Rate-dependent Repolarization Research Articles

Rate-Dependent Repolarization Dynamics: Correlation between Electrocardiographic T Wave and U Wave

Rate-Dependent Repolarization Dynamics: Correlation between Electrocardiographic T Wave and U Wave

ICaL and Ito mediate rate-dependent repolarization in rabbit atrial myocytes.

Rate-dependent repolarization (RDR) of action potential (AP) in cardiomyocyte plays a critical role in the genesis of arrhythmias and RDR in atrium has been linked with atrial fibrillation. However, detailed studies focusing on the role of RDR in rabbit atrium are scant. In this study, atrial cells were isolated from rabbit heart and rate-dependent property was explored in single atrial cell to elucidate the underlying mechanism. Our results indicated that rate-dependent prolongation was evident at the action potential duration at 20% (APD20) and 50% (APD50) repolarization but not at 90% repolarization (APD90) under control condition. Using transient outward potassium current (Ito) inhibitor 4-Aminopyridine (4-AP, 2mM) effectively eliminated the changes in APD20 and APD50, and unmasked the rate-dependent reduction of APD90 which could be diminished by further adding L-type calcium current (ICaL) inhibitor nifedipine (30μM). However, using the selective late sodium current (INaL) inhibitor GS-458967 (GS967, 1μM) caused minimal effect on APD90 of atrial cells both in the absence and presence of 4-AP. In consistence with results from APs, Ito and ICaL displayed significant rate-dependent reduction because of their slow reactivation kinetics. In addition, the magnitude of INaL in rabbit atrium was so small that its rate-dependent changes were negligible. In conclusion, our study demonstrated that Ito and ICaL mediate RDR of AP in rabbit atrium, while minimal effect of INaL was seen.

Latent pathogenicity of the G38S polymorphism of KCNE1 K+ channel modulator

KCNE1 encodes a modulator of KCNQ1 and KCNH2 channels. Although KCNE1(G38S), a single-nucleotide polymorphism (SNP) causing a G38S substitution in KCNE1, is found frequently, whether and how this SNP causes long QT syndrome (LQTS) remains unclear. We evaluated rate-dependent repolarization dynamics using Holter electrocardiogram (ECG) to assess the pathogenicity of KCNE1(G38S). Forty-five patients exhibiting long QT intervals, as assessed by their baseline ECGs, and 16 control subjects were enrolled. KCNE1(G38S) carriers were identified using genome sequencing. LQTS patients were classified into LQT1 or LQT2 using genetic analysis or epinephrine test. QT-RR relations were determined using 24-h Holter ECG recordings. Among the 15 patients (33.3%) with KCNE1(G38S), four patients without any mutations or amino acid changes in other major cardiac ion channels were categorized as KCNE1(G38S) carriers. In the QT-RR regression lines, the QT-RR slope was greater in the KCNE1(G38S) carriers and the LQT2 patients (0.215±0.021 and 0.207±0.032, respectively) than in the LQT1 patients (0.163±0.014, P<0.05) and the control subjects (0.135±0.025, P<0.001). The calculated QT intervals at an RR interval of 1200ms were longer in the KCNE1(G38S) carriers and LQT1 and LQT2 patients than in the control subjects. Patients with KCNE1(G38S) had a rate-dependent repolarization abnormality similar to patients with LQT2 and, therefore, may have a potential risk to develop lethal arrhythmias.

TCTAP A-129 Time of Onset of Acute Myocardial Infarction to First Balloon Dilatation and T Wave Alternans

T-wave alternans (TWA) is a heart rate dependent repolarization measurement and correlates with arrhythmia vulnerability in animal and human studies. TWA is one of established marker and can predict individuals at high risk of developing a potentially lethal cardiac arrhythmia. We evaluate the

Heterogeneous distribution of INa-L determines interregional differences in rate adaptation of repolarization.

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. The purpose of this study was to test our hypothesis that heterogeneous distribution in late sodium current (INa-L) is responsible for interregional differences in rate adaptation of repolarization. Action potential duration (APD), QT intervals, and their rate adaptation were studied in isolated arterially perfused ventricular and atrial wedge preparations. APD and INa-L were recorded in isolated rabbit myocytes using the microelectrode and the whole-cell patch clamp technique, respectively. 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, INa-L densities distributed heterogeneously and matched to interregional APDs and rate dependences as follows: left ventricle > right ventricle > left/right atria. Both dofetilide (an IKr blocker) and anemone toxin (a specific INa-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 INa-L blockade effect blunted QT/APD rate adaptation preferentially in the ventricles and significantly reduced bradycardia-dependent interregional dispersion of repolarization. Our results demonstrate that heterogeneous distribution of INa-L contributes importantly to the interregional heterogeneity of repolarization in response to rate changes and APD/QT-prolonging agents.

Role of the Late Sodium Current in Rate-Dependent Repolarization of the Canine Ventricle

Late sodium current I(NaL) is an inward current participating in maintaining the plateau of the action potential. So far its role in the repolarization of canine hearts is not well known. In this paper, by taking advantage of a computer simulation method, we developed a one-dimensional transmural tissue to study the impacts of I(NaL) on rate-dependent repolarization and its ionic basis in the canine ventricle. An OpenMP parallel algorithm was performed on a four-core personal computer to accelerate the simulation. The results demonstrated that action potential durations of midmyocytes showed greater rate dependence than the endo- and epi-myocytes. When the pacing rate was reduced, repolarization of the tissue was prolonged while the transmural dispersion of repolarization (TDR) was enlarged. The enhancement of I(NaL) further amplified this rate-dependent repolarization and TDR meanwhile increased the risk of arrhythmogenesis. I(NaL) was found highly sensitive to the pacing rate by calculating its kinetics. The study suggested that I(NaL) played an important role in the rate-dependent repolarization of the canine ventricle. Selective blockade of I(NaL) could have clinical benefits, especially for such pathological conditions with enhanced I(NaL) as long QT 3 syndrome and heart failure.

The role of the autonomic system in rate-dependent repolarization changes

The role of the autonomic system in rate-dependent repolarization changes

Abnormal transmural repolarization process in patients with Brugada syndrome

Repolarization abnormality, especially during bradycardia, might be critical for initiation of ventricular fibrillation (VF) in patients with Brugada syndrome (BrS), but the contribution of the rate-dependent repolarization dynamics to the occurrence of VF is still unknown. The aim of our study was to determine the differences in rate-dependent repolarization dynamics between BrS with and without spontaneous VF and between BrS with and without SCN5A mutation. The subjects were 37 BrS patients with VF (VF(+) group: 10 male subjects) and without VF (VF(-) group: 27 male subjects) and 20 control subjects. Genetic analysis of SCN5A was performed in all 37 BrS patients. The relationships between QT, QTp, Tp-e, and RR intervals were obtained from Holter recordings as first linear regression lines, and the slopes of QT/RR, QTp/RR, and Tp-e/RR linear regression lines as the sensitivity of rate-dependent repolarization dynamics were compared. QT/RR and Tp-e/RR slopes showed loss of a rate-dependent property in the VF(+) group compared with those in the VF(-) and control groups. There was no significant difference in QTp/RR slope among the VF(+), VF(-) and control groups. The Tp-e interval had a negative correlation with the RR interval in the VF(+) group and a positive correlation with the RR interval in the VF(-) and control groups. There was no significant difference in QT/RR, QTp/RR, and Tp-e/RR slopes between BrS patients with SCN5A mutation and those without SCN5A mutation. Loss of rate-dependent QT dynamics may be associated with occurrence of VF in BrS.

Modelling the molecular basis of cardiac repolarization

To study the properties of ion-channel gating (I(Ks), the slow delayed rectifier K+ channel) that underlie the channel's participation in rate-dependent repolarization of the cardiac action potential (AP). Computational biology approach was used to simulate the channel gating and the AP of a mammalian ventricular myocyte. At fast rate, channels accumulate at closed state near the open state, from which they can rapidly open to generate large repolarizing current late during the AP, effectively shortening its duration. I(Ks) builds an 'available reserve' of channels that can open 'on-demand' to repolarize the AP and shorten its duration at fast rate ('rate-adaptation'). This property also makes I(Ks) effective in providing repolarization reserve when other repolarizing currents are compromised by disease or drugs.

Abstract 1829: Circadian Changes in ST-RR and QT-RR Relationships During Daily Life of Patients with Brugada Syndrome

In patients with Brugada syndrome, abnormal rate-dependent repolarization dynamics has been proposed as a modulating factor of arrhythmogenesis. In the present study, we assessed the hypothesis that circadian changes in both ST-RR and QT-RR relationship could relate to occurrence of ventricular fibrillation (VF) in daily life of patients with Brugada syndrome. Methods: Thirty-five male patients with Brugada syndrome who had the type I ST elevation were categorized into 14 symptomatic (with documented VF or syncope) and 21 asymptomatic groups. Unipolar V 2 and V 5 leads digital Holter ECG was recorded, and ST level in V 2 and QT interval in V 5 were automatically measured. Both ST-RR and QT-RR relationships were evaluated by means of ST-RR and QT-RR linear regression lines according to four 6-hour periods. In all 14 symptomatic patients, the time of spontaneous episodes of VF were investigated from the implantable cardioverter defibrillator stored data. Results: In symptomatic patients, ST-RR slope was highest during 18:00–24:00 and was lowest during 0:00 – 6:00; however, these circadian changes were blunted in asymptomatic patients. ST-RR intercept was not different between the 2 groups and didn’t show distinct circadian changes in both groups. The QT-RR slope was always lower, except during 6:00–12:00, in symptomatic patients than in asymptomatic patients. Circadian changes in QT-RR relationship were not evident in both groups. QT-RR intercept was not different between the 2 groups and didn’t show distinct circadian changes in both groups. Nineteen (59%) of total 32 episodes of spontaneous VF of 14 symptomatic patients occurred between 18:00 and 24:00, and 9 episodes (28%), between 0:00 and 6:00. VF seldom occurred during the daytime. Conclusions: In symptomatic patients with Brugada syndrome, a combination of augmentation of ST elevation with inhibited prolongation of QT interval during bradycardia could relate to an occurrence of VF in the late evening. Circadian Changes in ST-RR and QT-RR Slopes

Comparison of acute effects of anthracyclines on cardiac electrophysiological parameters of isolated guinea-pig hearts

This study was performed to evaluate the acute effects of two anthracycline derivatives, doxorubicin and 4'O-tetrahydropyranyl-doxorubicin [(THP)-doxorubicin], on the conduction intervals, heart rate and refractoriness of isolated spontaneously beating guinea-pig hearts using a high-resolution ECG recording technique (SST-ECG). Doxorubicin as well as (THP)-doxorubicin were added to the perfusate in increasing concentrations of 0.1, 1 and 10 microM. Doxorubicin did not significantly alter the heart rate or conduction intervals. Only the rate-dependent QT interval was significantly shortened under the influence of 10 microM doxorubicin. In contrast, 10 microM (THP)-doxorubicin led to a significant reduction in the heart rate (-13% +/- 3%; P less than 0.01, n = 7) and to a prolongation of atrioventricular conduction time (24% +/- 10%; P less than 0.05, n = 7). The rate-dependent repolarization period (QT interval) was only insignificantly shortened in the presence of 10 microM (THP)-doxorubicin. The maximal following frequencies of each part of the conduction system were not changed by 10 microM doxorubicin. In the presence of (THP)-doxorubicin, the maximal following frequency of the ventricular myocardium was increased by as much as 36% +/- 8% (P less than 0.01, n = 7), indicating a shortening of the effective refractory period of the ventricular myocardium (V-ERP). These results show that the activation of (THP)-doxorubicin resembles the effects of Ca-antagonistic compounds on the heart (i.e. decrease in the spontaneous sinus rate and prolongation of the AV-nodal conduction interval). Changes in the QT interval exerted by doxorubicin and the shortening of the ventricular effective refractory period by (THP)-doxorubicin may indicate an alteration of the K(+)-conductance of the membrane. As the acute electrophysiological effects of doxorubicin and (THP)-doxorubicin are modest and occur only at excessive concentrations (10 microM), a direct influence on the generation of arrhythmias in healthy hearts is unlikely.