Search

The objective of this simulation was to study the physiological meaning of the novel index for arrhythmic risk stratification – Tpe/QT ratio (the interval from the peak to the end of the T-wave (Tpe) on electrocardiogram divided by QT interval). Methods and Results: The role of two factors determining Tpe/QT ratio – action potential duration (APD) and dispersion of repolarization (DOR) – was studied in silico at two levels: ventricular wall segment and the whole heart ventricles. The simulations performed in the framework of both the segment and the entire ventricles’ models showed that Tpe/QT magnitude reflects the dynamic relationship between the longest and the shortest APD rather than the magnitude of DOR, as interval Tpe does. Tpe/QT ratio remained unchanged even at large DOR, provided that the longer the ventricular APD, the greater the gap between the longest and the shortest of them. The imbalance between the longest and the shortest APD values led to the increased or decreased Tpe/QT. Conclusion: Simulations showed that Tpe/QT is not just a corrected Tpe interval, but it reflects the balance between the longest and the shortest APD in the heart ventricles.

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]

Aims: Differences of action potential duration (APD) in regions of myocardial scar and their borderzones are poorly defined in the intact human heart. Heterogeneities in APD may play an important role in the generation of ventricular tachycardia (VT) by creating regions of functional block. We aimed to investigate the transmural and planar differences of APD in patients admitted for VT ablation.Methods and Results: Six patients (median age 53 years, five male); (median ejection fraction 35%), were studied. Endocardial (Endo) and epicardial (Epi) 3D electroanatomic mapping was performed. A bipolar voltage of <0.5 mV was defined as dense scar, 0.5-1.5 mV as scar borderzone, and >1.5 mV as normal. Decapolar catheters were positioned transmurally across the scar borderzone to assess differences of APD and repolarization time (RT) during restitution pacing from Endo and Epi. Epi APD was 173 ms in normal tissue vs. 187 ms at scar borderzone and 210 ms in dense scar (P < 0.001). Endocardial APD was 210 ms in normal tissue vs. 222 ms in the scar borderzone and 238 ms in dense scar (P < 0.01). This resulted in significant transmural RT dispersion (ΔRT 22 ms across dense transmural scar vs. 5 ms in normal transmural tissue, P < 0.001), dependent on the scar characteristics in the Endo and Epi, and the pacing site.Conclusion: Areas of myocardial scar have prolonged APD compared with normal tissue. Heterogeneity of regional transmural and planar APD result in localized dispersion of repolarization, which may play an important role in initiating VT. [ABSTRACT FROM AUTHOR]

The rate of repolarization (RRepol) and so the duration of the cardiac action potential are determined by the balance of inward and outward currents across the cardiac membrane (net ionic current). Plotting action potential duration (APD) as a function of the RRepol reveals an inverse non-linear relationship, arising from the geometric association between these two factors. From the RRepol-APD relationship, it can be observed that a longer action potential will exhibit a greater propensity to shorten, or prolong, for a given change in the RRepol (i.e. net ionic current), when compared with one that is initially shorter. This observation has recently been used to explain why so many interventions that prolong the action potential exert a greater effect at slow rates (reverse rate-dependence). In this article, we will discuss the broader implications of this simple principle and examine how common experimental observations on the electrical behaviour of the myocardium may be explained in terms of the RRepol-APD relationship. An argument is made, with supporting published evidence, that the non-linear relationship between the RRepol and APD is a fundamental, and largely overlooked, property of the myocardium. The RRepol-APD relationship appears to explain why interventions and disease with seemingly disparate mechanisms of action have similar electrophysiological consequences. Furthermore, the RRepol-APD relationship predicts that prolongation of the action potential, by slowing repolarization, will promote conditions of dynamic electrical instability, exacerbating several electrophysiological phenomena associated with arrhythmogenesis, namely, the rate dependence of dispersion of repolarization, APD restitution, and electrical alternans. [ABSTRACT FROM AUTHOR]

Background The QT interval, an index of ventricular repolarization, is rate dependent. Exaggerated rate dependence of repolarization is arrhythmogenic. Whether there are differences in rate-dependent repolarization among different heart chambers is unknown. Objective The purpose of this study was to test our hypothesis that heterogeneous distribution in late sodium current (I Na-L ) is responsible for interregional differences in rate adaptation of repolarization. Methods Action potential duration (APD), QT intervals, and their rate adaptation were studied in isolated arterially perfused ventricular and atrial wedge preparations. APD and I Na-L were recorded in isolated rabbit myocytes using the microelectrode and the whole-cell patch clamp technique, respectively. Results There were distinct interregional differences in repolarization and its rate adaptations among different cardiac chambers: the left ventricle exhibited the longest QT and APD with the greatest rate dependence, followed by the right ventricle, whereas the atria had the shortest APD without significant rate dependence. Interestingly, I Na-L densities distributed heterogeneously and matched to interregional APDs and rate dependences as follows: left ventricle > right ventricle > left/right atria. Both dofetilide (an I Kr blocker) and anemone toxin (a specific I Na-L enhancer) amplified QT/APD rate adaptation preferentially in the left ventricle and therefore exacerbated interregional dispersion of repolarization. On the other hand, the atria exhibited blunted responses to both QT-prolonging agents. Mexiletine with an I Na-L blockade effect blunted QT/APD rate adaptation preferentially in the ventricles and significantly reduced bradycardia-dependent interregional dispersion of repolarization. Conclusion Our results demonstrate that heterogeneous distribution of I Na-L contributes importantly to the interregional heterogeneity of repolarization in response to rate changes and APD/QT-prolonging agents. [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]

Action potential duration is widely used as a measure of refractory period in ischemia. Although the end of repolarization closely corresponds to the end of refractoriness in the well-perfused, well-oxygenated myocardium, it is no longer true for the ischemic myocardium, in which the recovery of excitability lags behind full repolarization. The purpose the study was to review this phenomenon of postrepolarization refractoriness during ischemia and after application of various antiarrhythmic drugs. The findings showed that although postrepolarization refractoriness is profoundly proarrhythmic during ischemia, it may protect the heart from reentrant arrhythmias in the absence of depolarization of the resting membrane. An increase in postrepolarization refractoriness induced by sodium-channel–blocking drugs may exert an antifibrillatory action. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated electrocardiogram estimates of repolarization times (RTs) and action potential durations (APD) separately for initial and terminal repolarization periods in a reference group of 5376 healthy men and women and in 125 acute coronary syndrome patients with and 657 without diagnostic ST elevation (ST-elevation myocardial infarction [STEMI] and non-STEMI [NSTEMI], respectively). Two key covariates in the model are the rate-adjusted QT peak interval (QTpa), assigned to earliest epicardial RT (RTepi), and (Tp-Txd), the rate-invariant interval from Tp to the inflection point (Txd) at T wave downstroke. (Tp-Txd) defines the crossmural RT gradient (XMRTgrad). Transmural RTgrad (TMRTgrad) is obtained as CosΘ(Rmax|Tmax)*XMRTgrad, where Θ is the spatial angle between the maximal QRS and T vectors. Derived endocardial variables are the XMRTendo, equal to QTpa + XMRTgrad and TMRTendo, equal to QTpa + TMRTgrad. Noting that excitation time (ET) and RT define APD, APDepi = RTepi - QRp in V6 and TMAPDendo = TMRTendo - 10 milliseconds. Compared to the reference group, the estimates for APDepi and TMAPDendo were shortened in STEMI by 20 and 31 milliseconds, respectively, (p <0.001 for both) signifying transmural ischemia. In contrast, in NSTEMI, TMAPDendo was shortened by 28 milliseconds (P <0.001) with a lesser, 5 millisecond shortening of APDepi, signifying subendocardial ischemia. QT was prolonged by 6 milliseconds in STEMI (P <0.05) and by 8 milliseconds in NSTEMI (P <0.001). Prolonged QT with shortened APDepi suggests that prolonged repolarization in terminal possibly non-ischemic regions accounts for QT prolongation in both myocardial infarction groups. These substantial differences in ischemia-induced regional manifestations of repolarization abnormalities revealed by the repolarization model were not evident from evaluation of the global QT. [Copyright &y& Elsevier]

Abstract: Action potential duration (APD) changes increasing repolarization time (RT) dispersion are potentially arrhythmogenic. A repolarization model developed from electrocardiographic data of 5376 healthy men and women was used to derive parameter estimates for APD and RT and their transmural gradients (RTgrad and APDgrad, respectively) in myocardial infarction patients, 126 with and 658 without diagnostic ST elevation (STEMI and NSTEMI, respectively). The model uses, as covariates, rate-adjusted QT and QT peak intervals (QTa and QTpa, respectively) and diagonal crossmural RTgrad derived as Tp-Txd, the interval from Tp to the inflection point at descending limb of global T wave. An additional parameter is Θ(T|Tref), the spatial angle between a subject''s T vector and the average T vector of the normal reference group. If Θ(T|Tref) >0, QTpa is assigned to RTepi and QTpa + RTgrad to RTendo, with RTepi and RTendo assignments reversed if Θ(T|Tref) ≤0. Parameter estimates for APDepi and APDendo were shorter in men than in women (by 17 ms and 14 ms, respectively, P < .001 for both). Compared to the reference group, RTepi in the STEMI group was shortened by 14 ms in men and by 18 ms in women (P < .001 for both) with a lesser decrease in RTendo suggesting predominantly subepicardial ischemia. In NSTEMI only RTendo was shortened, by 6 ms in males (P < .01) and 10 ms in females (P < .001), suggesting subendocardial ischemia. RTgrad signifying local crossmural RT dispersion was prolonged in STEMI by 8 ms in men and by 11 ms in men (P < .001 for both). RTgrad was not changed significantly in NSTEMI. Rate-adjusted Tp-Te interval signifying global RT dispersion was increased in both MI and in both sex groups (P <.001 for all). In conclusion, QT prolongation observed in NSTEMI without prolongation of RTgrad and APDepi suggests a delay during terminal repolarization, and in contrast, in STEMI, QT is not changed significantly in spite of prolonged RTgrad because of shortened APDepi and RTepi. These repolarization abnormalities are not revealed by QT alone but readily by the repolarization model. [Copyright &y& Elsevier]

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]

Introduction: Increased dispersion of ventricular repolarization is observed in cardiac hypertrophy and is associated with sudden cardiac death. At present, there is little information about the effects of cardiac hemodynamics and antiarrhythmic drugs on dispersion of repolarization in disease states. We compared the effects of increasing afterload and the Class III antiarrhythmic drug, dofetilide, on dispersion of ventricular repolarization in hypertrophied rabbit hearts to normal rabbit hearts. Methods and Results: Cardiac hypertrophy was induced in rabbits by abdominal aortic banding. Isolated hearts were studied 49 ± 4 days postsurgery in the working heart mode using a bloodbuffer perfusate. The action potential duration (PD) was measured from eight sites on the epicardium of the heart at low (50 ± 7 mmHg) afterload and high afterload (97 ± 12 mmHg) at baseline and during dofetilide perfusion. APD dispersion, determined as the difference between the maximal and minimal APD, was greater in hypertrophied hearts (42 ± 8 msec) compared with control hearts (26 ± 8 msec, P < 0.05) at baseline and low afterload. Increasing afterload caused a decrease in APD dispersion in hypertrophied hearts (P < 0.05) but not in control hearts, and APD dispersion was similar in hypertrophied hearts (31 ± 9 msec) compared with control hearts (30 ± 9 msec, P = NS). During dofetilide perfusion, APD dispersion remained greater in hypertrophied hearts (60 ± 39 msec) compared with control hearts (30 ± 13 msec, P < 0.05) at low afterload but not high afterload. Increasing afterload caused shortening of the APD in most regions of the control hearts, whereas APD did not shorten significantly in hypertrophied hearts at baseline and tended to increase during dofetilide perfusion. During dofetilide perfusion, the maximal change in APD recorded from the posterior wall of the left ventricle following an increase in afterload was -18 ± 21 msec in control hearts and 7 ± 21 ms in hypertrophied hearts (P < 0.05). Conclusion: Epicardial APD dispersion decreases in hypertrophied hearts following an increase in afterload, and this response is mediated in part by the absence of afterload-induced shortening of the APD. This effect may be due in part to altered responses of the delayed rectifying current to cardiac loading conditions in the setting of cardiac hypertrophy. [ABSTRACT FROM AUTHOR]