optimizes duplex contractility and smoothes out intrinsic APD differences, thereby reducing dispersion in repolarization. This smoothing effect is not observed upon delayed activation of the slower (subendocardial type) duplex element. In both settings, changes in repolarization timing follow a nonlinear dependence of APD on activation delay. Furthermore, asynchronous activation of identical elements in a homogeneous duplex causes an impairment of contractile function and increases dispersion of repolarization. This suggests that the normal electrical activation sequence in the heart requires matching mechanical and electrical heterogeneity for optimal cardiac performance. On the subcellular level, our results suggest that mechanical modulation of Ca[sup 2+] handling is a key mechanism of MEF in heterogeneous myocardium, which contributes to the matching of local mechanical and/or electrical activity to global hemodynamic demand. [ABSTRACT FROM AUTHOR]