Repolarization Time Research Articles

Quantification of ventricular repolarization heterogeneity during moxifloxacin or sotalol administration using -index

Drug-induced alterations of ventricular heterogeneity must be limited to avoid induction of lethal ventricular arrhythmias. In here, a new parameter called -index, able to measure the standard deviation of myocites' repolarization times, was evaluated after moxifloxacin and sotalol administration. The two drugs are known to provide different alteration of the QT interval length ranging from subtle (moxifloxacin) to evident (sotalol). In fact, while the former is employed as active-comparator in thorough QT studies, the latter might induce torsades de pointes. 24 h Holter ECGs of 39 (sotalol) and 68 (moxifloxacin) healthy subjects were retrospectively analyzed. The recordings were performed after infusion of the drugs and after the placebo (moxifloxacin) or at baseline (sotalol). The corrected QT interval (QTc) was included as well in the study, for a direct comparison. In both populations, -index and QTc increased along with the drugs' serum concentration and were statistically different from values in the placebo arm or at baseline (p < 0.05).With sotalol, the maximum value of -index occurred, on average, after 5.64 h from the infusion, whereas for QTc after about 4.27 h. The two metrics displayed evident changes (-index: 27.79 ms ± 4.89 ms versus 60.13 ms ± 18.52 ms; QT corrected: 387.07 ms ± 19.84 ms versus 437.76 ± 32.05 ms; p < 0.05). Regarding moxifloxacin, maximum values were reached, on average, 5.01 h after administration for -index (30.70 ms ± 8.32 ms versus 40.48 ms ± 7.61 ms; p < 0.05), and 4.37 h for QTc (404.29 ms ± 29.05 ms versus 426.77 ± 36.67 ms; p < 0.05). They were statistically different from baseline values. With both drugs, the maximal percent variation after administration was higher for -index than QTc (moxifloxacin: 34.56% ± 24.60% versus 5.56% ± 2.98% ; sotalol: 114.77% ± 33.15% versus 12.13% ± 2.85% ; p < 0.05).The study suggests that the standard deviation of the ventricular repolarization times, as quantified by the -index, might be an effective measure of spatial heterogeneity.

Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome.

Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. We simultaneously recorded surface ECG and unipolar electrograms at baseline and after dofetilide in a canine model of dofetilide-induced LQT2 (6 male mongrel dogs). Standard ECG variables, T-wave duration, and moments of peaks of bifid T waves (Tp1 and Tp2) were correlated with moments of local repolarization. Epicardial electrograms were recorded over the left ventricular (LV) and right ventricular (RV) anterior walls (11 × 11 electrode grid, 5-mm interelectrode distance). In 5 of the 6 hearts, we also recorded intramural unipolar electrograms (n = 4-7 needles per heart). In each unipolar recording, we determined activation time, repolarization time (RTs), and activation-recovery interval. In addition, we studied RT response to heart rate changes. Dofetilide prolonged QT and QTc, induced bifid T waves in 4 of 6 animals, and prolonged RT heterogeneously in LV and RV, resulting in increased interventricular and LV intraventricular RT dispersion. Dofetilide did not induce a disparate response in activation-recovery interval across the transmural axis. Dofetilide-induced separation of RT across the RV-LV interface concurred with the moments of T-wave peaks. Dofetilide-induced steepening of restitution slopes was larger in LV than RV. Dofetilide-induced bifid T waves result from interventricular RT dispersion.

Cardiomyopathy confers susceptibility to particulate matter-induced oxidative stress, vagal dominance, arrhythmia and pulmonary inflammation in heart failure-prone rats

Acute exposure to ambient fine particulate matter (PM2.5) is tied to cardiovascular morbidity and mortality, especially among those with prior cardiac injury. The mechanisms and pathophysiological events precipitating these outcomes remain poorly understood but may involve inflammation, oxidative stress, arrhythmia and autonomic nervous system imbalance. Cardiomyopathy results from cardiac injury, is the leading cause of heart failure, and can be induced in heart failure-prone rats through sub-chronic infusion of isoproterenol (ISO). To test whether cardiomyopathy confers susceptibility to inhaled PM2.5 and can elucidate potential mechanisms, we investigated the cardiophysiologic, ventilatory, inflammatory and oxidative effects of a single nose-only inhalation of a metal-rich PM2.5 (580 µg/m3, 4 h) in ISO-pretreated (35 days × 1.0 mg/kg/day sc) rats. During the 5 days post-treatment, ISO-treated rats had decreased HR and BP and increased pre-ejection period (PEP, an inverse correlate of contractility) relative to saline-treated rats. Before inhalation exposure, ISO-pretreated rats had increased PR and ventricular repolarization time (QT) and heterogeneity (Tp-Te). Relative to clean air, PM2.5 further prolonged PR-interval and decreased systolic BP during inhalation exposure; increased tidal volume, expiratory time, heart rate variability (HRV) parameters of parasympathetic tone and atrioventricular block arrhythmias over the hours post-exposure; increased pulmonary neutrophils, macrophages and total antioxidant status one day post-exposure; and decreased pulmonary glutathione peroxidase 8 weeks after exposure, with all effects occurring exclusively in ISO-pretreated rats but not saline-pretreated rats. Ultimately, our findings indicate that cardiomyopathy confers susceptibility to the oxidative, inflammatory, ventilatory, autonomic and arrhythmogenic effects of acute PM2.5 inhalation.

Chronic Hyperglycemia and Inhomogenous Ventricular Repolarisation - an Electrophysiological Approach

The QT interval expresses the myocardial depolarization and repolarisation time. QTd is regarded as an index of myocardial electrical activity. Present study was done to investigate the differences in QTd between non-diabetics, well controlled diabetes patients and poorly controlled diabetics. The study group comprised of 60 type 2 diabetes patients within the age group of 40–60 years coming to diabetic clinic and those hospitalized in medicine wards, They were further classified in to two sub-groups(n = 30 in each group), Type2 diabetes patients with good glycemic control (HbA1c 7). Glycosylated hemoglobin level was detected by calorimetric method (spectronic -2). The control group consisted of 30 age matched healthy subjects (volunteers). After thorough examination of the subjects as per the proforma, 12 lead ECG was taken with (Montara instrument ELI 250), QT interval was measured on the 12 lead resting ECG. QTd was calculated manually. The value of QT dispersion was significantly high (p < 0.01) in Type2 Diabetes mellitus patients with poor glycemic control compared to well controlled diabetics and healthy subjects. Chronic hyperglycemia is associated with high QT dispersion which suggests that such patients have a greater inhomogeneity of repolarization and therefore they are more prone for adverse cardiovascular events.

Extra-Coding Characteristics of hERG mRNA are Essential for Channel Function

The KCNH2 gene encodes the hERG protein, the alpha subunit of the rapid delayed rectifying potassium channel. This potassium channel plays an essential role in cardiac repolarization, and malfunction of this channel caused by mutation leads to Long QT Syndrome, type 2 (LQT2). LQT2 causes increased repolarization time in the heart, leading to ventricular arrhythmias, syncope and sudden death. There are over 600 documented mutations in KCNH2 associated with Long QT syndrome, with more mutations being reported regularly. These mutations occur throughout the length of the gene, without definitive mutational hotspots.While much investigation has been done to characterize the impact that these mutations have on the hERG channel function, little investigation has been focused on what causes the hERG channel to be intolerant to mutation. Our hypothesis is that “extra-coding” characteristics on the mRNA level, such as GC content, rare codon usage and mRNA structure play a critical role in determining correct protein synthesis for the hERG channel, and that mutational changes that disrupt these characteristics lead to Long QT Syndrome. To investigate this hypothesis first, hERG SNPs will be analyzed to both identify trends in disease-causing SNPs, and to find differences between disease-causing and benign SNPs such as changes in local GC content or disruption of codon usage frequency. Secondly, using a codon-modified hERG mRNA with decreased rare codon usage, GC content and CpG islands when compared to native hERG mRNA, the role of mRNA structure and ribosomal movement in determining secondary and tertiary protein structure will be investigated.

Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses

Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF). The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart. Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times. Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment. SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses.

Genetic markers of repolarization and arrhythmic events after acute coronary syndromes

There is a genetic contribution to the risk of ventricular arrhythmias in survivors of acute coronary syndromes (ACS). We wished to explore the role of 33 candidate single nucleotide polymorphisms (SNPs) in prolonged repolarization and sudden death in patients surviving ACS. A total of 2,139 patients (1680 white ethnicity) surviving an admission for ACS were enrolled in the prospective Coronary Disease Cohort Study. Extensive clinical, echocardiographic, and neurohormonal data were collected for 12 months, and clinical events were recorded for a median of 5 years. Each SNP was assessed for association with sudden cardiac death (SCD)/cardiac arrest (CA) and prolonged repolarization at 3 time-points: index admission, 1 month, and 12 months postdischarge. One hundred six SCD/CA events occurred during follow-up (6.3%). Three SNPs from 3 genes (rs17779747 [KCNJ2], rs876188 [C14orf64], rs3864180 [GPC5]) were significantly associated with SCD/CA in multivariable models (after correction for multiple testing); the minor allele of rs17779747 with a decreased risk (hazard ratio [HR] 0.68 per copy of the minor allele, 95% CI 0.50-0.92, P = .012), and rs876188 and rs386418 with an increased risk (HR 1.52 [95% CI 1.10-2.09, P = .011] and HR 1.34 [95% CI 1.04-1.82, P = .023], respectively). At 12 months postdischarge, rs10494366 and rs12143842 (NOS1AP) were significant predictors of prolonged repolarization (HR 1.32 [95% CI 1.04-1.67, P = .022] and HR 1.30 [95% CI 1.01-1.66, P = .038], respectively), but not at earlier time-points. Three SNPs were associated with SCD/CA. Repolarization time was associated with variation in the NOS1AP gene. This study demonstrates a possible role for SNPs in risk stratification for arrhythmic events after ACS.

Effects of L-type calcium channel and human ether-a-go-go related gene blockers on the electrical activity of the human heart: a simulation study.

AimsClass III and IV drugs affect cardiac human ether-a-go-go related gene (IKr) and L-type calcium (ICaL) channels, resulting in complex alterations in repolarization with both anti- and pro-arrhythmic consequences. Interpretation of their effects on cellular and electrocardiogram (ECG)-based biomarkers for risk stratification is challenging. As pharmaceutical compounds often exhibit multiple ion channel effects, our goal is to investigate the simultaneous effect of ICaL and IKr block on human ventricular electrophysiology from ionic to ECG level.Methods and resultsSimulations are conducted using a human body torso bidomain model, which includes realistic representation of human membrane kinetics, anatomy, and fibre orientation. A simple block pore model is incorporated to simulate drug-induced ICaL and IKr blocks, for drug dose = 0, IC50, 2× IC50, 10× IC50, and 30× IC50. Drug effects on human ventricular activity are quantified for different degrees and combinations of ICaL and IKr blocks from the ionic to the body surface ECG level. Electrocardiogram simulations show that ICaL block results in shortening of the QT interval, ST elevation, and reduced T-wave amplitude, caused by reduction in action potential duration and action potential amplitude during the plateau phase, and in repolarization times. In contrast, IKr block results in QT prolongation and reduced T-wave amplitude. When ICaL and IKr blocks are combined, the degree of ICaL block strongly determines QT interval whereas the effect of IKr block is more pronounced on the T-wave amplitude.ConclusionOur simulation study provides new insights into the combined effect of ICaL and IKr blocks on human ventricular activity using a multiscale computational human torso model.

Electrophysiological and structural remodeling in heart failure modulate arrhythmogenesis. 1D simulation study.

BackgroundHeart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression.ObjectiveIn this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation.MethodsTwo different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias.ResultsSimulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+/Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure.ConclusionAn extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.

Impact of hypokalemia on electromechanical window, excitation wavelength and repolarization gradients in guinea-pig and rabbit hearts.

Normal hearts exhibit a positive time difference between the end of ventricular contraction and the end of QT interval, which is referred to as the electromechanical (EM) window. Drug-induced prolongation of repolarization may lead to the negative EM window, which was proposed to be a novel proarrhythmic marker. This study examined whether abnormal changes in the EM window may account for arrhythmogenic effects produced by hypokalemia. Left ventricular pressure, electrocardiogram, and epicardial monophasic action potentials were recorded in perfused hearts from guinea-pig and rabbit. Hypokalemia (2.5 mM K+) was found to prolong repolarization, reduce the EM window, and promote tachyarrhythmia. Nevertheless, during both regular pacing and extrasystolic excitation, the increased QT interval invariably remained shorter than the duration of mechanical systole, thus yielding positive EM window values. Hypokalemia-induced arrhythmogenicity was associated with slowed ventricular conduction, and shortened effective refractory periods, which translated to a reduced excitation wavelength index. Hypokalemia also evoked non-uniform prolongation of action potential duration in distinct epicardial regions, which resulted in increased spatial variability in the repolarization time. These findings suggest that arrhythmogenic effects of hypokalemia are not accounted for by the negative EM window, and are rather attributed to abnormal changes in ventricular conduction times, refractoriness, excitation wavelength, and spatial repolarization gradients.

Dynamic conduction and repolarisation changes in early arrhythmogenic right ventricular cardiomyopathy versus benign outflow tract ectopy demonstrated by high density mapping & paced surface ECG analysis.

AimsThe concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy.Methods22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol.ResultsDefinite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43±20 ms) more than RVOT ectopy patients (36±14 ms, p = 0.03) or Normals (25±16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18±20 ms; RVOT ectopy: 5±14, Normal: 1±18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls.ConclusionsSignificant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters.

Electrocardiographic T Wave and its Relation With Ventricular Repolarization Along Major Anatomical Axes

The genesis of the electrocardiographic T wave is incompletely understood and subject to controversy. We have correlated the ventricular repolarization sequence with simultaneously recorded T waves. Nine pig hearts were Langendorff-perfused (atrial pacing, cycle length 650 ms). Local activation and repolarization times were derived from unipolar electrograms sampling the ventricular myocardium. Dispersion of repolarization time was determined along 4 anatomic axes: left ventricle (LV)-right ventricle (RV), LV:apico-basal, LV:anterior-posterior, and LV:transmural. The heart was immersed in a fluid-filled bucket containing 61 electrodes to determine Tp (Tpeak in lead of maximum integral), TpTe (Tp to Tend), and TpTe_total (first Tpeak in any lead to last Tend in any lead). Repolarization was nonlinearly distributed in time. RT25 (time at which 25% of sites were repolarized, 288±26 ms) concurred with Tp. TpTe was 38±8 ms, and TpTe_total was 75±9 ms. TpTe_total correlated with dispersion of repolarization time in the entire heart (73±18 ms), but not with dispersion of repolarization times along individual axes (LV-RV, 66±17 ms; LV:apico-basal, 51±18 ms; LV:anterior-posterior, 51±27 ms; mean LV:transmural, 14±7 ms; all n=9). We provide a correlation between local repolarization and T wave in a pseudo-ECG. Repolarization differences along all anatomic axes contribute to the T wave. TpTe_total represents total dispersion of repolarization. At Tp, ≈25% of ventricular sites have been repolarized.

Hyperglycemia Is Associated With Corrected QT Prolongation and Mortality in Acutely Ill Patients

The QT interval on an electrocardiogram represents ventricular repolarization time. Increased length of this interval, known as corrected QT (QTc) prolongation, can be a precursor to torsade de pointes, a potentially life-threatening ventricular dysrhythmia. An association exists between blood glucose and QTc interval in ambulatory populations. Because both hyperglycemia and QTc prolongation are common in critically ill patients, we sought to examine the relationship between blood glucose, QTc interval prolongation, and all-cause mortality in critically ill patients. We studied adult patients admitted to cardiac monitoring units. Blood glucose and other clinical variables were abstracted from the medical record. Corrected QT measurements were automatically derived from continuous bedside cardiac monitoring systems. Twenty-five percent (233/940) of the patients had QTc prolongation, and 53% had elevated blood glucose (>140 mg/dL) during hospitalization. Adjusted odds for QTc prolongation were 2.1 (95% confidence interval, 1.5-3.1) for moderately elevated blood glucose (140-180 mg/dL) and 3.7 (95% confidence interval, 2.5-5.4) for severely elevated blood glucose (>180 mg/dL). Mortality rate was highest (16%) in patients experiencing both severely elevated blood glucose (>180 mg/dL) and QTc interval prolongation. Hyperglycemia is linked with QTc prolongation, and both are associated with increased odds of mortality in critically ill patients. Further studies are needed to extrapolate the relationship between glucose and ventricular repolarization, as well as appropriate glucose control parameters and QTc interval monitoring in critical care units.

Abstract P005: Evaluation of the Association between the Free Fatty Acid to serum Albumin Ratio with the Time to Cardiac Repolarization

Background: Elevated free fatty acid (FFA) levels have been shown to increase cardiac repolarization time and are a hypothesized mediator of arrhythmic death. However, as albumin binds and transports FFA, it has been argued that it is the ratio of serum FFA to serum albumin (SA) that is critical. As FFA are chronically elevated in type 1 diabetes and form a major part of the counterregulatory response to hypoglycemia, we investigated the association of the FFA-to-SA ratio with the corrected Q-T (Q-Tc) interval in 87 men and 96 women with type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study. We also investigated whether this relationship varied by cardiac autonomic neuropathy (CAN: R-R interval&lt;1.1) status. Methods: FFAs were measured using a colorimetric method in participants with a mean age and diabetes duration of 44 and 33 years, respectively. The corrected Q-T interval was calculated using Hogdes formula and the FFA-SA ratio determined as FFA (mmol/L) ÷ SA (mg/dL). Because of the sexual dimorphism in FFA metabolism and the Q-T interval, analyses were also conducted sex-specifically. Results: Mean (std) FFA levels were 0.95 (o.48) mmol/l and did not vary by sex (men vs women: 0.93 (0.46) vs 0.96 (0.49) mmol/L, p=0.76). The FFA-SA ratio demonstrated a modest association with Q-Tc interval in men (r=0.23, p=0.03), but no association in women (r=-0.07, p=0.48). Overall, in multivariable analyses controlling for sex, visceral adipose tissue, blood glucose levels and albumin excretion rate, FFA-SA, and CAN, a significant interaction was observed between the FFA-SA ratio and CAN in the association of the Q-Tc interval (p=0.03). FFA remained significantly associated with the Q-Tc interval in those without CAN (p&lt;0.05), but not in those with CAN (p=0.30). Sex-specific analyses revealed that although no significant FFA-SA ratio and CAN interaction was observed in men (p=0.42), a relationship between the FFA-SA ratio and Q-Tc interval existed in men free of CAN (p=0.04). No association was observed in women with or without CAN. Conculsion: We conclude that a higher FFA-SA ratio is associated with an increased time to cardiac repolarization in those without CAN, particularly in men, helping to explain why the "dead in bed" syndrome is predominantly seen in men.

Impaired epicardial activation–repolarization coupling contributes to the proarrhythmic effects of hypokalaemia and dofetilide in guinea pig ventricles

Activation-repolarization coupling refers to the inverse relationship between action potential duration and activation time in myocardial regions along the path of ventricular excitation. This study examined whether the activation-repolarization coupling plays a role in coordinating repolarization times between the right ventricular (RV) and left ventricular (LV) chambers, and if impaired coordination contributes to electrical instability produced by hypokalaemia or dofetilide, a blocker of the delayed rectifier K(+) current. In Langendorff-perfused, isolated guinea pig hearts, six monophasic action potential recording electrodes were attached to RV and LV epicardium. Local activation time and action potential duration (APD90 ) were determined during spontaneous beating, regular pacing and extrasystolic excitation. In regularly beating hearts, the RV epicardial sites had longer APD90 , but exhibited earlier activation times, as compared to LV sites, which minimized the interventricular difference in repolarization time. Upon extrasystolic stimulation, the APD90 was reduced to a greater extent in RV compared with LV, which translated to a reversed slope of APD90 -to-activation time relationship, and increased spatial repolarization gradients. Hypokalaemia and dofetilide prolonged APD90 , with the effect being greater in LV compared with RV. In hypokalaemic hearts, LV activation was delayed. These changes contributed to increased asynchrony in repolarization times in the LV and RV in both regular and extrasystolic beats, and enhanced susceptibility to tachyarrhythmia. Impaired RV-to-LV activation-repolarization coupling is an important determinant of electrical instability in the setting of non-uniformly prolonged epicardial APD90 or slowed interventricular conduction.

Analysis of the spatial and transmural dispersion of repolarization and late potentials derived using signal-averaged vector-projected 187-channel high-resolution electrocardiogram in patients with early repolarization pattern

BackgroundElectrophysiological characteristics of early repolarization syndrome (ERS), i.e., the spatial and transmural dispersion of ventricular repolarization and ventricular late potentials can be evaluated using a signal-averaged vector-projected 187-channel high-resolution electrocardiogram (187-ch SAVP-ECG). We investigated these characteristics as markers of ventricular fibrillation and sudden cardiac arrest in patients presenting with an ER pattern. MethodsThe 187-ch SAVP-ECGs were recorded for 8 patients with idiopathic ventricular fibrillation associated with ERS (ERS patients), and 5 patients with an ER pattern without arrhythmic events (ER pattern patients). ResultsThe ER pattern was located in the inferior leads (n=7), lateral leads (n=1), or both inferior and lateral leads (n=5). The corrected RT(RTc) (peak point of the R wave − positive maximum peak of the first derivative of the T wave interval corrected using the Bazett formula) interval and T(peak-end)-c interval from the 187 channels were calculated. Late potentials were positive in 7 of 8 ERS patients and in 3 of 5ER pattern patients (P=0.25). The average RTc was shorter in patients with ERS (192.6±29.8ms vs. 234.0±25.5ms, P=0.04). However, average T(peak-end)-c interval did not differ between the 2 groups. ConclusionLate ventricular potentials were common in ERS and ER pattern patients. Lethal arrhythmia in ERS patients appeared to be related to the relatively short average repolarization time rather than the spatial and transmural dispersion of repolarization.

Effects of Different Ventricular Pacing Modes on Ventricular Repolarisation in Patients Undergoing Cardiac Resynchronisation Therapy: A Single-centre Study

The aims of this study were to compare ventricular repolarisation parameters in patients who underwent cardiac resynchronisation therapy (CRT) at Sun Yat-sen University Memorial Hospital under different ventricular pacing modes and to understand effects of epicardial pacing on ventricular repolarisation. The study included 55 patients who underwent CRT. During follow-up outpatient visits three months after CRT implantation, the CRT devices were programmed to deliver no pacing (with the exception of patients with third-degree atrioventricular block), biventricular pacing (BivP), right ventricular endocardial pacing (RV-EndoP), and left ventricular epicardial pacing (LV-EpiP). Signals from the standard 12-lead ECG were recorded simultaneously to measure the QT interval, JT interval, and Tp-e interval, from which the heart rate-corrected QTc interval, JTc interval, and Tp-ec interval were determined. The JTc interval and Tp-ec interval were prolonged during LV-EpiP and BivP compared with those during spontaneous cardiac rhythm and RV-EndoP. The JTc dispersion and Tp-ec dispersion were not significantly different among the four pacing modes. Epicardial pacing prolongs myocardial repolarisation time and increases transmural dispersion of repolarisation. Epicardial pacing has no significant effect on the dispersion of regional ventricular repolarisation.

Race- and sex-associated differences in rate-adjusted QT, QTpeak, ST elevation and other regional measures of repolarization: The Atherosclerosis Risk in Communities (ARIC) Study

BackgroundData are limited about race-and sex-associated differences in prognostically important ECG measures of regional repolarization. Methods and resultsThe normal reference group from the Atherosclerosis Risk in Communities (ARIC) study included 8,676 white and African-American men and women aged 40–65years. Exclusion criteria included cardiovascular disease, hypertension, diabetes and major ECG abnormalities. Notable sex differences (p<0.001) were observed in the upper 98% limits for rate-adjusted QTend (QTea) which was 435ms in white and African-American men and 445ms in white and African-American women, and for left ventricular epicardial repolarization time (RTepi) which was 345ms in white and African-American men and 465ms in white and African-American women. These sex differences reflect earlier onset and end of repolarization in men than in women. Upper normal limits for STJ amplitude in V2–V3 were 100μV in white and African-American women, 150μV in white men and 200μV in African-American men (p<0.001 for sex differences), and for other chest leads, aVL and aVF 50μV in white women, 100μV in African-American women, 100μV in white men and 150μV in African-American men (p<0.001 for sex and race differences). ConclusionsShorter QTea and RTepi in men than in women reflect earlier onset and end of repolarization in men. STJ amplitudes in African-American men were higher than in other subgroups by race and sex. These sex and race differences need to be considered in clinical and epidemiological applications of normal standards.

The Application of Root Mean Square Electrocardiography (RMS ECG) for the Detection of Acquired and Congenital Long QT Syndrome

BackgroundPrecise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS).MethodsRMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II.ResultsAll measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3.ConclusionThese data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements.

Epilepsy Increases the Contribution of Tetrodoxin-Sensitive Channels to the Cardiac Sodium Current

Human mortality associated with status epilepticus (SE) in U.S and Canada is 21%-22%. Sudden death caused by epilepsy (SUDEP) accounts for 17% of all SE-related casualties. Clinical evidence linked SUDEP to arrhythmias such as conduction block and prolongation of the QT interval, an index of repolarization time, on the cardiac electrocardiogram. These observations suggest that SE altered the activity of the cardiac sodium current (INa) involved in both cardiac conduction and repolarization of the ventricle. We tested this hypothesis by characterizing INa in ventricular cardiomyocytes of epileptic rats induced induced by kainic acid injection. Our patch clamp results show that epilepsy increased peak INa by 18±6% and its sustained (late) component (INaL) by 53±13%. Activation of INa occurred at more negative potential in epileptic rats and recovery from activation was significantly delayed by epilepsy. Because epilepsy is known to increase the expression of neuronal channels (nNaVs) in the brain we next tested if the changes in INa were associated with increased sensitivity to tetrodotoxin (TTX), a hallmark of nNaVs. Our results indicate that TTX at a concentrations not affecting the cardiac sodium channel NaV1.5 (1 nM) blocked 34% and 50% of INaL in Sham and epileptic rats respectively. Epilepsy therefore increased the contribution of neuronal sodium channel to INa in the cardiac ventricle. In summary, our data indicate that epilepsy altered INa in a manner consistent with the alterations of conduction and QT prolongation observed in SUDEP and that TTX-sensitive channels play an important role in these changes. Our results suggest a new paradigm by which some of the arrhythmias observed during epilepsy are not centrally mediated but also occur as a consequence of electrical remodeling of the heart.