Repolarization Process Research Articles

The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block.

Drug-induced delayed cardiac repolarization is a recognized risk factor for proarrhythmia and is associated with block of IKr (the potassium current encoded by the human ether-a- go-go-related gene [hERG]). To evaluate the utility of 2 in vitro assays widely used to assess delayed repolarization, we compared the effects of haloperidol and 9 structurally diverse drugs in a hERG and repolarization (canine Purkinje fiber action potential duration [APD]) assay over wide concentrations. Despite potent hERG current block (IC50 = 0.174 microM), haloperidol elicited a bell-shaped concentration-response relationship for APD prolongation, with lesser prolongation (and reduced plateau height) observed with concentrations eliciting maximal hERG block, consistent with multi-channel block at higher concentrations. Consistent with this hypothesis, APD prolongation with the specific IKr blocker dofetilide was a) reduced by concomitant administration of nifedipine (calcium current block) and b) reversed by lidocaine (late sodium current block). Additional studies demonstrated prominent (>50%) hERG inhibition with most (9/10) drugs despite wide APD changes (158% prolongation - 16% shortening), consistent with multi-channel block. The poor correlation between hERG and repolarization assays suggests that the hERG assay oversimplifies drug effects on the complex repolarization process for drugs demonstrating multi-channel block and that neither assay alone adequately predicts proarrhythmic risk.

COMPARISON OF CARDIAC MAGNETIC FIELD DISTRIBUTIONS DURING DEPOLARIZATION AND REPOLARIZATION

Multichannel magnetocardiography measures the magnetic field distribution of the human heart noninvasively from many sites over the body surface. Multichannel magnetocardiogram (MCG) analysis enables regional temporal differences in the distribution of cardiac magnetic field strength during depolarization and repolarization to be identified, allowing estimation of the global and local inhomogeneity of the cardiac activation process. The aim of this study was to compare the spatial distribution of cardiac magnetic field strength during ventricular depolarization and repolarization in both normal subjects and patients with cardiac abnormalities, obtaining amplitude measurements by magnetocardiography. MCGs were recorded at 49 sites over the heart from three normal subjects and two patients with inverted T-wave conditions. The magnetic field intensity during depolarization and repolarization was measured automatically for each channel and displayed spatially as contour maps. A Pearson correlation was used to determine the spatial relationship between the variables. For normal subjects, magnetic field strength maps during depolarization (R-wave) showed two asymmetric regions of magnetic field strength with a high positive value in the lower half of the chest and a high negative value above this. The regions of high R-wave amplitude corresponded spatially to concentrated asymmetric regions of high magnetic field strength during repolarization (T-wave). Pearson-r correlation coefficients of 0.7 (p<0.01), 0.8 (p<0.01) and 0.9 (p<0.01) were obtained from this analysis for the three normal subjects. A negative correlation coefficient of -0.7 (p<0.01) was obtained for one of the subjects with inverted T-wave abnormalities, suggesting similar but inverted magnetic field and current distributions to normal subjects. Even with the high correlation values in these four subjects, the MCG was able to identify differences in the distribution of magnetic field strength, with a shift in the T-wave relative to the R-wave. The measurement of cardiac magnetic field distribution during depolarization and repolarization of normal subjects and patients with clinical abnormalities should enable the improvement of theoretical models for the explanation of the cardiac depolarization and repolarization processes.

Effects of mexiletine on the canine model of sparfloxacin-induced long QT syndrome

Potential utility of mexiletine for the treatment of sparfloxacin-induced long QT syndrome was assessed using the in vivo halothane-anesthetized canine model. At 30 min after the administration of a supratherapeutic dose of sparfloxacin (30 mg/kg, i.v.), the mean blood pressure and heart rate decreased, whereas repolarization process and effective refractory period of the ventricular muscle were significantly prolonged. Additional administration of a clinically recommended dose of mexiletine (3 mg/kg, i.v.) at this time point increased the mean blood pressure, suppressed ventricular contraction, delayed atrioventricular as well as intraventricular conduction, and shortened repolarization process and effective refractory period. The extent of abbreviation of the repolarization was more prominent than that of the refractoriness, indicating that mexiletine could decrease the electrical vulnerability of the heart during sparfloxacin overdose. Thus, mexiletine may become a promising pharmacological strategy against the drug-induced long QT syndrome.

Determinant of QT dispersion in patients with hypertrophic cardiomyopathy.

QT dispersion is thought to reflect a regional difference in repolarization process although QT interval is composed of depolarization and repolarization. This study was designed to investigate the effect of depolarization and repolarization on QT dispersion in hypertrophic cardiomyopathy. Standard 12-lead ECG was recorded in 70 hypertrophic cardiomyopathy patients with anteroseptal wall hypertrophy (HC-As), 8 patients with lateral wall hypertrophy (HC-L), 8 patients with diffuse hypertrophy (HC-D), and 46 normal controls. QRS, JTc, maximum and minimum QTc, and QTc dispersion were compared. The maximum QTc was greater in HC-As and HC-L than in the control; the minimum QTc was similar in all 3 groups; consequently, QTc dispersion was greater in HC-As and HC-L. In HC-D, the maximum QTc and the minimum QTc were greater than the control, which produced QTc dispersion similar to that in the control. JTc did not differ among 4 groups. In hypertrophic cardiomyopathy, both QTc and QRS duration were increased in the leads coinciding with the left ventricular portion of localized hypertrophy. We conclude that QTc dispersion depended on the heterogeneity of QRS duration or depolarization rather than repolarization, which in fact may be ascribed to the regionally different hypertrophy of the left ventricle in hypertrophic cardiomyopathy.

Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome?a case-control pilot study using i.v. sotalol

The aim of this pilot study was to evaluate provocative sotalol testing to unmask abnormal repolarization due to altered myocardial electrical properties as the key feature in acquired Long-QT-Syndrome. Reliable diagnosis and risk stratification for the individual patient are complicated by the multitude of mechanisms involved in acquired QT-prolongation. The combined influence of all components determines susceptibility to arrhythmias related to QT-prolongation. Twenty consecutive patients who had experienced torsades de pointes in association with QT-prolonging drugs were tested with i.v. D,L-sotalol (2mg/kg) with 24-h intensive care monitoring to evaluate the repolarization process by determining QT- and QTc-prolongations. Results were compared to age and sex matched controls. At baseline, no differences between control and study population with regard to QT and QTc were detected. After sotalol infusion, QTc increased from 422+/-17 to 450+/-22ms in controls and from 434+/-20 to 541+/-37ms in the study population. Torsades de pointes occurred in three out of 20 patients (15%) in the study population but in none of the control patients following i.v. sotalol testing. Controlled exposure to sotalol successfully identifies patients with normal QTc intervals but altered myocardial repolarization. This may be useful for clarifying diagnosis and pathogenesis of acquired Long-QT-Syndrome.

Famotidine does not induce long QT syndrome: experimental evidence from in vitro and in vivo test systems

The effects of famotidine on the cardiac repolarization process were assessed using four different levels of test systems described in the draft stage guideline ICH S7B. A supratherapeutic concentration of famotidine (10 −5 M), which is >8 times higher than C max obtained after its therapeutic dose, neither inhibited human ether-a-go-go-related gene (HERG) K + current expressed in human embryonic kidney 293 (HEK293) cells nor affected any of the action potential parameters of guinea pig papillary muscles. Therapeutic (0.3 mg/kg, i.v.) to supratherapeutic doses (3–10 mg/kg, i.v.) of famotidine did not affect the repolarization process of the halothane-anesthetized canine model, while only supratherapeutic doses exerted the positive chronotropic, inotropic and dromotropic effects without affecting the mean blood pressure. Moreover, supratherapeutic doses of famotidine (1–10 mg/kg, i.v.) neither induced torsades de pointes nor prolonged QT interval in the canine chronic atrioventricular conduction block model. These results suggest that famotidine possesses no cardiovascular effects at a therapeutic dose, while it may exert cardiostimulatory actions after drug overdoses that might potentiate the proarrhythmic potential of co-administered cardiotonic agents by increasing the intracellular Ca 2+ concentration.

Long QT syndrome and anaesthesia

Long QT syndrome (LQTS) is an arrhythmogenic cardiovascular disorder resulting from mutations in cardiac ion channels. LQTS is characterized by prolonged ventricular repolarization and frequently manifests itself as QT interval prolongation on the electrocardiogram (ECG). The age at presentation varies from in utero to adulthood. The majority of symptomatic events are related to physical activity and emotional stress. Although LQTS is characterized by recurrent syncope, cardiac arrest, and seizure-like episodes, only about 60% of patients are symptomatic at the time of diagnosis. 3 The clinical features of LQTS result from a peculiar episodic ventricular tachyarrhythmia called ‘torsade de pointes’. ‘Twisting of the points’ describes the typical sinusoidal twisting of the QRS axis around the isoelectric line of the ECG. Usually torsade de pointes start with a premature ventricular depolarization, followed by a compensatory pause. The next sinus beat often has a markedly prolonged QT interval and abnormal T wave. This is followed by a ventricular tachycardia that is characterized by variation in the QRS morphology, and a constantly changing R-R interval (Fig. 1). The ‘short-long-short’ cycle length sequence heralding torsade de pointes is a hallmark of LQTS. Commonly, the episode of torsade de pointes is self-terminating, producing a syncopal episode or pseudoseizure, secondary to the abrupt decrease in cerebral blood flow. The majority of episodes of sudden death in LQTS result from ventricular fibrillation triggered by torsade de pointes, although the mechanism of this deterioration is unknown. Traditionally, LQTS has been classified as either familial (inherited) or acquired. However, it is likely that many patients with previously labelled acquired LQTS carry a silent mutation in one of the genes responsible for congenital LQTS. 22 119 The evidence for this hypothesis has been gradually emerging over the past few years. It is important for anaesthetists to be aware of this concept, as it means that a much higher proportion of the general population may be affected by asymptomatic mutations in genes encoding cardiac ion channels than was thought previously. The prevalence of LQTS in developed countries may be as high as 1 per 1100‐3000 of the population. 32 119 About 30% of congenital LQTS carriers have an apparently normal phenotype, and thus a normal QT interval, and remain undiagnosed until an initiating event. 105 Fatal arrhythmias associated with primary electrical disease of the heart such as the Brugada and LQTS, probably account for 19% of sudden deaths in children between 1 and 13 yr of age, and 30% of sudden deaths that occur between 14 and 21 yr of age. 10 Furthermore, there is a strong association between prolonged corrected QT interval (QTc) in the first week of life and risk of sudden infant death syndrome. 86

Detection of repolarization abnormalities in patients with cardiomyopathy using current vector mapping technique on magnetocardiogram.

We have previously developed current vector maps of tangential components on the magnetocardiogram (MCG) to obtain cardiac current distribution images. The present study was conducted to detect repolarization abnormalities in patients with cardiomyopathy using the current vector map. Thirteen patients with cardiomyopathy (nine males and four females aged 7-16 years, mean, 11.5 +/- 3.1 years, +/- SD), and 15 age- and sex-matched normal subjects were studied. Normal components (Bz) of MCG were measured at rest with a multi-channel superconducting quantum interface device (SQUID) system, and differentiated in the tangential direction to obtain current vector maps. Homogeneity of current in the heart during repolarization was investigated. The direction of the maximum current vector was also calculated in each case. In all normal subjects, the current vector consistently showed a left downward direction on the frontal chest plane during the repolarization process. On the other hand, 8 out of 13 patients with cardiomyopathy showed different patterns; four of these patients showed multi-dipoles, and the other four showed a shift in the current vector direction. One of the eight cases showed no abnormality on electrocardiogram (ECG). Repolarization process in patients with cardiomyopathy was apparently different from those in normal subjects on the current vector map. It was easy to visualize the repolarization process as a projection to the frontal plane, including regional abnormalities, by the current vector maps, which might be more useful for early detection of repolarization abnormalities than ECG.

Cardiovascular effects of Y-27632, a selective Rho-associated kinase inhibitor, assessed in the halothane-anesthetized canine model

Y-27632, (+)-( R)- trans-4-(1-aminoethyl)- N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate, is a selective Rho-associated kinase inhibitor, which has been suggested to possess multiple clinical applications based on the in vitro observations. Since information regarding in vivo cardiovascular effects of Y-27632 is still limited, we assessed them using the halothane-anesthetized, closed-chest canine model. Administration of Y-27632 in a dose of 0.01 mg/kg, i.v. significantly decreased total peripheral vascular resistance together with an increase of cardiac output without affecting other cardiovascular parameters. Moreover, additional administration of Y-27632 in a dose of 0.1 mg/kg, i.v. significantly decreased blood pressure and left ventricular end-diastolic pressure, increased the heart rate and cardiac contractility, enhanced atrioventricular conduction and shortened the repolarization process as well as the effective refractory period. These results indicate that Y-27632 exerts a potent arterio-venodilator action with cardiostimulatory effects possibly through the sympathetic reflex in the in vivo canine model.

APKC kinase activity is required for the asymmetric differentiation of the premature junctional complex during epithelial cell polarization.

We have previously shown that aPKC interacts with cell polarity proteins PAR-3 and PAR-6 and plays an indispensable role in cell polarization in the C. elegans one-cell embryo as well as in mammalian epithelial cells. Here, to clarify the molecular basis underlying this aPKC function in mammalian epithelial cells, we analyzed the localization of aPKC and PAR-3 during the cell repolarization process accompanied by wound healing of MTD1-A epithelial cells. Immunofluorescence analysis revealed that PAR-3 and aPKClambda translocate to cell-cell contact regions later than the formation of the primordial spot-like adherens junctions (AJs) containing E-cadherin and ZO-1. Comparison with three tight junction (TJ) membrane proteins, JAM, occludin and claudin-1, further indicates that aPKClambda is one of the last TJ components to be recruited. Consistently, the expression of a dominant-negative mutant of aPKClambda (aPKClambdakn) in wound healing cells does not inhibit the formation of the spot-like AJs; rather, it blocks their development into belt-like AJs. These persistent spot-like AJs in aPKClambda-expressing cells contain all TJ membrane proteins and PAR-3, indicating that aPKC kinase activity is not required for their translocation to these premature junctional complexes but is indispensable for their further differentiation into belt-like AJs and TJs. Cortical bundle formation is also blocked at the intermediate step where fine actin bundles emanating from premature cortical bundles link the persistent spot-like AJs at apical tips of columnar cells. These results suggest that aPKC contributes to the establishment of epithelial cell polarity by promoting the transition of fibroblastic junctional structures into epithelia-specific asymmetric ones.

Evaluation of myocardial ischemia in Kawasaki disease using an isointegral map on magnetocardiogram.

The authors have recently reported on the usefulness of the isointegral mapping technique using magnetocardiography (MCG) for the diagnosis of adult ischemic heart disease. This study evaluated myocardial ischemia in patients with Kawasaki disease (KD). The ischemia has been considered difficult to diagnose with a standard ECG. The study included 32 patients (age 3 +/- 22 years, mean 12.9 +/- 4.1 years, +/- SD) with a history of KD and 21 age-matched healthy children. Coronary arterial lesions were present in 13 patients of the KD group, MCG was carried out at rest with a multichannel superconducting quantum interference device (SQUID) system. The integral value was computed for each channel and isointegral maps were constructed during depolarization and repolarization processes. In all subjects of the control group, the integral value of repolarization was higher than that of depolarization and the isointegral map of these two processes showed similar patterns. However, the integral value of repolarization in four cases with KD (one with a history of myocardial infarction, two with a stenotic lesion in the left coronary artery, one with an aneurysmal and stenotic lesion in the right coronary artery) was lower than that of depolarization, and abnormal patterns were evident in the isointegral map. All but the case with myocardial infarction showed only mild abnormalities or almost normal on the ECG. Although sensitivity of the method for detection of myocardial ischemia was not fully assessed because of the small number of cases with significant coronary arterial stenosis, noninvasive isointegral mapping technique using the MCG could be useful for evaluation of myocardial ischemia in patients with KD.

Rapidly and slowly activating components of delayed rectifier K(+) current in guinea-pig sino-atrial node pacemaker cells.

The components and properties of the delayed rectifier K(+) current (I(K)) in isolated guinea-pig sino-atrial (SA) node pacemaker cells were investigated using the whole-cell configuration of the patch-clamp technique. An envelope of tails test was conducted by applying depolarizing pulses from a holding potential of -50 mV to +30 mV for various durations ranging from 40 to 2000 ms. The ratio of the tail current amplitude elicited upon return to the holding potential to the magnitude of the time-dependent outward current activated during depolarizing steps was dependent on the pulse duration, while after exposure to the selective I(Kr) inhibitor E-4031 (5 microM) this current ratio became practically constant irrespective of the pulse duration. These observations are consistent with the presence of the E-4031-sensitive, rapidly activating and E-4031-resistant, slowly activating components of I(K) (I(Kr) and I(Ks), respectively) in guinea-pig SA node cells. The activation range for I(Kr), defined as the E-4031-sensitive current (half-maximal activation voltage (V(1/2)) of -26.2 mV) was much more negative than that for I(Ks), defined as the E-4031-resistant current (V(1/2) of +17.2 mV). I(Kr) exhibited a marked inward rectification at potentials positive to -50 mV, whereas I(Ks) showed only a slight rectification. In the current-clamp experiments, bath application of E-4031 (0.5 and 5 microM) initially slowed the repolarization at potentials negative to approximately -30 mV and produced a significant depolarization of the maximum diastolic potential, followed by the arrest of electrical activity, thus indicating that the late phase of the repolarization leading to the maximum diastolic potential at around -60 mV in spontaneous action potentials is primarily produced by I(Kr) in guinea-pig SA node cells. External application of the selective I(Ks) inhibitor 293B (30 microM) also delayed the repolarization process at potentials negative to about -20 mV and induced moderate depolarization of the maximum diastolic potential leading to the arrest of the spontaneous activity. These results provide evidence to suggest that both I(Kr) and I(Ks) are present and play crucial roles in the spontaneous electrical activity of guinea-pig SA node pacemaker cells.

Rapidly and slowly activating components of delayed rectifier K+ current in guinea-pig sino-atrial node pacemaker cells

The components and properties of the delayed rectifier K+ current (IK) in isolated guinea-pig sino-atrial (SA) node pacemaker cells were investigated using the whole-cell configuration of the patch-clamp technique. An envelope of tails test was conducted by applying depolarizing pulses from a holding potential of −50 mV to +30 mV for various durations ranging from 40 to 2000 ms. The ratio of the tail current amplitude elicited upon return to the holding potential to the magnitude of the time-dependent outward current activated during depolarizing steps was dependent on the pulse duration, while after exposure to the selective IKr inhibitor E-4031 (5 μm) this current ratio became practically constant irrespective of the pulse duration. These observations are consistent with the presence of the E-4031-sensitive, rapidly activating and E-4031-resistant, slowly activating components of IK (IKr and IKs, respectively) in guinea-pig SA node cells. The activation range for IKr, defined as the E-4031-sensitive current (half-maximal activation voltage (V1/2) of −26.2 mV) was much more negative than that for IKs, defined as the E-4031-resistant current (V1/2 of +17.2 mV). IKr exhibited a marked inward rectification at potentials positive to −50 mV, whereas IKs showed only a slight rectification. In the current-clamp experiments, bath application of E-4031 (0.5 and 5 μm) initially slowed the repolarization at potentials negative to approximately −30 mV and produced a significant depolarization of the maximum diastolic potential, followed by the arrest of electrical activity, thus indicating that the late phase of the repolarization leading to the maximum diastolic potential at around −60 mV in spontaneous action potentials is primarily produced by IKr in guinea-pig SA node cells. External application of the selective IKs inhibitor 293B (30 μm) also delayed the repolarization process at potentials negative to about −20 mV and induced moderate depolarization of the maximum diastolic potential leading to the arrest of the spontaneous activity. These results provide evidence to suggest that both IKr and IKs are present and play crucial roles in the spontaneous electrical activity of guinea-pig SA node pacemaker cells.

QT interval and final portion of T wave: measurements and dispersion in infants born at high altitude

Background: This research was conducted to determine whether the depolarization and repolarization cardiac process of children born at high altitude differs from that of children born at lower altitudes. Methods: We studied three groups of 30 healthy newborns in the Venezuelan Andes. Group 3500 m consisted of infants born at 3500 m above sea level; Group 3000 m of infants born at 3000 m above sea level and Group 1600 m of infants born at 1600 m above sea level. Conventional 12-lead electrocardiograms were recorded in the 90 newborns. Corrected QT interval, duration from the peak to the end of the T wave, dispersion of QT interval and of the final portion of T wave and heart rate were computed in each subject. Results: The findings of the present study show that infants born at high altitude (Groups 3500 and 3000 m) had a significantly longer corrected QT interval and a significantly shorter peak-to-end of T wave interval. Neither the heart rate nor the indexes of dispersion of the depolarization–repolarization process revealed abnormal values or significant differences among the groups. Conclusions: These results suggest that the depolarization and repolarization cardiac process of infants born at high altitude differs from that of children born at lower altitudes.

Prolonged repolarization in long QT3 syndrome: unusual electrocardiographic findings

Congenital long QT syndrome is a cardiovascular disease characterised by prolonged ventricular repolarization and propensity to life-threatening arrhythmias. On the surface ECG, the prolonged repolarization leads to a long QT interval and, sometimes, to T waves with distinct contours. In a small subset of patients (particularly infants and children) repolarization is so prolonged that AV conduction may be impaired [1,2]. In recent years, and thanks to linkage analysis provided by molecular biology techniques, mutations in genes encoding ion channels proteins, crucial in the repolarization process, were identified [3,4]. So far, genes on chromosomes 11 and 7 (which encode for two different potassium channels proteins, Ikr, Iks) and on chromosome 3 (which encodes the cardiac human sodium channel, SCN5A) are responsible for LQT1, LQT2 and LQT3, respectively. These genotypes, which account for 90% of all ion channel proteins mutations, are associated with distinct ST segment-T wave morphologies making the ECG useful in recognising congenitally determined forms of the syndrome [5].

QT dispersion and T-loop morphology in late pregnancy and after delivery.

The aim of the study was to detect changes of both the QT dispersion and T-loop morphology resulting from the changed spatial position of the heart during pregnancy. Electrocardiographic and vectorcardiographic recordings were obtained from 37 healthy women 19-36 years old in the 36th to 40th week of physiological pregnancy and 2 to 6 days after delivery. The same recordings were obtained from 18 healthy women of the same age. The average QT dispersion (±S.D.) in normal subjects was significantly lower (34±12 ms) than in those in late pregnancy (73±18 ms) (P<0.001). The average amplitude of T-loop (Ta) in women in late pregnancy was significantly (P<0.001) smaller (532±98 mV) and the width of T-loop (Tw) was wider (21.24±11.48 deg) than in the control group (793±114 mV and 7.17±3.02 deg, respectively). The partial post-partum restoration of all parameters was not significant. In all groups, the QT dispersion was significantly correlated with Tw but not with Ta. According to these results we can conclude that the QT dispersion is an indirect reflection of the complete process of ventricular repolarization, reflected in the morphology of the T-loop..

Rapidly and slowly activating components of delayed rectifier K+ current in guinea-pig sino-atrial node pacemaker cells

The components and properties of the delayed rectifier K+ current (IK) in isolated guinea-pig sino-atrial (SA) node pacemaker cells were investigated using the whole-cell configuration of the patch-clamp technique. An envelope of tails test was conducted by applying depolarizing pulses from a holding potential of −50 mV to +30 mV for various durations ranging from 40 to 2000 ms. The ratio of the tail current amplitude elicited upon return to the holding potential to the magnitude of the time-dependent outward current activated during depolarizing steps was dependent on the pulse duration, while after exposure to the selective IKr inhibitor E-4031 (5 μm) this current ratio became practically constant irrespective of the pulse duration. These observations are consistent with the presence of the E-4031-sensitive, rapidly activating and E-4031-resistant, slowly activating components of IK (IKr and IKs, respectively) in guinea-pig SA node cells. The activation range for IKr, defined as the E-4031-sensitive current (half-maximal activation voltage (V1/2) of −26.2 mV) was much more negative than that for IKs, defined as the E-4031-resistant current (V1/2 of +17.2 mV). IKr exhibited a marked inward rectification at potentials positive to −50 mV, whereas IKs showed only a slight rectification. In the current-clamp experiments, bath application of E-4031 (0.5 and 5 μm) initially slowed the repolarization at potentials negative to approximately −30 mV and produced a significant depolarization of the maximum diastolic potential, followed by the arrest of electrical activity, thus indicating that the late phase of the repolarization leading to the maximum diastolic potential at around −60 mV in spontaneous action potentials is primarily produced by IKr in guinea-pig SA node cells. External application of the selective IKs inhibitor 293B (30 μm) also delayed the repolarization process at potentials negative to about −20 mV and induced moderate depolarization of the maximum diastolic potential leading to the arrest of the spontaneous activity. These results provide evidence to suggest that both IKr and IKs are present and play crucial roles in the spontaneous electrical activity of guinea-pig SA node pacemaker cells.

三次元心磁図計測によるＷＰＷ患者の興奮伝播の解析

We performed three-dimensional vector measurement of magnetocardiograms (MCGs) for normal subjects and subjects with Wolff-Parkinson-White (WPW) syndrome, using a three-dimensional second-order gradiometer connected to 39-channel SQUIDs, which can simultaneously detect magnetic field components perpendicular to the chest wall (Bz) and those tangential to the chest wall (Bx,By). In order to analyze the accessory pathway of WPW syndrome, source estimation to the delta wave was performed using the equivalent current dipole (ECD) method.Magnetic field pattern Bz of the delta wave for WPW syndrome was not a dipole pattern, and it was difficult to estimate sources. Magnetic field patterns Bx and By, however can provide information on constraint conditions for estimation of multiple sources. It was found by three-dimensional measurement that the estimation of the accessory pathway received the effects of a repolarization process of the heart atrium when the accessory pathway was located far from a sinoatrial node. It was shown that three-dimensional MCG measurements are effective for detailed analysis of heart activity.

Modeling of Domain Processes in Piezoceramic Materials

By using the method of effective medium, modeling of the repolarization process in piezoceramics has been carried out with the reversible displacement of 90° domain walls, the geometry of domain structure in crystallites and its rearrangement under the polarizing field taken into account.

Effects of disopyramide and mexiletine on the terminal repolarization process of the in situ heart assessed using the halothane-anesthetized in vivo canine model.

This study was designed to assess the effects of typical class I drugs on the terminal repolarization process of the in situ heart, which is a useful marker of the potential of drug-induced long QT syndrome. Disopyramide (0.3 and 3.0 mg/kg per 10 min, n = 6) or mexiletine (0.3 and 3.0 mg/kg per 30s, n = 6) was intravenously administered to halothane-anesthetized beagle dogs under the monitoring of multiple cardiovascular parameters. Antiarrhythmic concentrations were obtained with the high dose of each drug. The low dose of disopyramide or mexiletine hardly affected any of the electrophysiological parameters assessed. The high dose of disopyramide prolonged the monophasic action potential duration (MAP90) and effective refractory period (ERP) to a similar extent, thus displacing the terminal repolarization period backward, which might provide a potential proarrhythmic substrate, particularly at a slow heart rate. On the other hand, the high dose of mexiletine shortened the MAP90, but prolonged the ERP, resulting in the disappearance of the terminal repolarization period, which could prevent premature excitation with its associated conduction slowing. These electrophysiological effects of disopyramide and mexiletine on the terminal repolarization phase may at least in part explain their clinically described antiarrhythmic and proarrhythmic properties.