Ventricular repolarization: an overview of (patho)physiology, sympathetic effects and genetic aspects

Most textbook knowledge on ventricular repolarization is based on animal data rather than on data from the in vivo human heart. Yet, these data have been extrapolated to the human heart, often without an appropriate caveat. Here, we review multiple aspects of repolarization, from basic membrane currents to cellular aspects including extrinsic factors such as the effects of the sympathetic nervous system. We critically discuss some mechanistic aspects of the genesis of the T-wave of the ECG in the human heart.

Obviously, the T-wave results from the summation of repolarization all over the heart. The T-wave in a local electrogram ideally reflects local repolarization. The repolarization moment is composed of the moment of local activation plus local action potential duration (APD) at 90% repolarization (APD₉₀). The duration of the latter largely depends on the balance between L-type Ca²⁺ current and the delayed rectifier currents. Generally speaking, there is an inverse relationship between local activation time and local APD₉₀, leading to less dispersion in repolarization moments than in activation moments or in APD₉₀. In transmural direction, the time needed for activation from endocardium toward epicardium has been considered to be overcompensated by shorter APD₉₀ at the epicardium, leading to the earliest repolarization at the subepicardium. In addition, mid-myocardial cells would display the latest repolarization moments. The sparse human data available, however, do not show any transmural dispersion in repolarization moment. Also, the effect of adrenergic stimulation on APD₉₀ has been studied mainly in animals. Again, sparse human data suggest that the effect of adrenergic stimulation is different in the human heart compared to many other mammalian hearts. Finally, aspects of the long QT syndrome are discussed, because this intrinsic genetic disease results from repolarization disorders with extrinsic aspects.     

Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome

The gain-of-function Scn5a+/ΔKPQ mutation in the cardiac Na⁺ channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K_ATP channel-opener nicorandil (20 μM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Δ hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD₉₀) that (2) restored transmural repolarization gradients, ΔAPD₉₀. Scn5a+/Δ hearts showed longer epicardial but not endocardial APD₉₀s, giving shorter ΔAPD₉₀s than WT hearts. Nicorandil reduced epicardial APD₉₀ in both Scn5a+/Δ and WT hearts thereby increasing ΔAPD₉₀. (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Δ hearts showed greater differences between APD₉₀ and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD₉₀ alternans. Scn5a+/Δ hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Δ hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Δ hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Δ and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Δ and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.     

Catecholamines are key modulators of ventricular repolarization patterns in the ball python (Python regius)

Ectothermic vertebrates experience daily changes in body temperature, and anecdotal observations suggest these changes affect ventricular repolarization such that the T-wave in the ECG changes polarity. Mammals, in contrast, can maintain stable body temperatures, and their ventricular repolarization is strongly modulated by changes in heart rate and by sympathetic nervous system activity. The aim of this study was to assess the role of body temperature, heart rate, and circulating catecholamines on local repolarization gradients in the ectothermic ball python (Python regius). We recorded body-surface electrocardiograms and performed open-chest high-resolution epicardial mapping while increasing body temperature in five pythons, in all of which there was a change in T-wave polarity. However, the vector of repolarization differed between individuals, and only a subset of leads revealed T-wave polarity change. RNA sequencing revealed regional differences related to adrenergic signaling. In one denervated and Ringer’s solution–perfused heart, heating and elevated heart rates did not induce change in T-wave polarity, whereas noradrenaline did. Accordingly, electrocardiograms in eight awake pythons receiving intra-arterial infusion of the β-adrenergic receptor agonists adrenaline and isoproterenol revealed T-wave inversion in most individuals. Conversely, blocking the β-adrenergic receptors using propranolol prevented T-wave change during heating. Our findings indicate that changes in ventricular repolarization in ball pythons are caused by increased tone of the sympathetic nervous system, not by changes in temperature. Therefore, ventricular repolarization in both pythons and mammals is modulated by evolutionary conserved mechanisms involving catecholaminergic stimulation.     

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 ± 5 vs. epi: 147 ± 4 ms; P < 0.05). During epicardial stimulation, this gradient reversed (epi: 162 ± 4 vs. endo: 148 ± 6 ms; P < 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall.     

The contribution of ventricular apicobasal and transmural repolarization patterns to the development of the T wave body surface potentials in frogs (Rana temporaria) and pike (Esox lucius)

The study aimed at the simultaneous determination of the transmural and apicobasal differences in the repolarization timing and the comparison of the contributions of these two repolarization gradients to the development of the body surface T wave potentials in animals with the single heart ventricle (fishes and amphibians). Unipolar potentials were measured on the body surface, epicardium and in the intramural (subepicardial, Epi; midmyocardial; and subendocardial, Endo) ventricular layers of 9 pike and 8 frogs. Activation times, repolarization times and activation-recovery intervals were determined. A transmural gradient in repolarization durations in frogs (Endo>Epi, P<0.024) corresponds to the gradient in repolarization times. No significant transmural difference in repolarization duration is observed in pike that produces a repolarization sequence from Endo to Epi (Endo相似文献   

Catecholamines help snakes have a change of heart

JGP study on python snakes reveals that the regulation of ventricular repolarization by the sympathetic nervous system is evolutionarily conserved.

The T-wave of an electrocardiogram (ECG) arises from local differences in ventricular repolarization and represents a vulnerable period for the generation of arrythmias when some, but not all, of the myocardium is still refractory and unable to generate a new action potential. In mammals, ventricular repolarization is regulated by catecholamines released by the autonomic nervous system. In this issue of JGP, Boukens et al. show that this mode of regulation is conserved in the ball python, Python regius (1).Bas Boukens (left), Bjarke Jensen (center), and colleagues reveal that, similar to mammals, catecholamines released by the autonomic nervous system regulate ventricular repolarization in ball pythons. An ECG (right) shows that, by altering the pattern of ventricular repolarization, adrenaline treatment causes an inversion of the T-wave (red arrowhead). A similar phenomenon is observed in snakes undergoing a rise in body temperature, when autonomic tone increases.Working together at Amsterdam UMC, Bas Boukens and Bjarke Jensen are interested in the electrophysiological adaptations that have occurred during cardiac evolution. Cold-blooded reptiles have a much longer ventricular repolarization phase than warm-blooded mammals, even at 37°C (2). Moreover, the T-wave is typically negative in reptiles, whereas in mammals it is usually positive. Anecdotal observations, however, suggest that, in some reptiles, the T-wave can invert and become positive at higher body temperatures (3, 4). “We were curious about what might underlie these observations,” Jensen says.The researchers therefore recorded ECGs in living ball pythons as their body temperatures were increased (1). The ball python’s heart is unique in having functionally distinct ventricles, with a high-pressure left side and a low-pressure right side, even though, as in other snakes, the two sides are not anatomically separated. Though results varied across individual pythons and ECG leads, raising body temperature from 25 to 35°C caused an inversion of the snakes’ T-wave, reflecting temperature-dependent changes in the pattern of ventricular repolarization.In 1880, Burdon-Sanderson and Page (5) showed in their classic experiments that local differences in temperature change T-wave polarity in the ectothermic heart, presumably due to a direct effect of temperature on the activity of cardiac ion channels. However, when Boukens et al. recorded an ECG from a decapitated python, they found that raising temperature did not cause T-wave inversion (1). “So, we realized that it might not be a direct effect of temperature but might involve another factor, namely catecholamines released by the autonomic nervous system,” says Boukens. Autonomic activity increases at higher temperatures, but the ability of catecholamines to modulate ventricular repolarization would be blunted in decapitated snakes lacking a functional nervous system.Sure enough, the researchers found that stimulating the β-adrenergic receptor induced T-wave inversion in pythons maintained at a stable temperature. In contrast, the β blocker propranolol largely prevented higher temperatures from inducing T-wave inversion.Thus, similar to mammals, catecholamines regulate ventricular repolarization in ball pythons, and the increase in autonomic tone at higher temperatures alters the pattern of repolarization and changes T-wave shape. “The T-wave inversion suggests that certain regions of the python heart respond more strongly to adrenergic stimulation than other regions,” Boukens says.To test this idea, the researchers performed RNA sequencing of tissue samples taken from different regions of the python heart. “Catecholamine-associated genes exhibited differential expression between the left and right sides of the ventricle, consistent with the repolarization of these regions being differentially modulated by adrenergic signaling,” says Jensen.This may provide some sort of advantage to pythons as their body temperature rises, though the resulting changes in repolarization pattern could also leave them vulnerable to developing arrythmias. Boukens and Jensen are now extending their studies to a different branch of the evolutionary tree, examining repolarization and arrhythmogenesis in zebra finches (6).     

Mechanisms of α1-adrenoceptor mediated QT prolongation in the diabetic rat heart

AimsDiabetes mellitus is associated with changes of α₁-adrenoceptor (α₁-AR) on heart electrical function and expression. In this study, we investigated the ionic basis underlying abnormal α₁-AR mediated QT prolongation in the diabetic rat hearts.Main methodsElectrophysiological and biochemical techniques were used in Streptozotocin (STZ)-induced diabetic and control rat hearts.Key findingsIn both control and diabetic rats, the α₁-AR agonist, phenylephrine (PE, 10–100 µM) prolonged the rate-corrected QT intervals (QTc) and action potential durations at 30% (APD₃₀) and 90% (APD₉₀) repolarization levels with the increased QTc and APD₉₀ significantly greater in diabetic rats. PE significantly decreased the transient outward K⁺ current (I_to) and the steady-state K⁺ current (I_ss) in both control and diabetic rats but had no effects on the delayed rectifier K⁺ current (I_k). However, PE induced a greater reduction mainly in the I_ss, but not I_to, in diabetic rats. Furthermore, using RT–PCR and Western blot analyses, we found that α_1A-ARs were over-expressed in the left ventricular tissues of the diabetic rat hearts at both the mRNA and the protein levels.SignificanceThese data suggested that in diabetic hearts, a greater sensitivity of the α_1A-AR mediated the larger suppression of I_ss and resulted in a more prolonged APD₉₀ and QTc. Thus, higher α_1A-AR expression levels in diabetic heart may underlie this type of diabetic cardiomyopathy and suggests that α_1A-AR may serve as a therapeutic target.     

Effect of heart electric stimulation on repolarization of ventricular myocardium of fish and amphibians

The distributions of repolarization durations and end of repolarization time were studied on the ventricular epicardium in pikes (Esox lucius) and frogs (Rana esculenta) and in the ventricular intramural layers in toads (Bufo bufo) at the ectopic heart excitation by using method of the synchronous multielectrode cartography (24 unipolar leads). The time of arrival of the excitation wave and the end of repolarization in each lead were determined from the minimum of time derivative of potential at the period of QRS complex and by minimum of T wave, respectively. It has been established that at the ventricle electrostimulation, alongside with deceleration and a change of sequence of myocardium activation, the redistribution occurs of the local durations of repolarization, being longer than in zones of early activation (p < 0.05). At stimulation, the apicobasal gradient of repolarization is predominantly changed due to electrophysiological processes in the apical areas. In all the studied species, at the ectopic excitation of the heart the sequence of its repolarization repeats the depolarization sequence due to a delay of activation (in fish) and redistribution of repolarization durations (in amphibians).     

Effect of metabolic inhibition on couplon behavior in rabbit ventricular myocytes

We investigated the effect of combined inhibition of oxidative and glycolytic metabolism on L-type Ca²⁺ channels (LCCs) and Ca²⁺ spikes in isolated patch-clamped rabbit ventricular myocytes. Metabolic inhibition (MI) reduced LCC open probability, increased null probability, increased first latency, and decreased open time but left conductance unchanged. These results explain the reduction in macroscopic Ca²⁺ current observed during MI. MI also produced a gradual reduction in action potential duration at 90% repolarization (APD₉₀), a clear decline in spike probability, and an increase in spike latency and variance. These effects are consistent with the changes we observed in LCC activity. MI had no effect on the amplitude or time to peak of Ca²⁺ spikes until APD₉₀ reached 10% of control, suggesting preserved sarcoplasmic reticulum Ca²⁺ stores and ryanodine receptor (RyR) conductance in those couplons that remained functioning. Ca²⁺ spikes disappeared completely when APD₉₀ reached <2% of control, although in two cells, spikes were reactivated in a highly synchronized fashion by very short action potentials. This reactivation is probably due to the increased driving force for Ca²⁺ entry through a reduced number of LCCs that remain open during early repolarization. The enlarged single channel flux produced by rapid repolarization is apparently sufficient to trigger RyRs whose Ca²⁺ sensitivity is likely reduced by MI. We suggest that loss of coupling fidelity during MI is explained by loss of LCC activity (possibly mediated by Ca²⁺-calmodulin kinase II activity). In addition, the results are consistent with loss of RyR activity, which can be mitigated under conditions likely to enlarge the trigger.     

A reliability analysis of cardiac repolarization time markers

Only a limited number of studies have addressed the reliability of extracellular markers of cardiac repolarization time, such as the classical marker RT_eg defined as the time of maximum upslope of the electrogram T wave. This work presents an extensive three-dimensional simulation study of cardiac repolarization time, extending the previous one-dimensional simulation study of a myocardial strand by Steinhaus [B.M. Steinhaus, Estimating cardiac transmembrane activation and recovery times from unipolar and bipolar extracellular electrograms: a simulation study, Circ. Res. 64 (3) (1989) 449]. The simulations are based on the bidomain - Luo-Rudy phase I system with rotational fiber anisotropy and homogeneous or heterogeneous transmural intrinsic membrane properties. The classical extracellular marker RT_eg is compared with the gold standard of fastest repolarization time RT_tap, defined as the time of minimum derivative during the downstroke of the transmembrane action potential (TAP). Additionally, a new extracellular marker RT90_eg is compared with the gold standard of late repolarization time RT90_tap, defined as the time when the TAP reaches 90% of its resting value. The results show a good global match between the extracellular and transmembrane repolarization markers, with small relative mean discrepancy (?1.6%) and high correlation coefficients (?0.92), ensuring a reasonably good global match between the associated repolarization sequences. However, large local discrepancies of the extracellular versus transmembrane markers may ensue in regions where the curvature of the repolarization front changes abruptly (e.g. near front collisions) or is negligible (e.g. where repolarization proceeds almost uniformly across fiber). As a consequence, the spatial distribution of activation-recovery intervals (ARI) may provide an inaccurate estimate of (and weakly correlated with) the spatial distribution of action potential durations (APD).     

Modeling the effect of Kv1.5 block on the canine action potential

A wide range of ion channels have been considered as potential targets for pharmacological treatment of atrial fibrillation. The Kv1.5 channel, carrying the I_Kur current, has received special attention because it contributes to repolarization in the atria but is absent or weakly expressed in ventricular tissue. The dog serves as an important animal model for electrophysiological studies of the heart and mathematical models of the canine atrial action potential (CAAP) have been developed to study the interplay between ionic currents. To enable more-realistic studies on the effects of Kv1.5 blockers on the CAAP in silico, two continuous-time Markov models of the guarded receptor type were formulated for Kv1.5 and subsequently inserted into the Ramirez-Nattel-Courtemanche model of the CAAP. The main findings were: 1), time- and state-dependent Markov models of open-channel Kv1.5 block gave significantly different results compared to a time- and state-independent model with a downscaled conductance; 2), the outcome of Kv1.5 block on the macroscopic system variable APD₉₀ was dependent on the precise mechanism of block; and 3), open-channel block produced a reverse use-dependent prolongation of APD₉₀. This study suggests that more-complex ion-channel models are a prerequisite for quantitative modeling of drug effects.     

Effects of ectopic pacing on repolarization of the chicken left ventricle

Effects of ectopic pacing on left ventricular repolarization were studied in six anesthetized open-chest chickens. In each animal, unipolar electrograms were acquired from as many as 98 sites with 14 plunge needles (seven transmural locations between epicardium and endocardium in each needle). Activation-recovery intervals (ARIs), corrected to the cycle length, were used for estimating repolarization. At baseline, the nonuniform ARI distribution in the left ventricle resulted in the apicobasal differences being greater than the transmural gradient. Nonuniform ARI prolongation caused by ectopic pacing resulted in decreasing the transmural repolarization gradient and increasing the differences in the apex-to-base direction. The basal, but not apical transmural differences contributed to the total left ventricular transmural gradient. The total left ventricular apicobasal gradient was contributed by the apicobasal differences in mid-myocardial and subendocardial layers more than in subepicardial ones. Thus, in in situ chicken hearts, the transmural and apicobasal ARI gradients exist within the left ventricle with the shortest ARIs in the basal subepicardium and the longest ARIs in the subendocardium of the apical and middle parts of the left ventricle. Apicobasal compared to transmural heterogeneity of local repolarization properties contributes more to the total left ventricular repolarization gradient.     

Lysophosphatidic Acid Increases the Electrophysiological Instability of Adult Rabbit Ventricular Myocardium by Augmenting L-Type Calcium Current

Lysophosphatidic acid (LPA) has diverse actions on the cardiovascular system and is widely reported to modulate multiple ion currents in some cell types. However, little is known about its electrophysiological effects on cardiac myocytes. This study investigated whether LPA has electrophysiological effects on isolated rabbit myocardial preparations. The results indicate that LPA prolongs action potential duration at 90% repolarization (APD₉₀) in a concentration- and frequency-dependent manner in isolated rabbit ventricular myocytes. The application of extracellular LPA significantly increases the coefficient of APD₉₀ variability. LPA increased L-type calcium current (I_Ca,L) density without altering its activation or deactivation properties. In contrast, LPA has no effect on two other ventricular repolarizing currents, the transient outward potassium current (I_to) and the delayed rectifier potassium current (I_K). In arterially perfused rabbit left ventricular wedge preparations, the monophasic action potential duration, QT interval, and Tpeak-end are prolonged by LPA. LPA treatment also significantly increases the incidence of ventricular tachycardia induced by S₁S₂ stimulation. Notably, the effects of LPA on action potentials and I_Ca,L are PTX-sensitive, suggesting LPA action requires a G_i-type G protein. In conclusion, LPA prolongs APD and increases electrophysiological instability in isolated rabbit myocardial preparations by increasing I_Ca,L in a G_i protein-dependent manner.     

New Aspects of HERG K+ Channel Function Depending upon Cardiac Spatial Heterogeneity

HERG K⁺ channel, the genetic counterpart of rapid delayed rectifier K⁺ current in cardiac cells, is responsible for many cases of inherited and drug-induced long QT syndromes. HERG has unusual biophysical properties distinct from those of other K⁺ channels. While the conventional pulse protocols in patch-clamp studies have helped us elucidate these properties, their limitations in assessing HERG function have also been progressively noticed. We employed AP-clamp techniques using physiological action potential waveforms recorded from various regions of canine heart to study HERG function in HEK293 cells and identified several novel aspects of HERG function. We showed that under AP-clamp I_HERG increased gradually with membrane repolarization, peaked at potentials around 20–30 mV more negative than revealed by pulse protocols and at action potential duration (APD) to 60%-70% full repolarization, and fell rapidly at the terminal phase of repolarization. We found that the rising phase of I_HERG was conferred by removal of inactivation and the decaying phase resulted from a fall in driving force, which were all determined by the rate of membrane repolarization. We identified regional heterogeneity and transmural gradient of I_HERG when quantified with the area covered by I_HERG trace. In addition, we observed regional and transmural differences of I_HERG in response to dofetilide blockade. Finally, we characterized the influence of HERG function by selective inhibition of other ion currents. Based on our results, we conclude that the distinct biophysical properties of HERG reported by AP-clamp confer its unique function in cardiac repolarization thereby in antiarrhythmia and arrhythmogenesis.     

Contributions of HERG current to repolarization of the human ventricular action potential

Action potential repolarization in the mammalian heart is governed by interactions of a number of time- and voltage-dependent channel-mediated currents, as well as contributions from the Na⁺/Ca²⁺ exchanger and the Na⁺/K⁺ pump. Recent work has shown that one of the K⁺ currents (HERG) which contributes to repolarization in mammalian ventricle is a locus at which a number of point mutations can have significant functional consequences. In addition, the remarkable sensitivity of this K⁺ channel isoform to inhibition by a variety of pharmacological agents and clinical drugs has resulted in HERG being a major focus for Safety Pharmacology requirements.For these reasons we and others have attempted to define the functional role for HERG-mediated K⁺ currents in repolarization of the action potential in the human ventricle. Here, we describe and evaluate changes in the formulations for two K⁺ currents, I_K1 and HERG (or I_K,r), within the framework of ten Tusscher model of the human ventricular action potential. In this computational study, new mathematical formulations for the two nonlinear K⁺ conductances, I_K1 and HERG, have been developed based upon experimental data obtained from electrophysiological studies of excised human ventricular tissue and/or myocytes. The resulting mathematical model provides much improved simulations of the relative sizes and time courses of the K⁺ currents which modulate repolarization. Our new formulation represents an important first step in defining the mechanism(s) of repolarization of the membrane action potential in the human ventricle. Our overall goal is to understand the genesis of the T-wave of the human electrocardiogram.     

Repolarization gradients in the intact heart: transmural or apico-basal?

Controversies regarding the genesis of the T wave in the electrocardiogram and the role of midmural M cells in the intact heart include: In normal, intact canine and human hearts there is no significant transmural gradient in repolarization times. The T wave results primarily from apico-basal differences in repolarization times. Also, in the intact heart there is no midmural region of prolonged action potential duration. This contrasts with isolated preparations, such as the wedge preparation or myocardial slices or disaggregated myocytes in which M cells, with action potentials longer than those of endocardial and epicardial myocardium, can be found. This disparity in action potential duration probably results from partial uncoupling of myocardial cells in the regions where measurements are made, e.g., the cut surface of a wedge preparation. In regions of a wedge where cellular coupling is normal, or in isolated myocardial bundles or sheets, no evidence for M cells is detected. In some wedge preparations, a drug-induced large transmural repolarization gradient, involving M cells, can lead to Torsade de Pointes, possibly caused by so-called phase two reentry. In contrast, when a gradient of repolarization times of more than 100?ms was created in intact hearts, no evidence for reentry was found and no spontaneous arrhythmias occurred. In conclusion, in the intact heart, M cells appear not to contribute to repolarization gradients and arrhythmias. Furthermore, no significant repolarization gradients between endocardium and epicardium exist. The T wave in the body surface electrocardiogram is caused by apico-basal and anterior-posterior differences in repolarization times.     

Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

The female sex is associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. This study examined the hypothesis that sex differences in repolarization may be associated with differential transmural ion-current distribution. Whole cell patch-clamp and current-clamp were used to study ionic currents and action potentials (APs) in isolated canine left ventricular cells from epicardium, midmyocardium, and endocardium. No sex differences in AP duration (APD) were found in cells from epicardium versus endocardium. In midmyocardium, APD was significantly longer in female dogs (e.g., at 1 Hz, female vs. male: 288 +/- 21 vs. 237 +/- 8 ms; P < 0.05), resulting in greater transmural APD heterogeneity in females. No sex differences in inward rectifier K+ current (I(K1)) were observed. Transient outward K+ current (I(to)) densities in epicardium and midmyocardium also showed no sex differences. In endocardium, female dogs had significantly smaller I(to) (e.g., at +30 mV, female vs. male: 2.5 +/- 0.2 vs. 3.5 +/- 0.3 pA/pF; P < 0.05). Rapid delayed-rectifier K+ current (I(Kr)) density and activation voltage-dependence showed no sex differences. Female dogs had significantly larger slow delayed-rectifier K+ current (I(Ks)) in epicardium and endocardium (e.g., at +40 mV; tail densities, female vs. male; epicardium: 1.3 +/- 0.1 vs. 0.8 +/- 0.1 pA/pF; P < 0.001; endocardium: 1.2 +/- 0.1 vs. 0.7 +/- 0.1 pA/pF; P < 0.05), but there were no sex differences in midmyocardial I(Ks). Female dogs had larger L-type Ca2+ current (I(Ca,L)) densities in all layers than male dogs (e.g., at -20 mV, female vs. male, epicardium: -4.2 +/- 0.4 vs. -3.2 +/- 0.2 pA/pF; midmyocardium: -4.5 +/- 0.5 vs. -3.3 +/- 0.3 pA/pF; endocarium: -4.5 +/- 0.4 vs. -3.2 +/- 0.3 pA/pF; P < 0.05 for each). We conclude that there are sex-based transmural differences in ionic currents that may underlie sex differences in transmural cardiac repolarization.     

Modulation of haloperidol induced electrophysiological alterations on cardiac action potential by various risk factors and gender difference

Haloperidol (HPL), well known antipsychotic drug can induce a marked QT prolongation and polymorphic arrhythmias. In this study we evaluated the influence of various induced risk factors such as electrolyte imbalance (hypokalemia and hypomagnesemia), gender difference, low pacing frequency, ischemia reperfusion insult on electrophysiological effect by haloperidol on electrically driven action potentials recorded from guinea pig papillary muscle. The doses of HPL ranging from 1 to 16 μM were used in this investigation. Action potentials (APs) were elicited electrically and recorded by classical microelectrode technique. HPL caused dose dependent prolongation of APD₉₀ the final stage of repolarization, increased triangulation, and led into dispersion of action potential, conduction delay and conduction block. Magnitude of the effect of haloperidol was amplified significantly by most of the risk factors. Among the various risk factors, electrolyte imbalance (hypokalemia, hypomagnesemia) caused more amplification of HPL effect. Most of the risk factors amplified prolongation of APD₉₀ by HPL. This effect is mainly due to the influence of these electrolytes and sex hormone on various ion channels involved in the repolarization phase of cardiac AP. This is the first report which provides an experimental evidence of amplification of electrophysiological effects of HPL in the presence of various risk factors.     

Tracking cardiac electrical instability by computing interlead heterogeneity of T-wave morphology.

Oscillations in T-wave morphology, particularly T-wave alternans (TWA), have been fundamentally linked to increased susceptibility to ventricular fibrillation (VF). We investigated whether the escalation in complexity of T-wave oscillations before VF is attributable to increased spatial heterogeneity of repolarization. Peak interlead T-wave heterogeneity (TWH) was measured by second central moment analysis of T-wave morphology in epicardial electrograms in dogs during left anterior descending coronary artery occlusion. TWH differentiated cases in which myocardial ischemia provoked VF from those without VF (563 +/- 56 vs. 139 +/- 36 microV, P < 0.01). In the former group, progressive, significant increases in TWH above preocclusion baseline (70 +/- 8 microV) began at 2.25 min after the start of occlusion and were associated successively with TWA (at 155 +/- 19 microV), T-wave multupling (at 386 +/- 100 microV), complex oscillatory T-wave forms (at 560 +/- 76 microV), discordant TWA (at 572 +/- 98 microV), and VF at 4.36 +/- 0.14 min. TWH in precordial ECGs in 12 pigs during angioplasty-balloon-induced myocardial ischemia also discriminated animals that experienced VF (from 90 +/- 14 at baseline to 382 +/- 39 microV, P < 0.05) from those without VF (from 96 +/- 17 at baseline to 199 +/- 61 microV, NS). Ischemia-induced changes in ST segment and T-wave amplitude did not predict VF. Heightened spatial heterogeneity of repolarization, as assessed by second central moment analysis of TWH, underlies TWA and increased risk for ischemia-induced VF. Monitoring spatial TWH from precordial leads could prove useful in stratifying risk for life-threatening arrhythmias.     

Cardiac electric field at the period of depolarization and repolarization of the frog heart ventricle

Multichannel mapping of electrical field on heart ventricle epicardium and the body surface in frogs Rana esculenta and Rana temporaria was performed at periods of the ventricular myocardium depolarization and repolarization. The zone of the epicardium early depolarization is located on epicardium of the ventricle base posterior wall, while the late depolarization zone—on its apex and on the base anterior wall. The total vector of sequence of the ventricle epicardium depolarization is directed from the base to the apex. The zone of the early repolarization is located in the apical area, while that of the late one—in the area of the base. On the frog body surface the cardioelectric field with the cranial zone of negative and the caudal zone of positive potentials is formed before the appearance of the QRS complex on ECG. At the period of the heart ventricle repolarization the zone of the cardioelectric field negative potentials is located in the cranial, while that of the positive ones—in the body surface caudal parts. The cardioelectric field on the frog body surface at the periods of depolarization and repolarization of the ventricle myocardium reflects adequately the projection of sequence of involvement with excitation and of distribution of potentials on epicardium.