Repolarization Interval Research Articles

Investigating the effect of sotalol on the repolarization intervals in healthy young individuals

Background The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced prolongations of the QTc, QTc apex and T-peak to T-end intervals. Methods We implemented a set of parameters describing the morphology of the T loop in its preferential plane. These parameters measure the time interval needed for the heart vector amplitude to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%, and 70%. These measurements are called early repolarization duration (ERD) when they are located before the T-wave apex and late repolarization duration (LRD) when measured after the apex. They depend on both the speed of the repolarization process and the morphology of the T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The plasma concentration of the drug was measured just before the ECG recordings. Results The values of all investigated parameters revealed a dose-dependent effect of sotalol (in average between parameters, ρ = 0.9, P < .001). Our investigations described profound and statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of sotalol: ΔERD 50% = 23 ± 6 msec, P < .05; ΔLRD 50% = 8 ± 3 msec, P = .05) and day 2 (peak effect of sotalol: ΔERD 50% = 51 ± 14 msec, P < .05; ΔLRD 50% = 20 ± 12 msec, P = .05). When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs (≥3.5 hours after dosing) and QTc/QTc apex profiles (<3.5 hours after dosing), suggesting that the time of maximum prolongation on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization. Conclusion This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel vectocardiographic parameters. These observations might help in improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.

Repolarization of the rabbit cardiac ventricles after an increase of potassium concentration in the plasma

The sequence of ventricular epicardium repolarization in rabbits with hypokalemia is directed from the apex of the heart to its base in accordance with distribution of local repolarization intervals. Under conditions of hyperkalemia, the propagation of excitation wave is inhibited without changes in its sequence; while the duration of repolarization decrease mainly in zones where it was initially long (the base of the right ventricle), as a result of which the distribution of local repolarization intervals becomes more uniform and a relationship between the repolarization and activation sequences is formed.

Improving the Detection of Subtle IKr-Inhibition

QT prolongation is an incomplete measure of drug-induced changes in repolarization. In this study, we investigated a novel, automatic ECG technique for describing ventricular repolarization morphology and we compared these results to corrected QT (QTc) prolongation for identifying ECGs of healthy individuals on moxifloxacin. We analysed data from the US FDA ECG Warehouse involving 160 standard ECGs from 40 healthy subjects enrolled in a randomized, parallel, placebo-controlled, 'thorough QT' study. Computerized ECG analysis included a series of scalar and vectorial parameters describing duration of repolarization segments and T-wave/loop morphology including its symmetry, amplitude and shape. Binary logistic models for the identification of moxifloxacin-induced abnormalities of the repolarization were developed. Moxifloxacin induced significant changes in several ECG parameters including QT and QT apex and early repolarization duration (ERD)(30)(%), T-wave amplitude and slopes of the ascending and descending arm of the T-wave. The logistic model based only on T-wave morphology parameters outperformed the model based on QTc interval for identifying the presence of moxifloxacin. Combining information about repolarization interval duration with T-wave morphology significantly improved the detection of presence of moxifloxacin (p < 0.01). The increased sensitivity of our novel ECG method contributes to a >40% reduction in the sample size required to detect significant QTc prolongation induced by moxifloxacin. Repolarization morphology is significantly altered by moxifloxacin. The computerized ECG technique provides a novel method for quantifying morphological changes of repolarization segment. Our new parameters reflecting the morphology of the T-wave outperformed QTc measurements when identifying moxifloxacin-induced blockade of the outward rapid components of the delayed rectifier repolarizing potassium current (I(Kr)). These data indicate that the analysis of T-wave morphology could play a role in the assessment of drug toxicity.

Spatial heterogeneity of myocardial perfusion predicts local potassium channel expression and action potential duration

In the heart, there is not only a transmural gradient of left ventricular perfusion and action potential duration (APD), but also spatial heterogeneity within each myocardial layer, where local blood flow and energy turnover vary more than three-fold between individual regions. We analysed at high spatial resolution whether a corresponding heterogeneity also extends to ion channel gene expression and APD. In the open-chest beagle dog, left ventricular 300 microL samples of very low or high flow were identified by radioactive microspheres and expression levels determined by quantitative PCR. The distribution of epicardial APD was assessed by mapping local activation repolarization intervals (ARIs) and QT interval (QT). ERG, the potassium channel mediating IKr, and KChIP2, the interacting protein modulating Ito, were increased in Low flow (3.3- and 2.5-fold, P < 0.001 and <0.05, respectively; n = 6 hearts, 30-31 samples each) as compared with High flow areas. This suggested enhanced repolarizing currents in Low flow areas, and in consequence, mathematical model analysis predicted a shorter local APD upon enhanced ERG and IKr. Epicardial mapping revealed a patchy, temporally stable APD pattern (n = 11), a small apico-basal gradient and an APD prolongation induced by the ERG blocker dofetilide predominantly in areas of short basal ARI or QT, respectively (n = 9). In addition, in Short QT areas, ERG expression was three-fold increased (P < 0.05, n = 4). The spatial pattern of perfusion is matched by the novel patterns of K+ channel expression and APD. Whenever this newly recognized intramural dispersion of APD increases, it may contribute to arrhythmogenesis.

Abstract 2859: Baseline Values and Drug-induced Changes of the Ventricular Repolarization Morphology in the Electrocardiograms of Patients with a History of Drug-induced Torsades de Pointes.

Background: Assessing propensity to torsades de pointes (TdP) when exposed to QT-prolonging drug is challenging because baseline QT-prolongation has limited predictive value for identifying risk of TdP. The aim of this study was to determine whether computer-based repolarization morphology parameters could identify individuals who developed drug-induced TdP. Method: Five-minute standard digital 12-lead ECGs were acquired at baseline and after a controlled sotalol challenge (2 mg/kg BW, i.v.) in 34 cardiac patients of whom 17 had a history of TdP (+TdPs) in the context of a QT prolonging drug and 17 had no history of TdP (-TdPs).Computerized ECG parameters including QT, TpTe (T peak to T end interval) and a morphological measure of the duration of the early part of the repolarization interval (ERD) were implemented. All parameters were corrected for the effect of heart rate (HR). Results: There were 9 females among the + TdP patients and 12 females in the -TdP group (p = 0.8). The drugs triggering TdPs were: antidepressant, antibiotics, antiarrhythmic and anti-migraine. They included sotalol, amiodarone, bisacodyl, erythromycin, imipramime, cipramil and sumatriptan. The table below shows the comparison of baseline values and the on-sotalol changes of the repolarization parameters after HR correction. The analysis revealed a longer QT interval duration at baseline in patient +TdPs. This prolongation was only present in the early part of the T-wave (ERD, p = 0.02). On sotalol, the patients with a history of TdPs have longer QT prolongation associated with a significant increased late part of the repolarization (TpTe, p = 0.01). Conclusion : Our results revealed that specific repolarization features are present at baseline and on sotalol challenge in patients with and without history of TdPs. These parameters could complement the role of the QT prolongation as a proarrhythmic surrogate marker. Baseline values and sotalol-induced changes in ECG parameters

Study of ventricular repolarization changes after carnitine deprivation in rats by contactless magnetocardiography

Carnitine deficiency can be associated with cardiomyopathy and life-threatening arrhythmias. The aim of this study was to assess changes of ventricular repolarization (VR) intervals by contactless magnetocardiographic mapping (MCG), in a rat model of carnitine deficiency. 21 anesthetized Wistar rats (WR), 11 males and 10 females, were investigated, with an unshielded 36-channel MCG instrumentation. After a basal recording 10 animals were randomized to carnitine-deprivation induced by a 3-weeks diet containing N-trimethyl-hydrazine-3-propionate (THP). All WR were restudied 1 week after the end of THP treatment. RR, QRS, QT peak, QT end, JT peak, JT end and T peak-end intervals were measured from MCG waveforms. A prolongation of all HR-corrected VR intervals was observed in THP-treated animals (range 7.6–12.8%), as compared to their basal values. However, only the lengthening of QT end and T peak-end was statistically significant ( p < 0.05). Compared to untreated age-matched controls, the cardiac intervals of TPH-treated WR values were longer, but the differences were not significant. After 3 weeks of THP-induced reduction of cardiac and plasma levels of carnitine, abnormalities in myocardial function are expected. In this study we have found only a prolongation of HR-corrected QT end and T peak-end in THP-treated animals. The lack of significance versus age-matched controls could be either due to too early re-evaluation after deprivation, or to the effect of aging. In fact, age-related prolongation of VR intervals has been reported in WR at the age of 14 months.

Changes in T‐type calcium channel and its subtypes in overactive detrusor of the rats with partial bladder outflow obstruction

To investigate the activity of the T-type calcium channel (TCC) and the expression of its subtypes in overactive detrusor (OD) myocytes in rats after partial bladder outflow obstruction (PBOO). Thirteen male Wistar rats with OD after PBOO (OD group) and eight sham-operated rats (control group) were studied. The two groups were compared regarding the expression of TCC subtype genes by reverse transcription-polymerase chain reaction (RT-PCR) and the TCC kinetics and cell action potential by whole-cell patch-clamp. The time course and density of the current were significantly higher in the OD cells than those in the control detrusor. Whole-cell patch-clamp analysis showed that the activation of TCCs in detrusor myocytes in the OD group was faster than the control group, but inactivation was almost the same in both groups, suggesting a significant enhancement of the Ca(2+) "window" current in the OD group. Patch-clamp recording of action potentials in the OD cells indicated an increase in excitability and a decrease in the repolarization interval. RT-PCR assay showed an abnormal expression of alpha1G subtype in the OD cells. TCCs could be one of the crucial factors for the abnormal excitation in OD cells. The development of OD after PBOO presumably relates to the increase in TCC current in the bladder cells, the enhancement of the Ca(2+) "window" current for Ca(2+) inflow, the prolongation of the intracellular calcium oscillations, and the acceleration of the cell depolarization.

Differences in QT interval determined from multi-lead ambulatory ECG during rest and physical exercise

Background Multi-lead ambulatory ECG recording offers recognised advantages for ventricular depolarisation–repolarisation (QT) interval analysis, especially during physical exercise. However, data are usually reported for a single lead and do not quantify between-lead variability, leading to possible misinterpretation. The aim of this study was to quantify between-lead agreement for QT recorded during rest and exercise. Method Nine males and eight females of similar age and aerobic fitness undertook progressive sub-maximal bicycle exercise. A three-lead ECG was recorded continuously during pre-exercise, exercise and recovery. Beat-to-beat cardiac cycle (RR) and QT data were measured for each sinus beat. Bland–Altman analysis was used to quantify between-lead agreement for RR and QT intervals, and the influence of gender was assessed. Results Mean between-lead bias was significantly ( p < 10 −6) greater for QT compared with RR, and in males the limits of agreement (LOA) for QT was significantly ( p < 10 −6) greater than for RR. Relative to mean parameter values the between-lead LOA for RR was low, with maximal values (% of mean) of 0.1% (male) and 0.3% (female). Paired-lead bias for RR was also relatively low (5.0% and 6.7%), but paired-lead bias for QT (8.3% and 6.9%) and paired-lead LOA for QT (13.1% and 12.8%) were notably larger. Conclusion The RR interval can be measured with equivalent accuracy and reliability from any ECG lead that demonstrate good signal quality. However, the between-lead bias and LOA for QT interval data should be quantified when reporting results from a multi-lead ambulatory ECG. Interpretation of the results of such studies should take account of between-lead and between-gender QT differences, and should note the physiological conditions during recording.

Hysteresis of electrocardiographic depolarization–repolarization intervals during dynamic physical exercise and subsequent recovery

The post-exercise electrocardiographic QT interval is shortened relative to that at similar heart rates during exercise or pre-exercise rest. This lag in QT adaptation to the recovering heart rate is described as ‘hysteresis’. No previous studies have quantified the influence of ECG electrode placement on hysteresis following physical exercise. Six males and six females of similar age, mass and aerobic fitness undertook progressive sub-maximal bicycle exercise. A three-channel ECG was recorded continuously during pre-exercise, exercise and recovery. Beat-to-beat NN (cardiac interval) and QTa interval (Q wave onset to T wave apex) data were measured for each sinus heart beat. QTa–NN hysteresis was calculated as the difference in QTa magnitude at identical heart rates during the rest/exercise and post-exercise recovery periods. There were some significant (p < 0.05) between-channel and between-gender differences in calculated hysteresis values. Hysteresis was generally greatest during the second or third minute post-exercise; ranges of means for all channels were 10.9 ± 11.7 ms to 25.5 ± 16.8 ms (males) and 19.1 ± 10.3 ms to 28.4 ± 3.0 ms (females). For males only, hysteresis values calculated using channel 1 between 1 and 3 min post-exercise were generally significantly (p < 0.05) different to those between 4 and 10 min. Similar trends were observed in females. QTa–NN hysteresis is significantly affected by the locations of the ECG electrodes used to record the surface ECG. These results emphasize the need for standardization of ECG electrode placement in future investigations.

Novel indices of ventricular repolarization to screen post myocardial infarction patients

We propose novel indices of ventricular repolarization intervals, the JTp/JT, Tpe/JTp and Tpe/JT ratios. These indices have been compared with the duration of the ventricular repolarization intervals and other ratios in 17 normal subjects and 17 patients with old myocardial infarction. In the intervals and other ratios, the best separation between groups is obtained with the Tpe/QTp and Tpe/QT ratios with 94% sensitivity and 82% specificity, the proposed ratios increased sensitivity to 100% and specificity to 94%. These indices should be further tested to determine their usefulness in discriminating between OMI patients with and without susceptibility to ventricular arrhythmias.

Spinal cord activation differentially modulates ischaemic electrical responses to different stressors in canine ventricles

Spinal cord stimulation (SCS) represents an acceptable treatment modality for patients with chronic angina pectoris refractory to standard therapy, but its mechanism of action remains unclear. To develop an experimental paradigm to study this issue, ameroid (AM) constrictors were implanted around the left circumflex coronary artery (LCx) in canines. Six weeks later, unipolar electrograms were recorded from 191 sites in the LCx territory in the open-chest, anesthetized state under basal pacing at 150 beats/min. We investigated the effect of SCS on ST segment displacements induced in the collateral-dependent myocardium in response to two stressors: (i) transient bouts of rapid ventricular pacing (TRP: 240/min for 1 min) and (ii) angiotensin II administered to right atrial neurons via their coronary artery blood supply. ST segment responses to TRP consisted of ST segment elevation in central areas of the LCx territory and ST depression at more peripheral areas. Such responses were unchanged when TRP was applied under SCS. Shortening of repolarization intervals in the metabolically compromised myocardium in response to TRP was also unaffected by SCS. In contrast, ST segment responses to intracoronary angiotensin II, which consisted of increased ST elevation, were attenuated by SCS in 6/8 preparations. The modulator effects of SCS were greatest at sites at which the greatest responses to angiotensin II occurred in the absence of SCS. These data indicate that spinal cord stimulation may attenuate the deleterious effects that stressors exert on the myocardium with reduced coronary reserve, particularly stressors associated with chemical activation of the intrinsic cardiac nervous system.

Identification of sotalol-induced changes in repolarization with T wave area-based repolarization duration parameters

In this study, we investigated the validity of T wave area-based parameters for the identification of drug-induced changes of repolarization. Based on electrocardiograms from 39 healthy patients, we computed the stability of repolarization measurements and compared the sotalol-induced repolarization changes when measured with area-based parameters and traditional QT interval techniques (manual and automatic). Also, we evaluated the effect of different types of heart rate correction on these repolarization measurements. The results show that the stability of the automatic repolarization measurements is higher when measured using computer algorithm than using manual QT measurement. By using a population-based heart rate correction, the area-based parameters reveal significant modification of the overall shape of the T wave in its early, middle, and final part. In conclusion, morphological parameters of T wave are able to identify the changes in repolarization interval induced by sotalol. These parameters are more stable and thus more reliable than the traditional QT interval measurements.

Marginal copper and high fat diet produce alterations in electrocardiograms and cardiac ultrastructure in male rats.

This study investigated whether a high fat diet in tandem with a marginal copper (Cu) diet exerts deleterious effects on copper status, cardiac morphology, and electrophysiology compared to a low-fat marginal copper diet. Male weanling Long-Evans rats were fed diets containing either marginal copper (42.5 mumol/kg) or adequate copper (97.6 mumol/kg), and low fat (50.0 g/kg) or high fat (150.0 g/kg) diet for 12 wk in a 2 x 2 factorial design. To simulate the western diet, fat was composed of a 1:2 polyunsaturated:saturated fatty acids using a coconut and corn oil mixture. High dietary fat increased liver Cu concentration. Marginal copper diets decreased liver Cu,Zn-superoxide dismutase activity. Dietary copper and fat level had no effect on volume densities of mitochondria and myofibril. However, lower mitochondrial pathologic scores were observed in the rats consuming the high fat diets. Marginal copper high fat diet prolonged atrial electric depolarization (PR) and ventricular electric depolarization and repolarization (QT) intervals. This study provided direct evidence that a high fat diet can exert detrimental effects on cardiac ultrastructure and lead to alterations in electrocardiograms. The combination of marginal copper-high fat diet appears to alter cardiac electric conductivity. Longer term studies should provide information more relevant to clinical situations and morphologic changes.

Conditional entropy approach for the evaluation of the coupling strength.

A method that enables measurement of the degree of coupling between two signals is presented. The method is based on the definition of an uncoupling function calculating, by means of entropy rates, the minimum amount of independent information (i.e. the information carried by one signal which cannot be derived from the other). An estimator of the uncoupling function able to deal with short segments of data (a few hundred samples) is proposed, thus enabling the method to be used for usual experimental recordings. A synchronisation index is derived from the estimate of the uncoupling function by means of a minimisation procedure. It quantifies the maximum amount of information exchanged between the two signals. Simulations in which non-linear coordination schemes are produced and changes in the coupling strength are artificially induced are used to check the ability of the proposed index to measure the degree of synchronisation between signals. The synchronisation analysis is utilised to measure the coupling strength between the beat-to-beat variability of the sympathetic discharge and ventilation in decerebrate artificially ventilated cats and the degree of synchronisation between the beat-to-beat variability of the heart period and ventricular repolarisation interval in normal subjects and myocardial infarction patients. The sympathetic discharge and ventilation are strongly coupled and the coupling strength is not affected by manoeuvres capable of increasing or depressing sympathetic activity. The synchronisation is lost after spinalisation. The synchronisation analysis confirms that the heart period and ventricular repolarisation interval are well coordinated. In normal subjects, the synchronisation index is not modified by experimental conditions inducing changes in the sympathovagal balance. On the contrary, it strongly decreases after myocardial infarction, thus detecting and measuring the uncoupling between the heart period and ventricular repolarisation interval.

Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry.

Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated the hypotheses that: (1) the activation patterns of the initial PVT beats would be consistent with an origin in the ventricular conduction system; and (2) the inhomogeneous prolongation of repolarisation intervals can provide refractory barriers for re-entrant activity. Unipolar electrograms were recorded from 127 epicardial (EPI) sites with a sock electrode array as well as from intramural and endocardial sites during PVTs. Electrograms were analysed to generate isochronal maps and measure the spatial distribution of activation-recovery intervals (ARI). Under S (9.9-14.5 mg.l-1), spontaneously terminating PVTs (cycle length of 270 +/- 43 ms, n = 45) (mean +/- s.d.) occurred when a PE bolus (10-50 micrograms.kg-1) was injected. The first beat of the PVTs occurred with a coupling interval of several hundred ms to the preceding idioventricular beat (IDV) without any bridging activity and its earliest EPI breakthrough occurred in areas overlying the terminations of the right or left bundle branch. ARI values measured in IDV (295 +/- 47 ms) were significantly prolonged prior to PVT (462 +/- 92 ms). Prolongation was greater in apical than in basal epicardial areas, and at endocardial than epicardial sites (to > 500 ms). Maximum delays > 200 ms developed in the regions of marked ARI prolongation and, in later beats, circus movement re-entry occurred around refractory barriers, shifting between various regions of the ventricles. Thus, PVTs occurring spontaneously under conditions of delayed repolarisation originate from shifting sites in the ventricular conduction system and re-entrant activity shifting between various regions of the ventricle may occur in later beats of the more sustained arrhythmias.

Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome.

To improve the diagnostic criteria of the congenital long QT syndrome in borderline cases we examined rate adaptation of ventricular repolarization phases during exercise and subsequent recovery in children with the long QT syndrome and controls. Nineteen children with definite long QT syndrome and 19 healthy controls underwent exercise testing. QT intervals were measured to the apex (early QT), to the end (total QT) and from apex to the end of the T wave (late QT) at heart rates from 90 by steps of 10 to 150 beats, min-1. In 11/19 long QT syndrome patients (61%) and 2/19 controls (12%) the total QT lengthened during the recovery phase compared with exercise (P = 0.005) at the lowest comparable heart rate. No difference was found between the groups during exercise. The sensitivity of rate adaptation of repolarization intervals was analysed by calculating linear regression slopes relating the QT intervals to the heart rates. During recovery, slopes relating the total QT to heart rate were steeper in long QT syndrome patients than those in controls (-2.50 +/- 0.82 vs -1.79 +/- 0.47, P = 0.003). Total QT/heart rate slopes differed between exercise and recovery phases in the long QT syndrome group only (-1.77 +/- 0.71 vs 2.50 +/- 0.82, P = 0.009). In long QT syndrome patients, the difference in total QT/heart rate slopes was mainly because the late QT/heart rate slopes indicating inhomogeneity of repolarization were steeper during recovery (-1.27 +/- 0.74) than during exercise (-0.46 +/- 0.29, P < 0.0001). After exercise in long QT syndrome children the QT interval lengthens abnormally and inhomogeneity of repolarization increases. Evaluation of the QT interval, and especially its late portion after exercise, may help in establishing the diagnosis of long QT syndrome.

Quantifying electrocardiogram RT-RR variability interactions.

A dynamic linear parametric model is designed to quantify the dependence of ventricular repolarisation duration variability on heart period changes and other immeasurable factors. The model analyses the beat-to-beat series of the RR duration and of the interval between R- and T-wave apexes (RT period). Directly from these two signals, a parametric identification procedure and spectral decomposition techniques allow RT variability to be divided into RR-related and RR-unrelated parts and allow the RT-RR transfer function to be calculated. RT variability is driven by RR changes at low frequency (LF, around 0.1 Hz) and high frequency (HF, at the respiratory rate), whereas, at very low frequencies, the RR-unrelated contribution to the total RT variability is remarkable. During tilt at LF the RR-related RT percentage power increases (p < 0.02), the RR-unrelated RT percentage power remains unchanged, the gain of the RT-RR relationship largely increases (p < 0.001), and the phase is not significantly modified. Both the RR-related and the RR-unrelated RT percentage powers at LF are not affected by controlled respiration, and an increase in the RT-RR gain at HF is observed (p < 0.02). The proposed analysis may help to describe the regulation of the ventricular repolarisation process and to extract indexes quantifying the coupling between heart period and ventricular repolarisation interval changes.

Electrophysiological abnormalities and arrhythmias in alpha MHC mutant familial hypertrophic cardiomyopathy mice.

A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of familial hypertrophic cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise. Wild-type animals had completely normal cardiac electrophysiology. In contrast, FHC mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiological abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy. These data identify distinct electrophysiologic abnormalities in FHC mice with a specific alpha-myosin mutation, and also validate a novel method to explore in vivo the relationship between specific genotypes and their electrophysiologic phenotypes.

Excitation-contraction coupling of cultured human skeletal muscle cells and the relation between basal cytosolic Ca 2+ and excitability

Cultured human skeletal muscle cells are frequently used as a model to study muscle pathology, in which Ca 2+ homeostasis might be affected. However, their excitation-contraction (E-C) coupling has been poorly investigated. In order to elucidate E-C coupling of cultured muscle cells, we activated the acetylcholine receptors, voltage-dependent Na + channels, dihydropyridine receptors or ryanodine receptors both in the presence and absence of external Ca 2+, as well as after specific inhibition, and measured the effects on the cytosolic Ca 2+ concentration ([Ca 2+] i) using Fura-2. Furthermore, we examined the excitability of these cells during iterative high (125 mM) K + stimulation with various repolarisation intervals. The resting [Ca 2+] i in muscle cells of controls is about 130 nM. Acetylcholine, veratridine, high K + and caffeine elicit dose-dependent Ca 2+ transients, which are independent of extracellular Ca 2+ and can be inhibited by α-bungarotoxin, tetrodotoxin, nifedipine or ryanodine. During repetitive K + stimulation, the excitability of the muscle cells depends on the repolarisation interval between successive stimulations. Upon shortening the repolarisation time the Ca 2+ transients become smaller and slower. Thereby, the basal [Ca 2+] i rises, the Ca 2+ response amplitude declines and both the half-increase and half-decay time increase. However, if the basal [Ca 2+] i equals the resting [Ca 2+] i, the initial Ca 2+ response can be recovered. The intracellular pH of 7.23, measured by BCECF, is unaffected by repeated K + stimulation, whatever the repolarisation interval was. In conclusion, cultured human skeletal muscle cells possess a ‘skeletal muscle type’ of E-C coupling and their excitability at iterative stimulation is set by their basal [Ca 2+] i.

QT interval and repolarization time in patients with intraventricular conduction delay

A prolonged QT interval is an important prognostic indicator for cardiac arrhythmias and sudden death. The conventional QT interval measurement, however, includes in its measure the cardiac depolarization (QRS) as well as the cardiac repolarization (JT) intervals. To evaluate the relative contribution of the depolarization and the repolarization time prolongation to the prolonged QT interval in patients with intraventricular conduction delay (IVCD), the QRS, QT, and JT intervals were measured in 72 subjects with various types of IVCD. The observed intervals in IVCD subjects were compared to similar intervals in 33 healthy individuals in whom there was no evidence for intraventricular conduction abnormalities. The QTc (QT interval corrected for heart rate) in subjects with IVCD were 445 +/- 6.8 msec (mean +/- SEM) in those with LAD, 470 +/- 9.1 msec with RBBB, and 489 +/- 6.9 msec with LBBB. All of these intervals were significantly prolonged compared to 430 +/- 4.3 msec in the control group. The prolongation of QTc interval in each category of IVCD subjects was entirely secondary to a prolonged depolarization time, as the repolarization intervals were not significantly different from those observed in the control group (F = 0.5, p = NS). These observations may provide an explanation for the differential prognosis for subjects with prolonged QT interval with prolonged repolarization time as compared to those with prolonged QT interval with prolonged depolarization time.